Oral Immunotherapy for Induction of Tolerance and Desensitization in Peanut-Allergic Children (ITN050AD)
Phase: PHASE2
Conditions: Peanut Hypersensitivity
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Oral Immunotherapy for Induction of Tolerance and Desensitization in 
Peanut-Allergic Children 
Protocol ITN050AD 
Version 5.0 (March 28, 2017) 
IND # 15215 
 
Protocol Chair 
Wesley Burks, MD 
Distinguished Professor and Chair 
Physician in Chief, North Carolina Children's 
Hospital 
University of North Carolina 
Campus Box 7220 
Chapel Hill, NC 27599-7220 
Tel: 919-966-4427   
Fax: 919-966-7299   
Email: wburks@email.unc.edu 
 
Protocol Co-chair 
Stacie M. Jones, MD 
Professor of Pediatrics 
Chief, Allergy and Immunology 
Dr. and Mrs. Leeman King Chair in Pediatric 
Allergy 
University of Arkansas for Medical Sciences 
Arkansas Children's Hospital 
13 Children's Way, Slot 512-13 
Little Rock, AR 72202 
Tel: 501-364-1060 
Fax: 501-364-3173  
Email: jonesstaciem@uams.edu 
 
ITN Clinical Trial Physician 
Srinath Sanda, MD 
Associate Director, Clinical Trials Group 
Immune Tolerance Network 
185 Berry Street, Suite 3515 
San Francisco, CA 94107 
Tel: 415-353-4414      
Fax: 415-353-4404 
Email: ssanda@immunetolerance.org 
 
NIAID Medical Monitor 
Marshall Plaut, MD 
Chief, Food Allergy, Atopic Dermatitis, and 
Allergic Mechanisms Section  
Division of Allergy, Immunology,  and 
Transplantation  
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane., Room 6B50 
Bethesda, MD, 20892-9827 
Tel: 240-627-3533 
Fax: 301-480-4258 
Email: mplaut@niaid.nih.gov 

ITN Associate Director, Biomarker and 
Discovery Research 
 
David Larson, Ph.D. 
Associate Director, Biomarker and Discovery 
Research 
Immune Tolerance Network  
7500 Old Georgetown Road, Suite 800 
Bethesda, MD 20814 
Tel: 240-235-6159 
Fax: 240-235-6198 
Email: dlarson@immunetolerance.org 
 
 
 
 
ITN Clinical Operations Manager 
Rachel Yan, MS 
Manager, Clinical Operations 
Clinical Trials Group 
Immune Tolerance Network 
185 Berry Street, Suite 3515 
San Francisco, CA 94107 
Tel: 415-353-4425     
Fax: 415-353-4404 
Email: ryan@immunetolerance.org 
 
 
 
Rho Scientist 
Michelle Sever, PhD  
Research Scientist 
Rho Building 
6330 Quadrangle Drive 
Chapel Hill, NC 27517  
Tel: 919-595-6382 
Fax 919-287-3009 
Email: michelle_sever@rhoworld.com 
 
NIAID Project Manager 
 
Joy Laurienzo Panza, RN, BSN 
NIAID Project Manager 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane, Room 6B51 
Bethesda, MD, 20892-9827 
Tel:  240-627-3515 
Fax:  301-480-4258 
Email: jlaurienzo@niaid.nih.gov 
 
NIAID Regulatory Officer 
Ling Li, PhD 
Regulatory Officer 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane., Room 7B37 
Bethesda, MD, 20892-9828 
Tel: 240-627-3765 
Fax: 301-480-1537 
E-mail: lil16@niaid.nih.gov 
 
 
Rho Biostatistician 
Jacqueline Johnson 
Senior Biostatistician 
Rho Building 
6330 Quadrangle Drive 
Chapel Hill, NC 27517  
Tel: 919-595-6456 
Fax 919-408-0999 
Email: Jacqueline_johnson@rhoworld.com 
 
This clinical study is supported and conducted by the Immune Tolerance Network, which is 
sponsored by the National Institute of Allergy and Infectious Diseases. 
This document is confidential. It is provided for review only to principal investigators, potential 
principal investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. It is understood that the contents of this document will not be disclosed 
to others without written authorization from ITN and NIAID unless it is necessary to obtain 
informed consent from potential study participants. 
 

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Protocol Approval 
 
 
Trial ID:  ITN050AD 
Protocol Version:    5.0 
Dated:   March 28, 2017 
IND: # 15215 
Protocol Chair:  Wesley Burks, MD 
Protocol Co-chair:  Stacie M. Jones, MD 
Title:     Oral Immunotherapy for Induction of Tolerance and Desensitization in Peanut-Allergic 
Children 
I confirm that I have read the above protocol in the latest version. I understand it, and I will 
work according to the principles of good clinical practice (GCP) as described in the US Code of 
Federal Regulations (CFR)—45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the 
International Conference on Harmonization (ICH) document Guidance for Industry: E6 Good 
Clinical Practice: Consolidated Guidance dated April 1996. Further, I will conduct the study in 
keeping with local legal and regulatory requirements. 
 
As the principal investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without written permission of the 
NIAID. 
 
 
 
__________________________________________                                        
Principal Investigator                        (Print)                     
 
 
__________________________________________         _________________ 
Principal Investigator                        (Sign)                      Date 
 
 
 
 

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Synopsis 
Title 
Oral Immunotherapy for Induction of Tolerance and Desensitization in 
Peanut-Allergic Children 
Short Title 
Peanut OIT in Children 
Sponsored by 
National Institute of Allergy and Infectious Diseases 
Conducted by 
Immune Tolerance Network 
Protocol Chair 
Protocol Chair:  Wesley Burks, MD 
Protocol Co-chair:  Stacie M. Jones, MD 
Accrual Objective 
144 participants 
Study Design 
This is a randomized, double-blind, placebo-controlled, multi-center study 
comparing peanut oral immunotherapy to placebo. Eligible participants with 
peanut allergy will be randomly assigned to receive either peanut OIT or 
placebo for 134 weeks followed by peanut avoidance for 26 weeks. 
 
An initial blinded oral food challenge (OFC) to 1 g of peanut flour (500 mg 
peanut protein) will be conducted. Participants must have a clinical reaction 
during this blinded OFC to initiate study dosing. After the initial blinded 
OFC, the study design includes the following: 
 
Initial Dose Escalation: This will occur on a single day in which multiple 
doses are given. Peanut or placebo dosing will be given incrementally and 
increase every 15-30 minutes until a dose of 12 mg peanut flour (6 mg 
peanut protein) or placebo flour is given. The first four doses will be 
administered as a peanut flour extract of 0.1 to 0.8 mg peanut protein, which 
is 10 to 80 microliters peanut flour extract, or placebo flour extract and the 
last three doses will be given as peanut flour of 3 to 12 mg peanut flour 1.5 
to 6 mg peanut protein or placebo flour. Participants must tolerate a dose of 
at least 3 mg peanut flour (1.5 mg peanut protein) or placebo flour to remain 
in the study. 
 
Build-up:  After the initial dose escalation day, the participant will return to 
the research unit the next morning for an observed dose administration of 
the highest tolerated dose from the initial escalation day. The participant 
will then continue on the daily OIT dosing at home and return to the 
research unit every 2 weeks for a dose escalation. The dosing escalations 
will be consistent with previous similar OIT studies. 
 
Participants who do not reach the 4000 mg peanut flour (2000 mg peanut 
protein) or placebo flour dose during the build-up phase may enter 
maintenance phase at their highest tolerated dose, which must be at least 500 
mg peanut flour (250 mg peanut protein) or placebo flour. 
 
The build-up phase will comprise 30 weeks. 
 
Maintenance:  The participant will continue on daily OIT with return visits 
every 13 weeks. At the end of this phase the participant will undergo a 
blinded OFC to 10 g peanut flour (5 g peanut protein). 
 

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This phase will comprise 104 weeks. 
 
Avoidance:  In this final phase participants stop OIT and will avoid peanut 
consumption They will be seen 2 weeks and 26 weeks after initiating this 
phase. At the completion of this phase participants will have a final blinded 
OFC to 10 g peanut flour (5 g peanut protein). Participants who do not have 
a clinical reaction to the challenge will receive an Open Food Challenge 
(OpFC). 
 
Avoidance will comprise 26 weeks. 
 
Post-challenge:  If participants do not have a clinical reaction during 
the OpFC at the end of avoidance, they will be allowed to consume 
peanut and will have one visit which will include peripheral blood 
sampling for mechanistic assays assessments. 
 
Post-challenge will comprise 2 weeks. 
Study Duration 
Total study duration will be up to 238 weeks (slightly more than 4 and one-
half years). 
 
• 
Enrollment will be up to 78 weeks. 
• 
Study participation will be 162 weeks, which includes the initial 
dose escalation, build-up, and maintenance, avoidance, and post-
challenge. 
Primary Endpoint 
The primary endpoint is the proportion of participants desensitized to peanut 
after 134 weeks OIT.  
 
Participants who pass a blinded OFC to 10 g of peanut flour (5 g of peanut 
protein) at this time without significant symptoms as described in Section 
6.4.1.4 will be considered desensitized to peanut. Failure will be defined as 
either unable to undergo the final food challenge or inability to tolerate the 
maximum dose because of significant symptoms such as hives, wheezing, 
vomiting, or laryngeal edema.  
Secondary Endpoints 
Efficacy 
• 
Tolerance Endpoint 
The proportion of participants who pass both the blinded OFC to 10 
g peanut flour (5 g peanut protein) and the Open OFC to 8 g peanut 
protein in natural food form at week 160.  
Passing a blinded OFC is defined in Section 3.3.1. 
            Passing an Open OFC is defined in Section 6.4.3.  
 
• 
Transient Desensitization Endpoint 
This is the change in proportion of participants who pass the 
blinded OFC to 10 g peanut flour (5 g peanut protein) at week 134 
and week 160.  

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Passing a blinded OFC is defined in Section 3.3.1. 
• 
Highest Tolerated Cumulative Dose Endpoint 
The highest tolerated cumulative dose of peanut protein during the 
blinded OFCs will also be collected and analyzed. 
Safety: 
• 
The incidence of all adverse events. 
• 
Rates of withdrawal from OIT or placebo. 
Mechanistic: 
Changes in the following markers of immune mediation: 
• 
Secreted cytokines 
• 
Anti-peanut IgE, IgG, IgG4 and secretory IgA  
• 
Epitope arrays 
• 
IgE-facilitated, CD23-dependent allergen binding to B cells  
• 
Serum, stools, and saliva assays 
• 
PBMC expression of transcription factors and cytokines relevant to 
food allergy 
• 
CD4+ CD25+ FoxP3+ Tregs  
• 
DNA-HLA genotyping  
• 
Peanut-specific T cells 
• 
Ara h 1 and Ara h 2 reactive T cells  
• 
Th2A Subset Analysis 
• 
Basophil activation  
• 
B cells 
Inclusion Criteria 
1. Age 12 months to less than 48 months, either gender. 
2. Clinical history of peanut allergy or avoidance of peanut without ever 
having eaten peanut. 
3. Serum IgE to peanut of  > 5 kUA/L determined by UniCAPTM  
4. Wheal ≥ 3mm on skin prick test to peanut extract compared to a 
negative control. 
5. A clinical reaction as defined in Section 6.4.1.3 at or below ingestion of 
1 g peanut flour (500 mg peanut protein) during screening blinded OFC. 
6. Written informed consent from parent/guardian.  
Exclusion Criteria 
1. History of severe anaphylaxis with hypotension to peanut. 
2. Documented clinical history of allergy to oat. 
3. Suspected allergy to oat and a wheal greater than or equal to 7mm on 
skin prick test to oat extract compared to a negative control.  

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4. Chronic disease other than asthma, atopic dermatitis, rhinitis requiring 
therapy; e.g., heart disease or diabetes. 
5. Active eosinophilic gastrointestinal disease in the past 2 years. 
6. Participation in any interventional study for the treatment of food allergy 
in the 6 months prior to visit -1. 
7. Inhalant allergen immunotherapy that has not yet reached maintenance 
dosing. 
8. Severe asthma, as indicated by repeated hospitalizations or hospital 
emergency department visits.  
9. Moderate asthma defined according to National Asthma Education and 
Prevention Program Expert Panel that requires more than fluticasone 
440 mcg or its equivalent daily for adequate control. 
10. Inability to discontinue antihistamines for skin testing, blinded OFC and 
the initial dose escalation. 
11. Use of omalizumab or other non-traditional forms of allergen 
immunotherapy (e.g., oral or sublingual) in the 12 months prior to visit -
1. 
12. Any systemic therapy which in the judgment of the investigator could be 
immunomodulatory (e.g. rituximab) in the 12 months prior to visit -1, 
Systemic corticosteroid therapy of up to a total of three weeks is 
allowed. 
13. Use of any investigational drug in 90 days prior to visit -1. 
14. Plan to use any investigational drug during the study period. 
15. The presence of any medical condition that the investigator deems 
incompatible with participation in the trial. 
 
 
 
 

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Table of Contents 
1. 
BACKGROUND AND RATIONALE ................................................................................ 14 
1.1 
BACKGROUND ............................................................................................................ 14 
1.2 
RATIONALE FOR APPROACH AND FOR TRIAL DESIGN ........................................... 14 
1.3 
SCIENTIFIC RATIONALE ............................................................................................. 14 
1.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR PARTICIPANTS 17 
1.4.1 
Risks .......................................................................................................................................... 17 
1.4.2 
Potential Benefits ...................................................................................................................... 18 
2. 
OBJECTIVES ................................................................................................................... 18 
2.1 
PRIMARY OBJECTIVE ................................................................................................. 18 
2.2 
SECONDARY OBJECTIVES .......................................................................................... 18 
3. 
STUDY DESIGN ............................................................................................................... 18 
3.1 
DESCRIPTION .............................................................................................................. 18 
3.2 
STUDY DURATION ...................................................................................................... 22 
3.3 
STUDY ENDPOINTS ..................................................................................................... 22 
3.3.1 
Primary Endpoint ...................................................................................................................... 22 
3.3.2 
Secondary Endpoints ................................................................................................................. 22 
3.4 
PREMATURE TERMINATION OR SUSPENSION OF THE TRIAL ................................ 23 
3.4.1 
Stopping Rules .......................................................................................................................... 23 
4. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .............................................. 23 
4.1 
INCLUSION CRITERIA ................................................................................................. 23 
4.2 
EXCLUSION CRITERIA ................................................................................................ 23 
4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY .................... 24 
5. 
STUDY MEDICATIONS .................................................................................................. 24 
5.1 
PEANUT ORAL IMMUNOTHERAPY ............................................................................ 24 
5.1.1 
Overview ................................................................................................................................... 24 
5.1.2 
Oral Immunotherapy Liquid Extract for Initial Dose Escalation ............................................... 25 
5.1.3 
Oral Immunotherapy for Initial Dose Escalation, Build-up and Maintenance .......................... 26 
5.2 
DISCONTINUATION OF STUDY TREATMENT ........................................................... 26 
5.3 
CONCOMITANT MEDICATIONS ................................................................................. 27 
5.3.1 
Required Medications ................................................................................................................ 27 
5.3.2 
Permitted Medications ............................................................................................................... 27 
5.3.3 
Rescue Medications ................................................................................................................... 27 
5.3.4 
Prohibited Medications .............................................................................................................. 27 
5.4 
DRUG ACCOUNTABILITY ........................................................................................... 27 
5.5 
ASSESSMENT OF COMPLIANCE WITH STUDY PRODUCT ........................................ 28 

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6. 
STUDY PROCEDURES .................................................................................................... 28 
6.1 
VISIT WINDOWS .......................................................................................................... 28 
6.1.1 
Scheduled Visits ........................................................................................................................ 28 
6.1.2 
Unscheduled Visits .................................................................................................................... 28 
6.2 
RANDOMIZATION, BLINDING AND UNBLINDING ................................................... 29 
6.2.1 
Enrollment, Randomization and Preparation of Doses .............................................................. 29 
6.2.2 
Blinding ..................................................................................................................................... 29 
6.2.3 
Unblinding ................................................................................................................................. 29 
6.3 
GENERAL ASSESSMENTS ........................................................................................... 30 
6.4 
DISEASE-SPECIFIC ASSESSMENTS ............................................................................ 30 
6.4.1 
Diet and Allergy History ........................................................................................................... 30 
6.4.2 
Skin Prick Test to Peanut Extract and Environmental Allergens .............................................. 30 
6.4.3 
Oral Food Challenges (500mg, 5g and Open Food Challenge) ................................................. 31 
6.4.4 
Oral Food Challenge Outcome .................................................................................................. 32 
6.5 
LOCAL LABORATORY ASSESSMENTS ...................................................................... 33 
6.6 
MECHANISTIC ASSESSMENTS ................................................................................... 33 
6.7 
STUDY VISITS .............................................................................................................. 33 
6.7.1 
Screening ................................................................................................................................... 33 
6.7.2 
Initial Dose Escalation - Study Visit 0 ...................................................................................... 34 
6.7.3 
Build-up ..................................................................................................................................... 36 
6.7.4 
Maintenance .............................................................................................................................. 39 
6.7.5 
Avoidance .................................................................................................................................. 39 
6.7.6 
Post-Challenge ........................................................................................................................... 39 
6.8 
MISSED DOSES AND DOSING DURING CONCURRENT ILLNESS ............................. 40 
6.8.1 
Missed Doses for Non-Compliance ........................................................................................... 40 
6.8.2 
Management of Dosing During Concurrent Illness ................................................................... 40 
6.9 
ASSESSMENT OF GASTROINTESTINAL SYMPTOMS ................................................ 40 
6.9.1 
Baseline Assessments ................................................................................................................ 40 
6.9.2 
Ongoing Assessments ................................................................................................................ 41 
6.9.3 
Modified Aceves Questionnaire33.............................................................................................. 41 
7. 
TOLERANCE ASSAYS .................................................................................................... 42 
7.1 
MECHANISTIC HYPOTHESES ..................................................................................... 42 
7.2 
PROPOSED MECHANISTIC ASSAYS ........................................................................... 43 
7.2.1 
Comparisons and Sample Flow ................................................................................................. 43 
7.2.2 
Serum and Mucosal Assays in Order of Priority ....................................................................... 43 
7.2.3 
Cellular Assays .......................................................................................................................... 44 
7.2.4 
Confirmation of Peanut Avoidance ........................................................................................... 47 
7.2.5 
Retention of Samples ................................................................................................................. 48 

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8. 
ADVERSE EVENTS ......................................................................................................... 48 
8.1 
OVERVIEW ................................................................................................................... 48 
8.2 
DEFINITIONS ............................................................................................................... 48 
8.2.1 
Adverse Event ........................................................................................................................... 48 
8.2.2 
Study Specific Adverse Events .................................................................................................. 49 
8.2.3 
Suspected Adverse Reaction and Adverse Reaction ................................................................. 49 
8.2.4 
Serious Adverse Event .............................................................................................................. 49 
8.2.5 
“Expected” versus Unexpected Suspected Adverse Reaction ................................................... 49 
8.3 
COLLECTING AND RECORDING ADVERSE EVENTS ................................................ 50 
8.3.1 
Methods of Collection ............................................................................................................... 50 
8.3.2 
Methods of Recording ............................................................................................................... 50 
8.4 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS ............................................. 51 
8.4.1 
Grading Criteria ......................................................................................................................... 51 
8.4.2 
Attribution Definitions .............................................................................................................. 53 
8.5 
REPORTING SERIOUS ADVERSE EVENTS ................................................................. 53 
8.5.1 
Reporting SAEs to the IND Sponsor ......................................................................................... 53 
8.5.2 
Reporting SAEs to Health Authorities ...................................................................................... 54 
8.5.3 
Reporting SAEs to the DSMB ................................................................................................... 55 
8.5.4 
Reporting SAEs to IRB/EC ....................................................................................................... 55 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ................................... 55 
9.1 
ANALYSIS SAMPLES ................................................................................................... 55 
9.2 
ANALYSIS OF ENDPOINTS ......................................................................................... 55 
9.2.1 
Overview ................................................................................................................................... 55 
9.2.2 
Primary Endpoint ...................................................................................................................... 56 
9.2.3 
Secondary Endpoints ................................................................................................................. 56 
9.2.4 
Missing Data.............................................................................................................................. 57 
9.2.5 
Medical History ......................................................................................................................... 58 
9.2.6 
Use of Medications .................................................................................................................... 58 
9.3 
SAMPLE SIZE ............................................................................................................... 58 
9.4 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN ................... 59 
10. ACCESS TO SOURCE DATA/DOCUMENTS .................................................................. 59 
11. QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 59 
12. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE 60 
12.1 
STATEMENT OF COMPLIANCE .................................................................................. 60 
12.2 
INFORMED CONSENT ................................................................................................. 60 
12.3 
PRIVACY AND CONFIDENTIALITY ............................................................................ 60 

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13. PUBLICATION POLICY ................................................................................................. 60 
14. REFERENCES.................................................................................................................. 61 
 
 
 
List of Appendixes 
Appendix 1. Schedule of Events: Screening, Initial Dose Escalation and Build-up ................................ 63 
Appendix 2. Schedule of Events: Maintenance, Avoidance and Post-Challenge (PC) ............................ 64 
Appendix 3: Anaphylaxis Staging System............................................................................................... 65 
 
 
List of Tables 
Table 1  Screening, Initial Dose Escalation, Build-up, Maintenance, Avoidance and Post-Challenge ... 20 
Table 2 Criteria for Determining the Outcome of Food Challenge ......................................................... 33 
Table 3 Grading of Symptoms and Events Related to Peanut Flour Administration ............................... 51 
Table 4 Attribution of Adverse Events .................................................................................................... 53 
 
 
List of Figures 
Figure 1  Screening, Initial Dose Escalation, Build-up, Maintenance, Avoidance and Post-Challenge .. 21 
Figure 2  Management of Symptoms during Initial Dose Escalation ...................................................... 36 
 

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Abbreviations  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CBC 
complete blood count 
CFR 
US Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DBPCFC 
Double Blind Placebo Controlled Food Challenge 
DSMB 
Data and Safety Monitoring Board 
FDA 
US Food and Drug Administration  
GCP 
Good Clinical Practice 
HEENT 
Head, Eyes, Ears, Nose, Throat 
ICH 
International Conference on Harmonisation 
IDE 
Initial Dose Escalation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITN 
Immune Tolerance Network 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events v 4.03 
OFC 
Oral Food Challenge 
OIT 
Oral Immunotherapy 
OpFC 
Open Food Challenge 
SAP 
Statistical Analysis Plan 
SPT 
 
Skin Prick Test 
SAE 
 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 

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SUSAR 
Suspected Unexpected Serious Adverse Reactions 
WHO 
World Health Organization 
 
 

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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND 
Allergy to cow’s milk, hen’s egg, and peanut comprise about 80% of food allergies in children in the 
United States.1,2 The prevalence of peanut allergy in the US has increased in the last decade and is 
estimated to be about 1%.2 Symptoms of food allergy can be mild to severe, with peanut being the 
leading cause of life threatening or fatal reactions. Unlike cow’s milk and hen’s egg allergy, peanut 
allergy tends to persist, and only 20% of children outgrow their disease.3  
The current standard of care in management of peanut allergy is dietary avoidance of peanut and 
education of the patient/family in the acute management of an allergic reaction.4 The burden of 
avoidance and constant fear of accidental exposure negatively impact the health-related quality of life 
for both patients and their families. Quality of life surveys indicate that families with children having 
food allergies have significant impact on food preparation, social activities, finding appropriate 
childcare, school attendance, and level of stress among other things.5-7 
1.2 RATIONALE FOR APPROACH AND FOR TRIAL DESIGN 
As evident from the previous section, there is clearly an unmet need in the treatment of peanut 
allergy. Various peanut immunotherapy approaches are being studied currently. Sub-cutaneous 
immunotherapy with peanut extract has shown some efficacy; however, this approach was associated 
with frequent and severe adverse reactions.8,9 Novel approaches such as treatment with anti-IgE 
antibody,10 immunotherapy with mutated recombinant protein11 or alternative medicine approaches12 
are currently under investigation or are lacking proof of efficacy in humans. 
This trial of peanut oral immunotherapy is based on data from previous work suggesting peanut OIT 
will desensitize and possibly tolerize peanut allergic subjects.13-15 A study published by Jones et al. 
suggested efficacy of the peanut OIT.15 In the study, peanut allergic children underwent an OIT 
protocol consisting of an initial dose escalation day, bi-weekly build-up (to 2 g) and daily 
maintenance phase followed by an OFC. After tolerating less than 50 mg peanut protein during an 
OFC at baseline, 27 of the 29 subjects ingested 3.9 g of peanut protein at the completion of OIT 
protocol.15 A follow-up double-blind, placebo-controlled trial of peanut OIT by Dr. Burks’ group 
demonstrated that at the completion of OIT, the OIT subjects ingested the maximum cumulative dose 
of 5000 mg during OFC while the placebo subjects ingested a median cumulative dose of 280 mg 
(p<0.001).16 This study proposes to investigate whether peanut OIT can induce long term tolerance in 
children with peanut allergy. 
1.3 
SCIENTIFIC RATIONALE 
Food allergy is believed to result from a breakdown of normal oral tolerance induction.17 There is 
limited published information regarding active treatment for food allergy. While traditionally allergen 
injection immunotherapy has proven unsafe in food allergy,8,9 some investigators have reported 
apparent success in using the oral route for administration of immunotherapy in food allergy.18,19 
Even if this therapy does not alter the natural history of food allergy, it may offer protection from 
potentially life-threatening reactions on accidental allergen exposure. 
The objectives in this investigation are to study the clinical effects, as well as the safety and 
immunologic effects, of a peanut OIT protocol. The long-term goal is to use peanut OIT to induce 
clinical and immunologic tolerance to peanut that will be sustained once the treatment protocol is 

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completed. The short-term goal of the protocol is to induce a desensitized state to peanut early in the 
course of treatment that will protect subjects from allergic reactions following accidental peanut 
ingestions. 
This study will seek to expand the knowledge already available regarding immunologic mechanisms 
about peanut allergy and immunotherapy by addressing gaps in the current information where more 
exploration is warranted. Currently it is known that food allergy and other allergic diseases 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-368, while IFN-γ expression and Th1 
differentiation is induced by the transcription factor T-bet.20 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 T cells. 
There is evidence that peanut allergy is characterized by a peanut-specific Th2 T cell response, but 
the evolution of T cell immunity concerning food allergy or peanut allergy specifically over the 
development of tolerance is not well understood. 
Another important immune mechanism potentially involved with the development of peanut allergy 
includes modulation of regulatory T cells. Several regulatory T cell subsets have been identified, 
including both thymus-derived “natural” as well as antigen-specific, adaptive Tregs, both of which 
have recently been associated with expression of the transcription factor FoxP321. 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 allergy22. 
Food-specific IgE generally decreases in concentration over time in individuals who are in the 
process of “outgrowing” the specific food allergy23. Aside from the degree of response (i.e., 
concentration of allergen-specific IgE antibodies), recent studies indicate that the profile of IgE 
binding to specific epitopes 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 two amino acids, revealed particular epitopes that are 
commonly targeted24-26. 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 denaturing elements may be 
associated with transient allergy. In addition, IgE recognition of certain immunodominant regions 
within the major peanut allergens Ara h 1-3, as well as broad IgE epitope specificity overall, 
correlates with persistent disease and more severe reactions27. In contrast a recent study showed that a 
binding “signature” of IgE to specific linear peanut peptides could accurately predict the development 
of spontaneous natural tolerance28.  
Peanut OIT studies conducted at Duke University and the University of Arkansas support the concept 
that tolerance can be achieved by a long period of OIT. In these studies, 9 of the original 29 subjects 

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have reached the 2.5-year point in the study29. The study was designed where subjects who were on 
OIT longer than 2.5 years and who had a peanut IgE <2 kUA/L would have a food challenge while on 
therapy. 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 kUA/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). Two thirds of 
subjects developed tolerance after 2.5 years on therapy. Additional studies with longer follow-up are 
required to characterize the development of tolerance with active OIT over time. 
The current protocol is based on the concept that peanut OIT for children who have food allergy is a 
practical and safe method of active treatment. The overall goals of this study are to show that oral 
tolerance to specific food allergens can be induced and that children can be protected from adverse 
reactions from accidental food ingestion (desensitized). In this prospective, multi-center 
interventional study, we will select relatively young children who have peanut allergy for a double 
blind, placebo-controlled trial of peanut OIT. This approach provides a unique opportunity to monitor 
the natural course of peanut allergy and 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 peanut allergy. 
The current study investigates long term tolerance by randomly assigning allergic subjects to peanut 
OIT or to placebo. After a dose escalation phase, subjects receive maintenance oral immunotherapy 
for an extended period. At the end of that period an assessment for peanut allergy is carried out. Then 
OIT or placebo is stopped, and subjects are observed during an avoidance phase. Participation will 
conclude with a final assessment for peanut allergy after the avoidance phase. This approach entails 
several design decisions, which can be justified by results of prior studies or regarded as assumptions.  
The age of potential participants was chosen with the aim of finding a group whose immune system is 
more likely to be modified by OIT. Older children tend to have higher IgE levels and may be less 
likely to undergo desensitization successfully and to develop tolerance. Other entry criteria such as 
skin test wheal size and peanut-specific IgE level were chosen to ensure that participants have strong 
evidence of established peanut allergy. These objective measures are considered more important for 
study entry than clinical history which is less reliable. 
Reactivity on an oral food challenge is part of the eligibility for the trial. While we expect children to 
react at different levels of peanut in an initial OFC, this level is not known to predict accurately the 
likelihood of desensitization or development of tolerance. Therefore stratification based on this level 
is not applied in this study. Children with asthma beyond a specified level of severity are excluded for 
safety considerations. Presence of a sibling in a subject’s household with peanut allergy will not be 
considered an exclusion because we judge the risk of exposure to the investigational product is small 
and can be managed by families. 
The protocol specifies minimum and target doses that must be achieved for the initial dose escalation, 
build-up and maintenance phases. The minimum dose for initial dose escalation is chosen based on 
findings in previous studies15,16 that such doses are tolerated in most subjects and allow continuation 
to the build-up phase. 
The minimum maintenance dose for oral immunotherapy is unknown. In the current trial we propose 
a minimum maintenance dose less than the dose specified for an initial challenge that confirms peanut 

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allergy. This is to allow children who might still react to a challenge dose to build-up to and continue 
maintenance. We propose a target maintenance dose that previous experience suggests is close to the 
maximum that is practical to give as peanut flour (or placebo) added to other food. 
The optimal duration of OIT is unknown. Previous studies indicate that one year or more of OIT 
results in desensitization. Results emerging in 2012 from studies with other food allergens, however, 
indicate that desensitization may not be long-lasting after OIT. These data indicate that when OIT is 
continued for up to two years the likelihood of more long-lasting tolerance is higher. 
The study aims to assess both desensitization and tolerance. The assessment of tolerance, which for 
this study is described as the ability to tolerate oral peanut after a specified period of desensitization 
followed by avoidance, is a key study goal. However, the likelihood and magnitude of the tolerance 
effect are unknown, whereas there are good preliminary data to indicate that desensitization is a 
reasonable goal to test. We therefore compromised by focusing the primary endpoint on 
desensitization but choosing a sample size to provide a chance of seeing a tolerance effect if at least a 
moderate one exists. 
1.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR 
PARTICIPANTS  
1.4.1 Risks  
The initial dose escalation day followed by the build-up phase is developed based on the 
investigators’ previous experience with peanut OIT. In the Principal Investigators’ experience, the 
initial doses have been well tolerated. Consequently, the initial escalation phase was 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 (0.2 mg 
peanut flour or 0.1 mg protein) of the peanut for dosing. Although few in number, the previous OIT 
studies have not reported significant clinical reactions during the build-up phase of treatment. 
The build-up and daily maintenance doses of peanut OIT may cause allergic symptoms including 
sneezing, rhinorrhea, urticaria, angioedema, flushing, flares of eczema, nausea, vomiting, abdominal 
discomfort, cough, wheezing, shortness of breath, or ocular, nasal, oral, or throat pruritus, in addition 
to severe anaphylaxis. The likelihood of a participant experiencing any allergic symptoms will be 
lessened by initiating dosing at extremely small amounts of the peanut protein and by build-up dosing 
under observation in a clinical setting until the maintenance dose is achieved. 
Oral food challenges may induce an allergic response. Three OFCs will be conducted: one at study 
entry, one at the end of therapy, and one 26 weeks after cessation of therapy. Allergic reactions can be 
severe and include life-threatening allergic reactions; however, the risk of an allergic reaction is 
reduced by initiating the challenge with a very small amount of the food, gradually increasing the 
dose, and stopping the challenge at the first sign of a reaction. If participants have an allergic reaction 
during the challenges, they may need oral, intramuscular, or intravenous medications (participants 
judged by the investigator to be at significant risk of severe reaction will have an IV catheter placed 
before the OFCs). Trained personnel, including a physician, as well as medications and equipment, 
will be immediately available to treat any reaction. The DBPCFCs will potentially be made safer by 
using orally ingested foods with masking agents instead of encapsulated peanut powder, thereby 
allowing for earlier detection of allergic reactions based on oral symptoms that would be missed with 
the use of capsules.30 It should be noted that life-threatening anaphylaxis is a known but rare 

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complication of oral food challenge among the investigators who are participating in this protocol. To 
date, there have been no deaths from oral food challenge among these investigators.31  
The risks of skin prick testing are small. Skin prick testing may result in a small, pruritic hive where 
the test is placed. Usually, the hives resolve within 1-2 hours, but rarely a subject may have local 
swelling that takes two to three days to clear entirely. In approximately 1out of 10,000 tests the 
subject may experience other allergic symptoms including sneezing, ocular pruritus and tearing, 
rhinorrhea, and/or urticaria. Very rarely, some individuals with these types of symptoms may develop 
a serious allergic reaction that is life threatening, but no deaths from skin prick testing using standard 
dosing techniques have been reported in fifty years.  
1.4.2 Potential Benefits 
The benefits include the potential of decreasing the participant’s reactivity to peanuts after an 
accidental ingestion and the altering of the natural progression of peanut allergy by inducing peanut 
tolerance. The subject may potentially become clinically and immunologically tolerant to peanut, 
which otherwise occurs in only about 20% of children. A major obstacle to the widespread 
implementation of current treatment strategies is the requirement for daily dosing. This outcome may 
provide new evidence that daily treatment is not required for an indefinite period to maintain a state 
of desensitization.  
In this way, this study will also help expand the knowledge of food allergy in general and may lead to 
new management and therapeutic protocols for individuals with food allergies.  
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective is to determine whether 134 weeks of peanut OIT induces desensitization in 
children with peanut allergy. 
2.2 
SECONDARY OBJECTIVES 
1. 
To determine whether 134 weeks of peanut OIT induces tolerance in children with peanut 
allergy. 
2. 
To assess the safety of peanut OIT and subsequent withdrawal of OIT in this population. 
3. 
To define the immunological responses underlying desensitization and tolerance to peanut. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION 
This is a randomized, double-blind, placebo-controlled, multi-center study comparing peanut oral 
immunotherapy to placebo. 
Eligible participants with peanut allergy will be randomly assigned to receive either peanut OIT or 
placebo for 134 weeks followed by peanut avoidance for 26 weeks. 
An initial blinded oral food challenge (OFC) to 1 g of peanut flour (500 mg peanut protein) will be 
conducted. Participants must have a clinical reaction during this blinded OFC to initiate study dosing. 
After the initial blinded OFC, the study design includes the following: 

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Initial Dose Escalation:  This will occur on a single day in which multiple doses are given. Peanut or 
placebo dosing will be given incrementally and increase every 15-30 minutes until a dose of 12 mg 
peanut flour (6 mg peanut protein) or placebo flour is given. The first four doses will be administered 
as a peanut flour extract of 0.1 to 0.8 mg peanut protein, which is 10 to 80 microliters peanut flour 
extract, or placebo flour extract. The last three doses will be given as peanut flour of 3 to 12 mg 
peanut flour (1.5 to 6 mg peanut protein) or placebo flour. Participants must tolerate a dose of at least 
3 mg peanut flour (1.5 mg peanut protein) or placebo flour to remain in the study. 
Build-up:  After the initial dose escalation day, the participant will return to the research unit the next 
morning for an observed dose administration of the highest tolerated dose from the initial escalation 
day. The participant will then continue on the daily OIT dosing at home and return to the research 
unit every 2 weeks for a dose escalation. The dosing escalations will be consistent with previous 
similar OIT studies. The dosing escalation table is as below. Participants who do not reach the 4000 
mg peanut flour (2000 mg peanut protein) or placebo flour dose during the Build-up phase may enter 
maintenance phase at their highest tolerated dose, which must be at least 500 mg peanut flour (250 
mg peanut protein) or placebo flour. 
The build-up phase will comprise 30 weeks. 
Maintenance:  The participant will continue on daily OIT with return visits every 13 weeks. At the 
end of this phase the participant will undergo a blinded OFC to 10 g peanut flour (5 g peanut protein). 
The maintenance phase will comprise 104 weeks. 
Avoidance:  In this phase participants will stop OIT and will avoid peanut consumption. They will be 
seen 2 weeks and 26 weeks after initiating this phase. At the completion of this phase participants will 
have a blinded OFC to 10 g peanut flour (5 g peanut protein). Participants who do not have a clinical 
reaction to the blinded OFC will undergo an Open Food Challenge (OpFC) (See Section 6.4.1.3). 
The avoidance phase will comprise 26 weeks. 
Post-challenge:  If participants do not have a clinical reaction during the OpFC at the end of 
avoidance, they will be allowed to consume peanut and will have one visit which will include 
peripheral blood sampling for mechanistic assays assessments. 
The post-challenge phase will comprise 2 weeks. 

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Dose Escalation for Maximum Initial 
Dose Escalation of: 
First 
day at 
Dose 
Week 
Number 
6 mg1 
3 mg 
1.5 mg 
Initial Dose 
Escalation 
0.12 
0.12 
0.12 
0 
0 
0.2 
0.2 
0.2 
0 
0 
0.4 
0.4 
0.4 
0 
0 
0.8 
0.8 
0.8 
0 
0 
1.53 
1.53 
1.53 
0 
0 
3.0 
3.0 
 
0 
0 
6.0 
 
 
0 
0 
 
Build-up 
 
6.0 
3.0 
1.5 
1 
0 
12 
6.0 
3.0 
14 
2 
25 
12 
6.0 
28 
4 
50 
25 
12 
42 
6 
100 
50 
25 
56 
8 
150 
100 
50 
70 
10 
250 
150 
100 
84 
12 
400 
250 
150 
98 
14 
600 
400 
250 
112 
16 
900 
600 
400 
126 
18 
1200 
900 
600 
140 
20 
1600 
1200 
900 
154 
22 
2000 
1600 
1200 
168 
24 
2000 
2000 
1600 
182 
26 
2000 
2000 
2000 
196 
28 
Maintenance 
2000 
2000 
2000 
210 
30 
Avoidance 
0 
0 
0 
938 
134 
Post-
challenge  
0 
0 
0 
1120 
160 
 
Table 1  Screening, Initial Dose Escalation, Build-up, Maintenance, Avoidance and Post-Challenge 
1 Amounts expressed in mg peanut protein 
2 Peanut flour extract (0.1 to 0.8 mg doses) 
3 Peanut flour (1.5 to 6.0 mg doses) 
 

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Screen
Randomly 
assign
2:1
Peanut OIT
N=96
Placebo
N=48
Initial dose escalation
1 day
500mg
OFC*
React
N=144
STOP
Do not react
Build-up
 to week 30
Maintenance
from week 30 to 134
Avoidance
from week 134 to 160
5g
OFC
5g
OFC
Fail
Eligible up to 
OFC
STOP
Yes
>1.5mg
Yes
No
Pass
>250mg
STOP
Yes
STOP
No
No
Initial dose escalation
1 day
Build-up
 to week 30
Maintenance
from week 30 to 134
5g
OFC
5g
OFC
Fail
>1.5mg
Yes
Pass
>250mg
Yes
Primary endpoint
week 134
Avoidance
from week 134 to 160
Tolerance 
endpoint
week 160
No
No
Post-challenge 
from week 160 to 
162
Post-challenge 
from week 160 to 
162
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3.2 
STUDY DURATION 
Total study duration will be up to 238 weeks (slightly more than 4 and one-half years). 
• 
Enrollment will be up to 78 weeks. 
• 
Study participation will be 162 weeks, which includes the initial dose escalation, build-up, 
maintenance, avoidance, and post-challenge. 
3.3 
STUDY ENDPOINTS 
3.3.1 Primary Endpoint 
The primary endpoint is the proportion of participants desensitized to peanut after 134 weeks OIT.  
Participants who pass a blinded OFC to 10 g of peanut flour (5 g of peanut protein) at this time 
without significant symptoms as described in Section 6.4.3 will be considered desensitized to peanut. 
Failure will be defined as either unable to undergo the final food challenge or inability to tolerate the 
maximum dose because of significant symptoms such as hives, wheezing, vomiting, or laryngeal 
edema.  
3.3.2 Secondary Endpoints 
Efficacy: 
1. 
Tolerance Endpoint 
The proportion of participants who pass both the blinded OFC to 10 g peanut flour (5 g peanut 
protein) and the Open OFC to 8 g peanut protein in natural food form at week 160. 
Passing a blinded OFC is defined in Section 3.3.1. 
Passing an Open OFC is defined in Section 6.4.3.  
2. 
Transient Desensitization Endpoint 
This is the change in proportion of participants who pass the blinded OFC to 10 g peanut flour 
(5 g peanut protein) at week 134 and week 160.  
Passing a blinded OFC is defined in Section 3.3.1. 
3. 
Highest Tolerated Cumulative Dose Endpoint 
The highest tolerated cumulative dose of peanut protein during the blinded OFCs will also be 
collected and analyzed. 
Safety: 
1. 
The incidence of all adverse events. 
2. 
 Rates of withdrawal from OIT or placebo. 
Mechanistic: 
Changes in the following markers of immune mediation: 
1. 
Secreted cytokines 
2. 
Anti-peanut IgE, IgG, IgG4 and secretory IgA  
3. 
Epitope arrays 
4. 
IgE-facilitated, CD23-dependent allergen binding to B cells  
5. 
Serum, stools, and saliva assays 
6. 
PBMC expression of transcription factors and cytokines relevant to food allergy 

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7. 
CD4+ CD25+ FoxP3+ Tregs  
8. 
DNA-HLA genotyping  
9. 
Peanut-specific T cells 
10. 
Ara h 1 and Ara h 2 reactive T cells  
11. 
Th2A Subset Analysis Basophil activation  
12. 
B cells 
3.4 
PREMATURE TERMINATION OR SUSPENSION OF THE TRIAL 
3.4.1 Stopping Rules 
If any of the stopping rules listed below are met, study enrollment will be suspended, the initial dose 
escalation days will be suspended, dose escalation during Build-up will be stopped, and all enrolled 
participants will remain on their current dose pending expedited review of all pertinent data by the 
Data Safety Monitoring Board: 
• 
Any death related to peanut OIT dosing 
• 
More than one event comprising systemic allergic symptoms with significant hypotension at any 
stage of the protocol 
• 
More than 3 participants require more than 2 injections of epinephrine during dosing of the 
peanut product 
• 
More than 3 of the following events:   
o Severe adverse event, other than anaphylaxis, related to investigational product 
o Eosinophilic esophagitis 
4. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
4.1 
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be eligible for this study: 
1. 
Age 12 months to less than 48 months, either gender. 
2. 
Clinical history of peanut allergy or avoidance of peanut without ever having eaten peanut. 
3. 
Serum IgE to peanut of > 5 kUA/L determined by UniCAPTM. 
4. 
Wheal ≥ 3mm on skin prick test to peanut extract compared to a negative control. 
5. 
A clinical reaction as defined in Section 6.4.3 at or below ingestion of 1 g peanut flour (500 mg 
peanut protein) during screening blinded OFC. 
6. 
Written informed consent from parent/guardian.  
4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will not be eligible for this study: 
1. 
History of severe anaphylaxis with hypotension to peanut. 
2. 
Documented clinical history of allergy to oat. 

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3. 
Suspected allergy to oat and a wheal greater than or equal to 7mm on skin prick test to oat 
extract compared to a negative control.  
4. 
Chronic disease other than asthma, atopic dermatitis, rhinitis requiring therapy; e.g., heart 
disease or diabetes. 
5. 
Active eosinophilic gastrointestinal disease in the past 2 years. 
6. 
Participation in any interventional study for the treatment of food allergy in the 6 months prior 
to visit -1. 
7. 
Inhalant allergen immunotherapy that has not yet reached maintenance dosing. 
8. 
Severe asthma, as indicated by repeated hospitalizations or hospital emergency department 
visits.  
9. 
Moderate asthma defined according to National Asthma Education and Prevention Program 
Expert Panel that requires more than fluticasone 440 mcg or its equivalent daily for adequate 
control. 
10. 
Inability to discontinue antihistamines for skin testing, blinded OFC and the initial dose 
escalation. 
11. 
Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral or 
sublingual) in the 12 months prior to visit -1. 
12. 
Any systemic therapy which in the judgment of the investigator could be immunomodulatory 
(e.g., rituximab) in the 12 months prior to visit -1. Systemic corticosteroid therapy of up to a 
total of 3 weeks is allowed. 
13. 
Use of any investigational drug in 90 days prior to visit -1. 
14. 
Plan to use any investigational drug during the study period. 
15. 
The presence of any medical condition that the investigator deems incompatible with 
participation in the trial. 
4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY 
Participants who prematurely terminate from the study will not be replaced. 
Participants may be terminated from the study for the following reasons: 
• 
The participant elects to withdraw consent from all future study activities, including follow-up. 
• 
The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to 
reestablish contact with the participant have failed). 
5. 
STUDY MEDICATIONS 
5.1 
PEANUT ORAL IMMUNOTHERAPY 
5.1.1 Overview 
There will be two forms of peanut oral immunotherapy. Both will be derived from Partially Defatted 
Peanut Flour—12% fat—Light Roast from the Golden Peanut Company, Blakely, Georgia. 
One form will be a liquid extract derived from the peanut flour source material. This will be used 
during initial dose escalation for doses 0.1 to 0.8 mg of peanut protein (see Table 1). Another form 

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will be the peanut flour. This will be used for the remainder of dose escalation, build-up, and 
maintenance. 
There will be two forms of placebo. Both will be derived from oat flour purchased commercially from 
Arrowhead Mills, Inc., Melville, New York. 
One form will be a liquid extract derived from oat flour source material. This will be used during 
initial dose escalation for doses 0.1 to 0.8 mg (see Table 1). Another form will be oat flour. This will 
be used for the remainder of dose escalation, build-up, and maintenance. 
The peanut and placebo extract and flour are similar in appearance, texture, and taste. This will help 
protect blinding. 
All liquid extract peanut and placebo oral immunotherapy products that will be used for the initial 
dose escalation day, will be manufactured centrally at the University of North Carolina GMP 
manufacturing facility by qualified personnel as specified in the investigational product Drug Master 
File. The liquid extracts will then be frozen and sent to all sites.  
5.1.2 Oral Immunotherapy Liquid Extract for Initial Dose Escalation 
5.1.2.1 
Formulation and Packaging  
Peanut flour extract 
The peanut flour extract will be derived from peanut flour source material. The extract will be 
produced using a protein extraction process performed at the University of North Carolina GMP 
manufacturing facility. The final protein concentration of the extract will be 10mg/mL. The extract 
will be aliquoted into vials and frozen. 
Placebo extract 
The placebo extract will be derived from oat flour source material. The extract will be produced using 
a protein extraction process performed at the University of North Carolina GMP manufacturing 
facility. The final protein concentration of the placebo extract will be 10mg/ml. The extract will be 
aliquoted into vials and frozen. 
5.1.2.2 
Dosage, Preparation, and Administration 
• 
The frozen vial of peanut flour extract or placebo extract will be removed from the freezer a 
maximum of 24 hours prior to the subject’s visit. The extract may be thawed overnight in a 2-8 C 
refrigerator if removed from the freezer on the day prior to the subject’s visit, or may be thawed 
on a countertop (i.e. room temperature) for 30 minutes and placed in an ice bucket if removed 
from the freezer on the same day as the subject’s visit. Vials will not be re-frozen. 
• 
The unblinded pharmacist will dispense one vial per participant - to the clinical staff. Any unused 
thawed extract will be discarded.  
• 
Study personnel at each site trained in preparing the doses of the peanut or placebo liquid extract 
will pipette the appropriate dose (see table below) of the extract and mix it with an appropriate 
food vehicle. 
• 
A licensed and qualified nurse coordinator will oversee administration of the dose to the 
participant. A physician is required to be available on site during administration and must be 
available at all times for emergency treatment for anaphylaxis. 
Peanut Protein (mg) 
Amount of Solution 
0.1 mg 
10 microliters 

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0.2 mg 
20 microliters 
0.4 mg 
40 microliters 
0.8 mg 
80 microliters 
5.1.2.3 
Recommended Storage Conditions 
Peanut and placebo liquid extract will be stored at -200C. 
5.1.3 Oral Immunotherapy for Initial Dose Escalation, Build-up and Maintenance 
5.1.3.1 
Formulation and Packaging  
Peanut flour 
Peanut flour will be packaged and labeled by the weight (mg) of the source material in each cup per 
dose at the University of North Carolina GMP manufacturing facility.  
Placebo flour 
Oat flour will be packaged and labeled by the weight (mg) of the source material in each cup per dose 
at the University of North Carolina GMP manufacturing facility.  
5.1.3.2 
Dosage, Preparation and Administration 
The unblinded investigational pharmacist will dispense the appropriate dose to the clinical staff. The 
peanut flour or placebo will be mixed into a food vehicle (applesauce, yogurt, or other tolerated food) 
for the subject to consume. Refer to Section 3.1 for dosing schedule. 
5.1.3.3 
Recommended Storage Conditions 
Peanut flour and placebo will be stored between 2 and 8° C.  
5.2 
DISCONTINUATION OF STUDY TREATMENT 
Participants will be terminated from further allergen therapy for the following reasons: 
• 
Severe anaphylaxis with hypotension secondary to OIT dosing or any peanut food challenge. 
• 
Inability to reach 3 mg peanut flour (1.5 mg peanut protein) during the initial dose escalation.  
• 
Inability to reach 500 mg (250 mg peanut protein) during the Build-up phase. 
• 
Poor control or persistent activation of secondary atopic disease (e.g., AD, asthma). 
• 
Development of eosinophilic gastrointestinal disease. 
• 
Circumstances (e.g., concurrent illness, such as gastroenteritis) requiring missed home dosing of 
> 14 consecutive days. 
• 
Non-adherence with home dosing protocol with excessive missed days, defined as 3 occasions 
on which more than 3 consecutive home doses of study medication are missed. 
• 
Eosinophilic esophagitis. 
• 
Severe adverse event other than anaphylaxis related to investigational product. 
Further care will be provided according to the judgment and practice of the site investigator. 
Any subject deemed to have severe symptoms and who receives aggressive therapy at any time per 
investigator’s discretion, should be discontinued from further escalation and followed-up as 
appropriate. 

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Participants who cease therapy should be asked to complete all assessments listed for Discontinuation 
Visit in Appendix 2. 
If study treatment is discontinued, the DAIT/NIAID Medical Monitor will be notified. 
5.3 
CONCOMITANT MEDICATIONS 
5.3.1 Required Medications 
5.3.1.1 
Prophylactic Medications 
No prophylactic medications are required during study participation. 
5.3.2 Permitted Medications   
All participants may continue their usual medications, including those taken for asthma, allergic 
rhinitis, and atopic dermatitis, during the study. However, participants must be able to temporarily 
discontinue antihistamines (5 half-lives of the antihistamine) prior to skin testing and oral food 
challenges. Regular topical steroid use is permitted at the time of skin testing. 
5.3.3 Rescue Medications 
Treatment of individual allergic reactions during OIT therapy will be with either an antihistamine 
and/or epinephrine, along with IV fluids, albuterol, and corticosteroids as indicated. Participants and 
parents are likely to have self-injectable epinephrine but for those who do not, self-injectable 
epinephrine will be prescribed. Participants will be trained in proper use of self-injectable epinephrine 
and will be able to demonstrate proper technique. All subjects will be given a food allergy action plan 
to follow while in this study. 
5.3.4 Prohibited Medications 
Use of the following medications is prohibited during study participation: 
• 
Omalizumab (Xolair). 
• 
Systemic corticosteroids of longer than 3 weeks duration at any time throughout the study. 
5.4 
DRUG ACCOUNTABILITY 
Under federal regulations (21CFR 312.62) an investigator is required to maintain adequate records of 
the disposition of the investigational product, including the date and quantity of drug that was 
received, the participants to whom drug was dispensed (participant by participant accounting), and an 
account of any drug accidentally or deliberately destroyed. The investigator will ensure that the 
investigational product supplies are stored as specified in the protocol and pharmacy manual in a 
secured area, with access limited to authorized study personnel. 
Records for receipt, storage, use, and disposition of the study drug will be maintained by the study 
sites. A drug-dispensing log will be kept current for each participant and will contain the 
identification of each participant and the date and quantity of drug dispensed.  
All records regarding disposition of the investigational product will be available for inspection by the 
clinical trial monitor. 

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5.5 
ASSESSMENT OF COMPLIANCE WITH STUDY PRODUCT 
Participants will maintain diary logs to document daily dosing of the study product. Additionally, 
subjects will be instructed to return all empty packages as well as all unused study product at each 
visit, which will be recorded by the site. Participant compliance with administration of study product 
will be performed regularly. 
6. 
STUDY PROCEDURES 
6.1 
VISIT WINDOWS 
6.1.1 Scheduled Visits 
Appendix 1 and Appendix 2 present the schedule of events for this trial. All other scheduled study 
visits must occur within the time limits specified below: 
Visit -2  
up to 30 days prior to visit 0 
Visit -1  
occurs between visit -2 and 0 
Visit 0:  
no window 
Visit 1:  
no window 
 
Visits 2 through 16:  
-3 to +7 days based on the previous visit 
 
A subject can be in the build-up phase, which is visit 1 up to visit 16, for up to 45 weeks. Thus visit 
16 can occur up to day 315 relative to day 0. 
 
Visits 17 through 26:   -3 to +7 days based on visit 16 
 
A subject can be in the maintenance and avoidance phases, which comprise visit 16 through visit 26, 
for up to 131 weeks. 
 
Visit 27: 
 
-2 to +2 days based on visit 26 
 
A subject can be in the post-challenge phase for as long as 2 weeks and 2 days. 
 
Combining build-up, maintenance, avoidance and post-challenge phases, a subject could be in the 
study for up to 45 weeks plus 131 weeks plus 2 weeks and 2 days or 178 weeks and 2 days after 
randomization (visit 0). 
6.1.2 Unscheduled Visits 
Unscheduled visits may be performed as determined by the PI and study staff for dose observation if 
the subject has had symptoms with the home doses, missed consecutive doses as a result of 
concurrent illnesses, or has had symptoms outside of the usual 2 hour dosing window. Assessments 
for an unscheduled visit are listed in Appendix 1 and 2 and will be done at the study physician’s 
discretion. 
Participants may be asked to return to obtain additional samples if the samples need to be repeated. 
This can be done as unscheduled visit or the next scheduled visit.  

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6.1.3 Discontinuation Visits 
 Participants who prematurely terminate due to withdrawal of the consent or investigator decision  will 
be invited to attend a discontiuation visit prior to discharge from the study.  
6.2 
RANDOMIZATION, BLINDING AND UNBLINDING  
6.2.1 Enrollment, Randomization and Preparation of Doses  
Participants who provide informed consent and meet the eligibility criteria will be randomized in a 
2:1 active to placebo ratio. At screening, a unique participant identification number will be assigned 
to each participant through a password-protected, web-based, electronic data capture (EDC) system 
that is developed, validated, and maintained by the Statistical and Data Coordinating Center (SDCC). 
Randomization will be stratified by site and will be accomplished through a password-protected, web-
based, randomization system (RhoRAND™) maintained by the SDCC. Authorized clinical study 
personnel, who will remain blinded, will enter the participant identification number and eligibility 
criteria for randomization into the system. The system will generate an unblinded electronic treatment 
assignment notification to the unblinded investigational pharmacist and a blinded participant 
randomization notification to the clinical study personnel via email.  
The manufacturing facility will centrally prepare, package, label, and store, investigational product in 
individual unblinded doses and distribute to the investigational pharmacy. 
The investigational pharmacist will obtain individual unblinded participant doses consistent with 
participant’s treatment assignment and current dose level. The investigational pharmacist will link the 
unique participant identification number to a unique barcoded label on the treatment doses from the 
site’s inventory to confirm the correct treatment assignment.  
Participant doses will be dispensed to clinical study personnel in a blinded manner for dispensing to 
the participant. Prior to dispensing the doses, the blinded study personnel will scan the unique 
barcoded labels linked to the participant’s doses to confirm the correct treatment assignment using the 
EDC system. 
During site visits, an unblinded site monitor will check the pharmacy logs to ensure that appropriate 
randomization assignments were received, recorded, and maintained. 
6.2.2 Blinding 
Blinding will be maintained for all study participants through the time of the final blinded 10 g peanut 
flour (5 g peanut protein) OFC, which will occur 26 weeks after cessation of OIT at the end of the 
study (week 160).  
6.2.3 Unblinding 
Unblinding before the study is completed will occur only if a participant’s well-being is threatened 
and the investigator believes unblinding is necessary to protect the participant.  
Before treatment assignment for an individual participant is unblinded, the investigator must confer 
with the DAIT/NIAID Medical Monitor. In the event of extreme medical emergencies, the site 
investigator will contact the ITN SDCC Client Support Services staff to obtain treatment assignment 
information. The site investigator will notify the Protocol Chair or co-Chair of the unblinding event, 
and the DAIT/NIAID Medical Monitor will notify the study management team (SMT). 

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The emergency unblinding will be recorded and reported by the Medical Monitor to the NIAID 
Allergy and Asthma DSMB, an independent data safety monitoring body that is appointed by NIAID. 
A full account of the event will be recorded, including the date and time of the emergency, the reason 
for the decision to unblind, and the names of the Medical Monitor and others who were notified of the 
emergency. During site visits, the site monitor must verify that the Medical Monitor was notified and 
that a written account was completed. The reasons for unblinding of a participant’s treatment will be 
included in the final study report. 
ITN and DAIT/NIAID approval is required for unblinding the treatment of an individual participant 
or subgroups of participants for unplanned interim analyses to support DSMB reviews and final 
analysis. 
An exception to the above rule is that IND Safety Reports will be reported to the FDA, DSMB and 
IRBs in an unblinded fashion as requested by current FDA guidance. 
6.3 
GENERAL ASSESSMENTS 
• 
Informed Consent. 
• 
Demographics. 
• 
Medical history to determine if there are any clinically significant diseases or medical 
procedures other than the disease under study. 
• 
Comprehensive physical examination to include skin, HEENT, respiratory, cardiovascular, 
gastrointestinal, endocrine/metabolic, neurological, blood/lymphatic, musculoskeletal.  
• 
Brief physical examination to include skin, HEENT, respiratory, cardiovascular, gastrointestinal. 
• 
Vital signs. Weight, height, temperature, blood pressure, respiration, and pulse will be obtained 
at all visits.  
• 
Concomitant medications. All concomitant medications will be recorded. 
• 
Adverse events. Participants will be assessed for AEs. 
6.4 
DISEASE-SPECIFIC ASSESSMENTS 
6.4.1 Diet and Allergy History 
Diet and allergy history will be collected at all visits. 
6.4.2 Skin Prick Test to Peanut Extract and Environmental Allergens 
Participants will have skin prick tests performed using study approved procedures for food and 
environmental allergens. Participants will be required to be off of antihistamines for an appropriate 
length of time (5 half-lives of the antihistamine that is being used). 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.  
 
The following allergens will be tested:  
 
Food allergens:  Peanut, egg white, cow's milk, soy, wheat, sesame, tree nuts (cashew, walnut, 
hazelnut, almond, pecan, pistachio, and Brazil nut) 
Inhalant allergens:  Cockroach, dust mite, cat, dog, Bermuda grass, Timothy grass, ragweed, oak, 
birch, Alternaria sp. 

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In addition, IgE testing will be done for the food allergens and inhalant allergens listed above (see 
Appendix 1 and 2).  
Oat will be tested by skin prick testing for participants who have a suspected clinical reaction to oat. 
6.4.3 Oral Food Challenges (500mg, 5g and Open Food Challenge) 
All OFCs conducted in the study are double blind and placebo controlled and will be performed so 
that neither the participant, nor the participant’s caregiver, nor the physician knows which challenge 
contains the peanut or the placebo. The 500 mg OFC results will be unblinded in order to determine 
eligibility for the study since the participant must have a clinical reaction to this OFC to begin dosing. 
The results of the 500 mg OFC will be made available to study staff in order to determine eligibility.  
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 a blinded OFC, participants will be off antihistamines for an appropriate length of time (5 
half-lives of the antihistamine that is being used) and participants will be assessed for an exacerbation 
of asthma as determined by active wheezing and for a current flare in atopic dermatitis (Section 
6.7.2).  
Participants judged by the investigator to be at significant risk of severe reaction will have an 
intravenous line placed prior to the blinded OFC. Such participants would include those with a history 
of life-threatening anaphylaxis to any food, or a reaction to any food which caused dehydration and 
required intravenous fluid resuscitation. 
A uniform approach for food challenges will be used. The blinded OFC will consist of 1 g or 10 g of 
peanut flour (500 mg or 5 g of the peanut protein) or placebo flour in gradually increasing doses at 
15-30 minute intervals.  
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. For the 500 mg blinded OFC, the set of doses will be comprised of 
the following: 1%, 4%, 10%, 20%, 20%, 20%, 25%. For the 5 g blinded OFC, the set of doses will be 
comprised of the following: 0.1%, 1%, 4%, 10%, 20%, 20%, 20%, 25%. Though many published 
challenges begin with 5% initial doses, the minimum dose for this study was chosen to be a lower 
dose according to additional recent recommendations and consensus32.  
If conducted in a single day, at least 2 hours must separate the last dose of the first set of doses from 
the first dose of the second set. 
Open Oral Food Challenge of week 160  
An OpFC will be conducted for all participants who pass a 5g blinded OFC at week 160. During an 
OpFC, the participant must ingest a meal size portion (approximately 8 grams of peanut protein) of 
the food in its natural form (e.g., 2 tablespoons peanut butter) in an open setting in which all of the 
involved parties are aware of the identity of the food to make sure that it is tolerated.  
The OpFC will be conducted 2 hours after passing a 5g blinded OFC. The peanut-containing food 
should be consumed during a 120 minutes maximum (30-60 minute preferred) time period at the 
participant’s own pace (i.e., not in a stepwise or graded fashion). If the participant passes the OpFC, 

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the participant should be observed for a minimum of 2 hours or longer as indicated by the 
participant’s status. 
If the participant has negative reaction during OpFC but could not consume the full amount of open 
challenge material, a repeat OpFC may be scheduled within 14 days to determine the outcome.  The 
investigator should discuss the case with the NIAID medical monitor and protocol chairs before 
scheduling a repeat OpFC.  
6.4.4 Oral Food Challenge Outcome 
Frequent assessments will be made for symptoms affecting the skin, gastrointestinal tract, and/or 
respiratory tract. Outcome of the challenge will be determined by evaluating the participant at 
frequent intervals using the criteria in the table below: 
A positive food challenge will be defined by the presence of either of the following: 
o One or more major criteria. 
o Two or more minor criteria. 
Otherwise, the food challenge will be considered negative. A challenge may be discontinued and 
considered positive if in the judgment of the investigator, the subject is experiencing an allergic 
reaction even though scoring criteria are not fulfilled. The investigator should document why she or 
he believes the subject is experiencing an allergic reaction. 
All symptoms should be of new onset and not due to ongoing disease. Symptoms must occur no later 
than 2 hours after the last dose. 
During a challenge, if a participant has a false positive reaction to the placebo, both the peanut and 
placebo challenge can be repeated, at the study physician’s discretion. 
In the event a conclusive 5 g OFC outcome can not be determined at week 134, the participants 
should be scheduled to return to the clinic for repeat 5 g OFC and continue taking maintenance dose 
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Major Criteria 
Confluent erythematous pruritic rash 
Respiratory signs (at least one of the following): 
      Wheezing 
      Inability to speak 
      Stridor 
      Dysphonia 
      Aphonia 
At least 3 urticarial lesions 
At least 1 site of angioedema 
At least 2 distinct episodes of vomiting 
Hypotension for age not associated with vasovagal episode 
Evidence of severe abdominal pain (such as abnormal stillness or doubling over) that persists 
for ≥ 5 minutes  
Minor Criteria 
1 – 2 urticarial lesions  
Single episode of vomiting 
Diarrhea 
Notably distressed because of nausea and/or abdominal pain with decreased activity 
Dry hacking cough that lasts for at least 4 minutes 
Complaint of throat tightness and/or pruritus plus at least 4 episodes of throat clearing 
Persistent rubbing of nose or eyes that lasts for at least 5 minutes 
Persistent rhinorrhea that lasts for at least 5 minutes 
Continuous, hard scratching that lasts for at least 3 minutes 
Distinct change in affect: whining, crying, and/or clinging to parent 
Table 2 Criteria for Determining the Outcome of Food Challenge  
6.5 
LOCAL LABORATORY ASSESSMENTS 
• 
CBC with differential 
6.6 
MECHANISTIC ASSESSMENTS 
• 
IgE [UniCAP™] to peanut 
• 
Basophil activation assay 
• 
Cellular assays 
• 
Plasma assays 
• 
Stool and saliva assays 
• 
HLA 
6.7 
STUDY VISITS 
6.7.1 Screening 
6.7.1.1 
Study Visit -2 
See Appendix 1 for detailed assessments. 

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6.7.1.2 
Visit -1 
Participants who meet visit -2 eligibility criteria may return for visit -1 to undergo an initial blinded 
OFC of 500 mg peanut protein. Visit -2 and visit -1 procedures may occur on the same day. See 
Appendix 1 for detailed assessments. 
6.7.2 Initial Dose Escalation - Study Visit 0 
The initial dose escalation will occur on a single day at the clinical research center. Peanut or placebo 
dosing will begin with 0.2 mg peanut flour extract (0.1 mg peanut protein) or placebo flour extract 
with graduated doses every 15-30 minutes up to 12 mg peanut flour (6 mg peanut protein) or placebo 
flour, if tolerated, in one day. A table listing dose increments during initial dose escalation is 
in Section 3.1. 
Participants will not have active wheezing or a current flare in atopic dermatitis. If symptoms occur 
preventing escalation to 12 mg peanut flour (6 mg peanut protein) or placebo flour, the highest 
tolerated dose of at least 3 mg peanut flour (1.5 mg peanut protein) or placebo flour will be accepted 
as the dose for further escalation. Participants must tolerate at least 3 mg peanut flour (1.5 mg peanut 
protein) or placebo flour as a final dose to remain in the study. 
Intravenous access will be established prior to initial day of dosing and maintained with a 
saline/heparin lock, per investigator’s discretion. Intramuscular epinephrine will be available. If 
necessary, albuterol will be used for lower respiratory symptoms (wheezing). A licensed and qualified 
nurse coordinator will oversee administration of the dose to the participant. A physician is required to 
be available on site during administration and must be available at all times for emergency treatment 
for anaphylaxis.  
Since the participants are very young children, they may have clear liquids, JELL-O, or other small 
amounts of food such as crackers, cereal, etc. during the day of the initial dose escalation while they 
are being given the desensitization doses. 
Participants may develop symptoms during the initial escalation. The investigator’s judgment will be 
required to determine the best course of action with possible actions being: 
1. Extend time interval between dosing (up to an additional 30 minutes). 
2. Return to previously tolerated dose (i.e., repeat of last tolerated dose) then advance forward. 
3. Discontinue protocol. 
For oral or pharyngeal pruritus, the action should be to continue the normal dosing in 30 minutes. 
For mild symptoms, defined as: 
• 
skin — limited or localized hives or swelling, skin flushing or pruritus 
• 
respiratory — rhinorrhea or sneezing, nasal congestion, occasional cough, throat discomfort 
• 
GI — mild abdominal discomfort or minor episode of vomiting 
the action should be either to repeat the last dose in 30-60 minutes or to advance in 30-60 minutes 
depending on the physician’s discretion. 
For moderate symptoms, defined as: 
• 
skin — systemic hives or swelling 
• 
respiratory — throat tightness without hoarseness, persistent cough, wheezing without dyspnea 

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• 
GI — persistent moderate abdominal pain/cramping/nausea, increased vomiting 
 
the action should be to implement a 30-60 minute observation period and if symptoms resolve, reduce 
the dose by one step, repeat the same dose, or increase the dose by one step; 
if symptoms continue or worsen, the participant can be treated with appropriate rescue medication: 
 
if symptoms resolve, reduce the dose by one step, repeat the same dose, or increase the dose by one 
step; 
if symptoms require additional treatment, then consultation with the Protocol Chair or Co-Chair as 
listed on the cover page of the protocol is warranted to determine the next course of action. The 
Protocol 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 Monday through Friday. 
For severe symptoms, 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 initial escalation dose should be discontinued and the appropriate rescue medications 
administered. 
If the subject requires treatment for symptoms with antihistamines on one occasion during the initial 
escalation protocol, then the rest of the protocol may be followed. If the subject requires more than 
one medication (e.g., albuterol, diphenhydramine, epinephrine, or others) or multiple doses of 
antihistamines, the initial escalation protocol should be terminated. 
For a completed initial escalation protocol 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. 

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Symptoms during dose 
escalation
Oral or pharyngeal 
pruritus
Continue dosing in 
30 minutes.
Mild symptoms
Repeat last dose or 
advance to next 
dose in 30-60 
minutes.
Moderate symptoms
Observe for 30-60 
minutes.
Severe symptoms
Treat for severe 
symptoms. 
Discontinue 
escalation.
Symptoms 
resolved?
Treat 
Symptoms 
resolved?
Consult with 
protocol chair or co-
chair.
No
Reduce the dose by one step, keep the 
same dose, or increase the dose by one 
step.
Yes
No
Yes
 
Figure 2  Management of Symptoms during Initial Dose Escalation 
6.7.3 Build-up 
After the initial dose escalation day, the participant will return to the research unit the next morning 
for a dose of the highest tolerated dose from the initial escalation day. This dose will be at least 3 mg 
peanut flour (1.5 mg peanut protein) and will be maximum 12 mg peanut flour (6 mg peanut protein). 
The dosing escalation will be incremental based on previous OIT studies.  
The first daily dose of peanut will be given in the clinical research unit to ensure there are no ill 
effects of the once-daily dosing. Thereafter, the daily dose will be given at home. Every 2 weeks (12 
to 21 days), the participant will return to the research unit for a dose escalation. During observed dose 
escalation visits, if there are no symptoms after a 30 minute-to-2 hour observation period, the subject 
will be discharged. The observation time period is dependent on the length of time on the study, the 
subject’s previous dosing history for the immediate past 2 weeks and throughout the study, and 
number of missed doses during the past 2 weeks.  
With observed dose escalations, vital signs will be performed prior to dosing, before discharge, and 
anytime moderate symptoms occur. Physical assessment will be performed at each of these set times 
and at 30 minute intervals while the subject is in the clinical research unit for dose escalations. If 
symptoms occur that do not require treatment, the participant will be observed until they resolve. If 
symptoms occur that require diphenhydramine or albuterol, the subject will be observed for a 
minimum of 2 hours or until the participant’s symptoms resolve. If symptoms occur that require 
epinephrine, the participant will be observed a minimum of 4 hours or until the participant’s 

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symptoms resolve. If symptoms do not fully resolve after 4 hours or if new symptoms occur, the 
participant will be transferred to a hospital and observed overnight at the physician’s discretion. 
Participants will be given the contact information for the study staff which includes email addresses, 
pager numbers,  and office phone numbers for questions or concerns as they arise during the study. 
An on-call physician at each site will be reachable by subjects day or night. At each dose escalation 
visit to assess for dosing compliance and dosing reactions the contact information will be reinforced 
to the family. 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. Participants should withhold their daily 
home dose of study product on the escalation day but should take all other prescribed medications 
unless told to hold for study procedures.  
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. Participants that 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. 
Participants will be allowed to take their other daily medications during the build-up and maintenance 
phases of the study (i.e., antihistamines, albuterol). 
Participants will be free from active wheezing or a flare of atopic dermatitis prior to any dose 
escalation. Participants will be maintained on their current dose of study product until their flare of 
asthma or atopic dermatitis resolve.  
Participants 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: 
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 the clinical research center. 
4. Return for dosing of previously tolerated dose (without escalation) in the clinical research center. 
5. Discontinuation of dosing. 
If a participant 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 participant 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 or sneezing, nasal congestion, occasional cough, throat discomfort 
• 
GI — mild abdominal discomfort or minor episode of vomiting 
 
The action should be to either repeat the dose the next day (day 2) at home or to have the participant 
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 participant will 

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continue on that dose and return at the normal interval. If the dose causes mild symptoms again, then 
the participant 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 participant will continue on this dose for the normal time 
interval. If mild symptoms recur, a 1-2 step reduction would be administered the next day (day 4). If 
tolerated then that dose would be continued for 2 weeks. If not tolerated, consultation with the 
Protocol Chair would be indicated. 
For moderate symptoms, defined as— 
• 
skin — systemic hives or 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 day’s dose or the last tolerated dose under observation. If the dose is 
tolerated, the participant will continue on that daily home dose for the normal time interval per 
protocol. If the subject does not tolerate this dose, the participant 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 at the clinical research center (day 4). If this next dose is not tolerated, then a discussion with 
the Protocol Chair or Co-Chair will ensue to make a decision about whether to continue the subject on 
active treatment in the study. 
For more severe symptoms, 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 to treat the participant, and at the physician’s discretion either: (1) have them 
return to the clinical research center the next day (day 2) for dosing with a two-step reduction in dose 
under observation or (2) discontinue them from the active treatment. If the participant 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 Protocol Chair or Co-Chair may ensue to make a 
decision about whether to continue the subject on active treatment in the study. 
For a completed dose escalation with no symptoms, participants should be observed for a minimum 
of 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. 
If a participant fails dose escalation after 3 consecutive (with 2-4 weeks between) attempts, he or she 
will be considered a dose escalation failure, and the last tolerated dose will be accepted as the 
maintenance dose. If the participant has attained a dose of 500 mg peanut flour (250 mg peanut 
protein), this dose will become the maintenance daily home dose. If 500 mg peanut flour (250 mg 
peanut protein) has not been attained, the subject will be removed from the dosing arm and will be 
followed only as a longitudinal follow-up participant.  

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If a child reaches the 2g dose prior to visit 15 (week 28) (either at visit 13 or visit 14) per the schedule 
of events, there will be two scenarios.  
Scenario 1)  If the child reaches 2g at visit 13, the child will be dispensed 2 weeks of 2g home dosing  
and  return for their next visit in two weeks (visit 14). If the child is tolerating 2g well, then the child 
will be dispensed 4 weeks of the 2g dose and visit 15 can be a telephone visit. The child must return 
to the clinic for visit 16 (week 30) within the protocol-specified windows (-2 to 7 days).  
Scenario 2) If the child reaches the 2g dose at visit 14, the child will be dispensed 2 weeks of 2g 
home dosing and the child will have to come to the clinic for visit 15 and visit 16 within the protocol 
specified visit windows. There will be no visit 15 telephone visit with this scenario.  
Participants who initially tolerated a certain dose may at some point no longer accept it. Dosing can 
be reduced to the next lower level. If the participant still does not accept the dose, it may be reduced 
again to the next lower level. If the participant still does not accept the dose, the participant will be 
considered a failure at Build-up. 
6.7.4 Maintenance 
This phase consists of the subject receiving the daily dose of 4000 mg peanut flour (2000 mg peanut 
protein or highest tolerated dose) daily for at least 104 weeks at home. The participants will continue 
to follow an otherwise peanut-restricted diet. 
Participants who did not reach the 4000 mg peanut flour (2000 mg peanut protein) dose during the 
build-up phase will continue at their highest tolerated dose, which will be at least 500 mg peanut flour 
(250 mg peanut protein). 
A consistent time (within a 4-hour time period) will be recommended for home dosing, and it will be 
stressed that it is critical to take the dose every day. Participants will be informed to separate the dose 
by at least 12 hours. Participants will continue to take all their regularly prescribed medications 
consistent with the eligibility criteria for the protocol. 
For any noted symptoms during the maintenance phase, the same study dosing rules for the build-up 
phase will be followed. 
The participant will continue on daily OIT with return visits every 13 weeks.  
6.7.5 Avoidance 
After completion of 104 weeks of maintenance dosing and a 10 g blinded OFC to peanut flour (5 g 
peanut protein), participants will stop daily dosing. Participants will avoid consumption of peanut, 
either as a daily dose or as part of their regular diet for 26 weeks.  
After 26 weeks of avoidance, participants will undergo a final 10 g blinded OFC to peanut flour (5 g 
peanut protein). Participants who do not have a clinical reaction to the challenge will receive an Open 
Food Challenge (OpFC) (See Section 6.4.3). 
6.7.6 Post-Challenge  
If participants do not have a clinical reaction during the OpFC at the end of avoidance, they will be 
allowed to consume peanut and will have one visit which will include peripheral blood sampling for 
mechanistic assays assessments. 

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Post-challenge will comprise 2 weeks. 
6.8 
MISSED DOSES AND DOSING DURING CONCURRENT ILLNESS 
6.8.1 Missed Doses for Non-Compliance 
Missed 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: 
• 
1 dose — the next dose would be the current dose and could be given at home 
• 
2 doses in a row — the next dose would be the current dose and could be given at home 
• 
3 or 4 doses in a row — the next dose would be the current dose and would be given under 
observation in the clinical research unit 
• 
5 to 7 doses in a row-— the next dose would be 75% of the current dose and would be given 
under observation in the clinical research unit 
• 
8 to 14 doses in a row — initiate the next dose as approximately 50% of the last tolerated dose. 
This would be done under observation in the clinical research unit.  
After any dose reduction, dose escalation would occur in the clinical research unit with an escalation no sooner 
than weekly and no longer than every 4 weeks with dose increases of 1 dose level at each escalation. If 
symptoms occur, the dosing symptom rules in the build-up phase would apply.Study site staff will contact 
the investigator if 1 or 2 missed doses are due to an allergic reaction or symptom. Study staff will 
contact the investigator for all missed doses of 3 or more.  
6.8.2 Management of Dosing During Concurrent Illness 
If a participant has gastroenteritis, nausea and vomiting, upper-respiratory infection, active wheezing, 
fever greater than 100.5° C, or other similar illness, the parent should hold the dose and call the study 
center for instructions regarding dosing. Depending on the severity of the illness, the study center 
may instruct the parent to hold dosing for one or more days. Reinitiating dosing will be according to 
the algorithm described in Section 6.8.1.  
6.9 
ASSESSMENT OF GASTROINTESTINAL SYMPTOMS 
6.9.1 Baseline Assessments 
Gastrointestinal (GI) symptoms will be assessed at baseline as follows:  
Question 1 “Prior to enrollment in the study, did your child have:” 
 
No 
Yes and active 
but infrequent 
(less than 
3x/mo) 
Yes and 
active 
(3x/month or 
more) 
Yes, active, 
(3x/month or 
more) and 
requiring 
treatment* 
“Colic” 
 
 
 
 
Intolerance of formula or 
breastmilk 
 
 
 
 
“Reflux” or frequent spitting up 
 
 
 
 
Abdominal pain 
 
 
 
 
Constipation 
 
 
 
 
Poor appetite 
 
 
 
 

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*please specify any medications or diet changes 
 
Question 2 “Currently, does your child exhibit any of the following:” 
 
No 
Yes and active 
but infrequent 
(less than 
3x/mo) 
Yes and 
active 
(3x/month or 
more) 
Yes, active, 
(3x/month or 
more) and 
requiring 
treatment*  
Difficulty swallowing 
 
 
 
 
Refusal to eat 
 
 
 
 
Abdominal pain 
 
 
 
 
Vomiting 
 
 
 
 
*please specify any medications or diet changes 
 
Questions 1 and 2 will be administered at baseline (visit -2). For participants enrolled prior to 
protocol v.3.0, only Question 2 will be administered at the first visit after the implementation of 
protocol v.3.0. 
6.9.2 Ongoing Assessments 
GI symptoms will be assessed during the study as follows:  
Question 3 “Has your child experienced a change in any of the following since his/her last study 
visit (mark all that apply)?” 
 
Does Not 
Apply 
(NA) 
Newly 
Appeared 
in Interval 
Better 
Same 
Worse 
Difficulty swallowing 
 
 
 
 
 
Refusal to eat 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
6.9.3 Modified Aceves Questionnaire33 
For any “yes” responses to Question 2 (Section 6.9.1), and for any “yes” responses to Question 3 
falling in the shaded cells (Section 6.9.2), GI symptoms will be further assessed with the completion 
of the following questionnaire:   
 
0 
1 
2 
1. Does your child ever feel food coming back up into his / her throat  
And /or 
Do you observe your child repetitively or forcefully swallowing?  
 
 
 
2. Does your child complain about stomach pains 
And /or 
Is your child often irritable for no apparent reason and you suspect belly pain?  
 
 
 
3. How often does your child complain about feeling like throwing up?  
And /or 
How often does your child throw up?  
 
 
 
4. How often does your child eat too little or get full before finishing his or her 
meal?  
 
 
 

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5. How often does your child wake up during the night from belly pain?  
 
 
 
6. How often have you noticed blood in your child’s stool during the last 3 
months?  
 
 
 
7. Does your child have difficulty swallowing 
And /or 
Does swallowing feel painful to your child?  
 
 
 
 
Subsequent actions will be determined by the total score as follows: 
 
Scoring Key:  
0 
Not at all. 
1 
Mild. No problem with daily activities; medications given as needed.  
2 
Moderate-severe. Interferes with daily activities or requires daily medications.  
 
A total score of 5 or more will be reported to the site investigator. The investigator will follow-up 
with a discussion with the participant’s family to collect additional history. Depending on the severity 
of the symptoms, the investigator may instruct the participant’s family to consult with the 
participant’s primary provider about further workup and treatment, review dosing instructions, or 
hold and/or adjust dosing for one or more days. In addition, the investigator will consider whether to 
refer the participant to a gastroenterologist. The DAIT/NIAID Medical Monitor, the Protocol Chair or 
co-Chair, and the ITN Clinical Trial Physician will be notified based on the principal investigator’s 
judgment.  
7. 
TOLERANCE ASSAYS 
7.1 
MECHANISTIC HYPOTHESES 
Peanut allergy is characterized by Th2-skewing and production of IgE to peanut proteins. A recent 
study by Jones et al.15 demonstrated several immunological changes induced by peanut OIT 
including: (1) decreased peanut specific IgE after 24 months of OIT; (2) increased peanut-specific 
IgG and IgG4 following 12 months of OIT; (3) decreased basophil reactivity following 12 months of 
OIT; (4) increased number of CD4+CD25hiFoxP3+ T regulatory cells (Tregs); and (5) decreased Th2 
cytokine secretion (IL-5, IL-4, and IL-13) after 12 months of OIT. Results from a trial of oral 
immunotherapy with egg suggest that immunotherapy-induced tolerance (vs. a non-tolerant state) is 
associated with increased levels of egg-specific IgG4 antibody and reduced size of skin prick test to 
egg. 
Peanut-specific CD4+ T cells are known to be involved in the pathophysiology of peanut allergy. 34,35 
New reagents that allow quantification and phenotyping of these cells using Ara h 1-specific class II 
tetramers36 with standard flow cytometry markers will allow us in the current trial to monitor the 
effects of immunotherapy on peanut specific T cells over time.  
A report by Wambre et al.37 suggests that a unique subset of Th2 cells may be a biomarker for 
allergy, and that a decrease in this cell subset may be indicative of densitization or tolerance to 
peanut. Wambre et al. used ex vivo MHC-class II tetramer staining to detect, characterize and sort 
allergen-specific CD4+ T cells. Transcriptome and surface marker immuno-phenotyping of these 
allergen-specific CD4+ T cells from allergic and non-allergic subjects revealed a “pathogenic 
footprint” that could be analyzed by flow cytometry. These T cell biomarkers were then assessed in 
allergic individuals and non-allergic individuals to test for their ability to discriminate allergen-
specific T cells from the rest of the T cell repertoire. This analysis identified a distinct Th2 subset 

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involved in allergic disease that is virtually absent in non-allergic individuals. This subset is 
characterized by the unique expression of five T cell surface markers and includes the vast majority 
of allergen-specific CD4+ T cells as determined by tetramer analysis. We intend to monitor the 
frequency of these cells, denoted Th2A, to determine if modification of this cell subset could serve as 
a surrogate end-point for clinical outcomes in patients undertaking immunotherapy. 
Based on these findings the following mechanistic hypotheses are proposed: 
1. Subjects who become desensitized to peanut after 134 weeks of OIT and exhibit tolerance at 
week 160 will have decreased peanut-IgE, increased peanut-IgG4, basophil hyporesponsiveness 
to peanut allergens, increased Treg functional cytokines, fewer peanut-specific CD4+ T cells, a 
reduction over time in the Th2A cell sub-set and decreased Th2 cytokine responses relative to 
baseline that will remain unaltered after OIT is discontinued. 
2. Subjects who become desensitized to peanut after 134 weeks of OIT but do not exhibit tolerance 
at week 160 will have increased peanut-induced basophil reactivity from week 134 (while still on 
OIT) to week 160 (off OIT for 26 weeks). This will be driven by parallel increases in Th2 
cytokines and peanut-specific IgE during the 26 weeks off OIT, which will be detectable at week 
160. We predict that we would also see a reduction in the Th2A cell sub-set but we may not see a 
significant change in the numbers of peanut-specific CD4+ T cells. 
3. Subjects who become desensitized to peanut after 134 weeks of OIT and exhibit tolerance at 
week 160 will have decreased IgE binding to epitopes in Ara h 1, 2, and 3 (fewer epitopes 
recognized and decreased quantity to persistent epitopes) with a parallel increase, or spreading, of 
IgG4 epitopes in Ara h 1, 2, and 3. 
4. Subjects on placebo that develop natural tolerance to peanut will have decreased peanut-IgE, 
decreased basophil reactivity to peanut allergens, and an increase in peripheral Tregs that precede 
the development of tolerance. We also predict that over time these patients would also show a 
reduction in peanut-specific CD4+ T cells, and the Th2A cell sub-set. 
7.2 
PROPOSED MECHANISTIC ASSAYS  
7.2.1 Comparisons and Sample Flow 
Comparisons for each of the parameters discussed below could occur between: 
• 
treatment and placebo groups, 
• 
on-treatment and baseline time points for each subject, and  
• 
subjects with tolerant versus desensitized versus allergic clinical outcomes. 
7.2.2 Serum and Mucosal Assays in Order of Priority 
Serum and mucosal assays 
Assay l 
Volume needed for each sample collection 
Specific IgE, IgG4, IgA anti-
peanut and component-resolved 
diagnostics (most likely IgE and 
IgG4 anti-Ara h 1, 2, 3, 6 and 8) 
1 mL 
Facilitated Antigen Binding assay 
1.5 mL 
Epitope Array Peanut 
0.350 mL 

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Salivary IgA and stool samples 
~ 0.5 mL saliva collected by suction and < 5g of stool 
 
Explanation of Serum and Mucosal Assays: 
Plasma immunoglobulin assays: IgE, IgG, IgA, and IgG4 anti-peanut will be measured at baseline 
and longitudinally on an ImmunoCAP™ instrument (Phadia) or equivalent.  
Component-resolved assays: Phadia’s ImmunoCAP™ peanut component tests for quantification of  
serum IgE and IgG4 against specific peanut allergens, such as Ara h 1, 2, 3, 6, and 8 and may be used 
to evaluate changes in specific reactivity over time and between groups.  
Epitope arrays: Epitope-specific IgE and IgG4 in the plasma may be measured for Ara h 1, 2, and 3, 
as previously described.27,38  The arrays include 20-mer peptides offset by 3 amino acids, and cover 
the entire sequence of these 3 major peanut allergens. Note that this approach does not measure 
conformational epitopes. 
Facilitated antigen binding (FAB) assay: The FAB assay uses FACS to measure serum inhibitory 
activity for IgE-facilitated CD23-dependent allergen binding to B cells. Increases in allergen-specific 
IgG are accompanied by elevations in IgG-associated serum inhibitory activity for IgE-facilitated 
binding of allergen-IgE complexes to B cells (IgE-FAB). We hypothesize that persistent increases in 
serum inhibitory activity for IgE-FAB correlate with desensitization and tolerance. Longitudinal 
serum samples from the current trial will be assessed for inhibitory activity as a functional measure of 
blocking antibodies in plasma potentially induced by peanut OIT. 
Serum, stools, and saliva assays: Saliva and stool samples will be collected at baseline and then, as 
specified in the SOE, stored at -80ºC. Peanut-specific secretory IgA (s-IgA) could be measured in 
saliva samples via ELISA assays. DNA may be extracted from stool samples for microbiome 
analysis.  
 
Expected results for serum and mucosal assays according to clinical status 
Parameter 
On Therapy 
Tolerance 
Desensitization 
Refractory 
Specific IgE 
and specific IgG4 
Progressive 
decrease in specific 
IgE to peanut and 
increase in specific 
IgG4 
Low specific IgE 
and increased IgG4 
which persists 
during the 26-week 
period of avoidance 
Low specific IgE 
and increased IgG4 
which reverses 
during the 26-week 
period of avoidance 
No change in 
specific IgG4 
Epitope array  for 
IgE for peanut 
peptides—
predictive marker 
for outcome 
Progressive 
inhibitory 
antibodies detected 
in epitope array 
Lowest epitope 
spreading at 
baseline predicts 
tolerance 
Intermediate epitope 
spreading at baseline 
predicts 
desensitization 
Highest epitope 
spreading at 
baseline predicts 
refractory outcome 
Specific IgA 
Progressive 
increases in specific 
IgA over time 
Increased specific 
IgA which persists 
during the 26-week 
period of avoidance 
Intermediate levels 
of specific IgA 
which persists during 
the 26-week period 
of avoidance 
No change 
7.2.3 Cellular Assays 
Blood will be collected throughout the study as specified in the SOE and sent to a core laboratory for 
PBMC preparation. We expect 10 mL of blood from children in this study to yield approximately 20 
million PBMCs. These cells will be used as described below and will be available for future studies 
such as B reg, TCR sequencing and functional studies when remaining cells numbers are sufficient to 

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make these assays technically feasible. Blood will also be shipped fresh for the basophil activation 
assays. 
DNA-HLA Genotypes: MHC tetramers bind to the T-cell receptor in an HLA-specific context. 
Therefore, DNA will be isolated from participants’ buccal mucosa to perform sequence-based HLA 
typing, so that appropriate candidates can be identified for tetramer analysis as described below. 
Tetramer reagents for peanut have been focused on the HLA class II molecules DRB1 and DRB3. 
However, we will type DQ and DP as well as DR alleles in the event that new data suggests that those 
alleles are also important. 
Tetramer Assays: We anticipate that tetramer assays will be done in collaboration with Dr. W. 
Kwok at the Benaroya Institute in Seattle. Dr. Kwok has generated tetramer reagents for Ara h 1 
restricted by 8 HLA class II alleles and successfully used these reagents to examine the frequency and 
phenotype of peanut-specific CD4+ T cells in individuals with and without peanut allergy36. These 
reagents have been successfully used to stain previously frozen PBMCs. The ability to use these 
reagents will depend on the overlap between HLA alleles among study participants and available 
reagents. These and similar reagents can be used to track changes in frequency of CD4+ T cells in 
response to therapy. For optimum use, these assays require 20 million viable cells per assay, so it is 
important that every effort is made to collect the full planned blood volumes at the time points 
specified the SOE. 
Th2A Subset Analysis. We may also use surface flow cytometry to determine the frequency of Th2A 
cells36 as this subset of Th2 cells may be a biomarker for allergy. This assay has the advantage that it 
can be reliably performed with only one million previously frozen, viable PBMCs. Work by 
Wambre36 suggests that this subset includes the vast majority of allergen-specific CD4+ T cells as 
determined by tetramer analysis. 
Basophil Activation Assays: Ocmant et al.39 reported that after in vitro peanut challenge, the 
basophils from peanut-allergic children showed significantly higher levels of activation than those 
from controls. Positive SPTs for food allergens and specific IgE in serum indicate sensitization but do 
not enable the distinction between sensitized but tolerant and clinically allergic patients. Therefore, 
measuring basophil activation should improve discrimination between allergic and non-allergic 
individuals. 
We have demonstrated that the flow cytometry-based basophil activation test (BAT) works well on 
blood up to 24 hours post-collection. Approximately 200 µL of blood (from finger prick or blood 
draw) in potassium/EDTA will be collected. To minimize variation all BAT assays will be performed 
by the laboratory of Dr. Kari Nadeau. The 200 µL aliquots of fresh whole blood will be stimulated for 
20 minutes with peanut protein extract (containing all major allergens) as well as glycerin and 
polyclonal-IgE as negative and positive controls respectively. Cells will be stained and flow 
cytometry used to assess activation status. Basophils will be defined as CD123+ HLA-DR- and 
activation status defined as a percentage of basophils that are CD63 and/or CD203c positive. 
Expected results for basophil activation according to clinical status 
Parameter 
On Therapy 
Tolerance 
Desensitization 
Refractory 
CD203c/CD63 
During course of therapy, there 
will be a decrease in basophil 
reactivity sooner than lowering 
of specific IgE 
Lack of basophil 
reactivity to peanut 
stimulation persists after 
26 weeks avoidance 
Basophil reactivity 
returns during the 
26 week avoidance 
No change in 
basophil 
reactivity 
 

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Additional Flow Cytometry Assays may be done using banked PBMC samples. For example: 
Treg quantification and functional cytokine intracellular measurements: We have shown an 
increase in CD4+ CD25hi FoxP3+ Tregs after 12 months of peanut OIT. We hypothesize that an 
increase in Treg number and intracellular suppressive cytokines will occur in subjects on OIT and that 
this phenotype will persist for those who exhibit tolerance. 
T cell immunoprofiling: Teff cell immunoprofiling may be carried out to determine if parallel 
mechanisms of anergy, exhaustion or deletion are occurring in the peanut-specific Teff cell subset. 
Live/dead (for deletion evaluation) and apoptosis marker staining can occur in parallel with 
phenotyping for tetramer-positive, CD45RO+, Ki67+, IL-2 dependency (for exhaustion vs. anergy 
evaluation), Th1, Th2, Th9 and Th17 phenotypes of Teff cells. We expect to see Teff cell anergy and a 
transition to Th1 subtypes during the course of successful oral immunotherapy. 
Other immune cells: Through high throughput multiplex immunoprofiling, we will be able to 
determine absolute counts of subsets of other immune cells such as dendritic cells, natural killer T 
cells, and others.  
 

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Expected results for cellular assays according to clinical status 
Parameter 
On Therapy 
Tolerance 
Desensitization 
Refractory 
Th2 
Progressive decrease in 
Th2 absolute numbers 
and ICS transcription 
factors and Th2 
cytokines 
Low Th2 cell numbers 
and decreased ability to 
proliferate in response 
to peanut which persists 
despite the 26 week 
period of abstinence 
Low Th2 cells and 
low ability to 
proliferate in 
response to peanut 
which does not 
persist within the 26 
week period of 
abstinence 
No change 
(compared to 
placebo or to 
baseline) 
Th1 
Progressive increase in 
Th1 absolute numbers 
and ICS transcription 
factors and Th1 
cytokines 
HighTh1 cell numbers 
and increased ability to 
proliferate in response 
to peanut which persists 
despite the 26 week 
period of abstinence 
High Th1 cell 
numbers and ability 
to proliferate in 
response to peanut 
which does not 
persist within the 26 
week period of 
abstinence 
No change (ibid) 
Th17 
Do not expect change 
Do not expect change 
Do not expect 
change 
Do not expect 
change (ibid) 
Treg 
Progressive increase in 
absolute counts of Treg 
but then decline by 12 
months. 
High Treg cell numbers 
and decreased ability to 
proliferate in response 
to peanut which persists 
despite the 26 week 
period of abstinence 
Intermediate Treg 
cell numbers and 
decreased ability to 
proliferate in 
response to peanut 
which does not 
persist within the 26 
week period of 
abstinence 
No change  (ibid) 
NKT 
Progressive increase in 
absolute counts of NKT 
cells 
High NKT cell numbers 
associated with 
tolerance 
Intermediate NKT 
cell numbers 
associated with 
desensitization 
No change (ibid) 
DC 
Progressive decrease of 
TSLP receptor in 
mDCs, progressive 
increase in CD103 and 
CCR9 in DCs 
Low TSLP receptor 
expression in mDCs, 
High DC expression of 
CD103 and CCR9  
Intermediate TSLP 
receptor expression 
in mDCs and 
intermediate DC 
expression of CD103 
and CCR9 
No change (ibid) 
Cell death 
markers 
Progressive increase in 
cell death of allergen-
specific Th2 memory 
cells 
Highest cell death of 
allergen-specific Th2 
memory cells 
Intermediate cell 
death of allergen-
specific Th2 memory 
cells 
No change (ibid) 
Chemokine 
receptors 
Progressive increase in 
CCR4 and CCR8 in 
Treg 
Highest expression of 
CCR4 and CCR8 in 
Treg 
Intermediate 
expression of CCR4 
and CCR8 in Treg 
No change (ibid) 
7.2.4 Confirmation of Peanut Avoidance 
One of the secondary objectives of this trial is to determine whether 134 weeks of peanut OIT induces 
tolerance in children with peanut allergy. To assess this, participants will be evaluated for tolerance to 
peanut after 26 weeks of avoidance. To obtain corroborations that participants truly avoided peanut 
we may perform studies on serum IgG4 levels or measure peanut protein levels in participant bed 
linens. This latter assay has been pioneered by the laboratory of Dr. Gideon Lack and is based on the 
assumption that a person who consumes high levels of peanut-containing foods will have high levels 
of peanut in dust collected from their bed-sheets. Dr. Lack has validated a polyclonal ELISA to detect 
peanut antigens in bed-dust and has demonstrated that persons who report peanut consumption have a 
significant increase in peanut in their bed-sheet dust on the following day. The Lack group has 
reported a high level of correlation between peanut consumption measured by a validated peanut food 

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frequency questionnaire and peanut in bed-sheet dust (r=0.732, p<0.001). They additionally 
demonstrated that the peanut in dust is biologically active and is capable of basophil activation in 
peanut-allergic patients. 
7.2.5 Retention of Samples 
A major priority of the Immune Tolerance Network, in partnership with the National Institute of 
Allergy and Infectious Diseases of the NIH, USA, is the development of novel immunoassays in 
order to better understand mechanisms of tolerance and to develop biomarkers to predict the 
development and maintenance of clinical tolerance. As in all Immune Tolerance Network-funded 
clinical trials, informed consent will be obtained from all participants for their samples to be stored 
for use in future studies. Biological specimens collected in this trial will be stored long-term in order 
to re-evaluate biologic responses as new research tools to study tolerance become available. The 
specimens will therefore be stored at the ITN sample repository for a minimum of 10 years. Residual 
specimens may be used by the investigators for development of new immunologic assays or for cross-
trial comparisons. Although specimens in this protocol are described in the context of assays to be 
performed, it should be noted that not necessarily all assays will be performed for all participants at 
each time point. Decisions to perform assays will be made based on statistical and scientific planning, 
hypotheses to be tested, and technologies available. Finally, clinical outcomes will be taken into 
account to determine the potential value of the assays. For example, if a clinical effect fails to occur, 
it may be decided that there is minimal value in performing certain mechanistic assays. 
8. 
ADVERSE EVENTS 
8.1 
OVERVIEW 
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 8.2.1 
and 8.2.2. 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 about withdrawing any participant and/or terminating the study 
because of safety concerns. 
Adverse events that are classified as serious according to the definition of FDA must be reported 
promptly and appropriately to the DAIT/NIAID Medical Monitor, Protocol Chair or co-Chair, the 
ITN Clinical Trial Physician, IRBs, and FDA. This section defines the types of AEs and outlines the 
procedures for appropriately collecting, grading, recording, and reporting them. 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, 4.03 (June 14, 2010). This document is referred to herein as 
the “NCI - CTCAE Manual.” 
8.2 
DEFINITIONS 
8.2.1 Adverse Event 
An AE is any occurrence or worsening of an undesirable or unintended sign, symptom, laboratory 
finding, or disease that occurs during participation in the trial. An AE will be followed until it 
resolves or until 30 days after a participant terminates from the study, whichever comes first. All AEs 

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will be reported as specified in Sections 8.3 and 8.5 whether they are or are not related to disease 
progression or study participation. 
8.2.2 Study Specific Adverse Events 
During the study it is anticipated that participants undergoing study procedures involving 
administration of peanut flour (blinded OFC, IDE, home or clinic OIT/placebo dosing) will 
experience allergic symptoms related to peanut allergy. Events related to these study procedures will 
be captured on procedure-specific forms, and will NOT be recorded as adverse events, unless they 
meet certain criteria as defined in Section 8.3.2.2. 
8.2.3 Suspected Adverse Reaction and Adverse Reaction  
Suspected adverse reaction (SAR) means any adverse event for which there is a reasonable possibility 
that the study 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)). 
An adverse reaction (AR) means any adverse event caused by a study drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. 
8.2.4 Serious Adverse Event  
An AE or SAR is considered “serious” if, in the view of either the investigator or DAIT/NIAID it 
results in any of the following outcomes (21 CFR 312.32(a)): 
• 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. 
• A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either 
the investigator or DAIT/NIAID, 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.  
• Inpatient hospitalization or prolongation of existing hospitalization. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• An event that requires intervention to prevent permanent impairment or damage. 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. 
• Congenital anomaly or birth defect. 
8.2.5 “Expected” versus Unexpected Suspected Adverse Reaction 
A suspected adverse reaction (SAR) is considered “expected” when it is listed in the General 
Investigational Plan of the IND or the protocol. A suspected adverse reaction is considered 
“unexpected” when the specificity or severity is not consistent with the risk information described in 

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the safety section provided in the General Investigational Plan of the IND or the protocol (21 CFR 
312.32(a)). A suspected unexpected serious adverse reaction is referred to as a SUSAR. 
8.3 
COLLECTING AND RECORDING ADVERSE EVENTS 
8.3.1 Methods of Collection 
Adverse events, as defined by this protocol, will be collected from the time the participant signs the 
informed consent until the time an event is resolved or until 30 days after the participant completes 
study treatment, whichever comes first.  
Adverse events may be collected as follows: 
• Observing the participant. 
• Questioning the participant in an objective manner. 
• Receiving an unsolicited complaint from the participant. 
An AE that is an asymptomatic abnormal value or result from a clinical or laboratory evaluation (e.g., 
a radiograph, an ultrasound, or an electrocardiogram) will be documented and maintained in the 
source records. Asymptomatic adverse events must be recorded on the AE CRF when they meet the 
criteria for a Grade 3 or greater AE per CTCAE criteria. The evaluation that produced the value or 
result should be repeated until that value or result returns to normal or can be explained and the 
participant’s safety is not at risk. 
8.3.2 Methods of Recording 
8.3.2.1 
Adverse Events 
Throughout the study, the investigator will record all AEs, as defined by the protocol, on the 
appropriate CRF regardless of their severity or relation to study participation. The investigator will 
treat participants experiencing AEs appropriately and observe them at suitable intervals until their 
symptoms resolve or their status stabilizes. 
8.3.2.2 
Adverse Events Occurring During Peanut Flour / Placebo Administration 
Guidelines for recording events that occur during investigational product or placebo administration, 
which include blinded OFC, IDE and daily home and clinic dosing: 
All symptoms or events that occur within two hours and that are expected according to the General 
Investigational Plan and related to administration of investigational product or placebo will be 
recorded on the dosing-specific CRFs for blinded OFC, IDE, home or clinic dosing. They will be 
graded according to table 3 (Section 8.4).  
Any of the following symptoms or events that occur at any time related to dosing, should also be 
recorded as an adverse event: 
• 
hypotension  
• 
cyanosis 
• 
SpO2< 92% 
• 
confusion 
• 
collapse 
• 
loss of consciousness 

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• 
incontinence 
• 
required more than 2 injections of epinephrine 
Any such symptom or event that meets the serious criteria in Section 8.2.4 will also be reported as an 
SAE. 
Any symptom or event that occurs more than two hours after dosing will be recorded as an adverse 
event. 
Any symptom or event that is not expected according to the General Investigational Plan will be 
recorded as an adverse event. 
8.3.2.3 
Serious Adverse Events Related to Peanut Flour / Placebo Administration 
If systemic allergic reactions, anaphylaxis, and Eosinophilic Esophagitis meet the criteria for Serious 
Adverse Event, as defined in Section 8.2.4, they will be recorded on the SAE CRF within 24 hours 
and the FDA will be notified as outlined in Section 8.5.  
An SAE notification will be sent by Rho Safety within 24 hours to the DAIT/NIAID Medical 
Monitor, the Protocol Chair or co-Chair, and the ITN Clinical Trial Physician. Together the 
DAIT/NIAID Medical Monitor, the Protocol Chair or co-Chair, and the ITN Clinical Trial Physician 
will determine whether the SAE meets expedited reporting criteria and if stopping rules (Section 
3.4.1) have been met. 
8.4 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS 
8.4.1 Grading Criteria 
8.4.1.1 
Adverse Events Related to Study Procedures 
Symptoms associated with systemic allergic reactions and/or anaphylaxis that occur during 
administration of peanut flour or placebo will be graded according to Table 3 below.  
All AEs will be collected and recorded in the source documents from visit -1 until the time the 
participant completes the study (visit 27), or prematurely withdraws from the study. Table 3 was 
adapted from the grading of allergic reactions in the Consortium of Food Allergy Research (CoFAR3) 
protocol, entitled “Oral Desensitization to Egg with Subsequent Induction of Tolerance for Egg-
Allergic Children”. CoFAR3 protocol is conducted under the IND #13239 sponsored by the 
DAIT/NIAID. This completed study assessed the oral desensitization to egg and induction of 
tolerance in egg-allergic children between the ages of 5 and 18 years (ClinicalTrials.gov Identifier: 
NCT00461097). 
 Table 3 Grading of Symptoms and Events Related to Peanut Flour Administration 
Grade 
1 
 
(Mild) 
2 
(Moderate) 
3 
(Severe) 
4 
(Life threatening) 
General 
Transient or mild 
discomforts (< 48 
hours) 
Symptoms that 
produce mild to 
moderate limitation in 
activity some 
assistance may be 
needed 
Marked limitation in 
activity, some 
assistance usually 
required 
 
Medical intervention; 
hospitalization is 
possible 
 
 
Extreme limitation in 
activity, significant 
assistance required;  
 
Intervention is 
required; 
hospitalization is 
probable 

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Cardio-vascular  
 
Level of 
conscious-ness 
 
 
Hypotension  
 
Change in mental 
status  
 
Persistent hypotension 
and/or hypoxia with 
resultant decreased 
level of consciousness 
associated with 
collapse and/or 
incontinence or other 
life threatening  
symptoms.  
Skin 
Skin flushing or 
pruritus, limited 
localized hives, 
swelling or rash 
Persistent systemic 
hives, swelling 
 
 
Respiratory 
Transient symptoms 
such as rhinorrhea, 
sneezing, nasal 
congestion, throat 
discomfort, and 
occasional cough 
Wheezing without 
dyspnea,  
persistent cough 
 
Bronchospasm, 
wheezing with 
dyspnea 
 
Laryngeal edema  
Throat tightness with 
hoarseness 
 
Gastro-
intestinal 
Abdominal discomfort, 
minor episode of 
vomiting 
Persistent moderate 
abdominal pain, 
cramping, nausea 
 
Increased vomiting or 
other symptoms such 
as throat tightness 
without vomiting 
Significant 
abdominal pain, 
cramping 
 
Repetitive vomiting 
 
 
Adverse events related to study procedures other than peanut flour / placebo administration, will be 
graded according to the criteria set forth in the National Cancer Institute, Common Terminology 
Criteria for Adverse Events, Version 4.03 (June 14, 2010)  and documented on an Adverse Event 
form. 
8.4.1.2 
All Other Adverse Events 
Adverse events not associated with study procedures will be graded according to the criteria set forth 
in the NCI-CTCAE National Cancer Institute’s Common Terminology Criteria for Adverse Events (v 
4.03) manual which provides a common language to describe levels of severity, to analyze and 
interpret data, and to articulate the clinical significance of all AEs. 
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-
CTCAE manual: 
• Grade 1 = mild adverse event 
• Grade 2 = moderate adverse event 
• Grade 3 = severe and undesirable adverse eventgra 
• Grade 4 = life-threatening or disabling adverse event 
• Grade 5 = death 
For additional information and a printable version of the NCI-CTCAE manual, go 
to http://ctep.cancer.gov/reporting/ctc.html   

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8.4.2 Attribution Definitions 
The site investigator will make the initial determination of the relation, or attribution, of an AE to 
study drug and will record the initial determination on the appropriate CRF and/or SAE reporting 
form. The relation of an AE to study drug will be determined using definitions in Table 4. Final 
determination of attribution for safety reporting will be decided by DAIT, NIAID.  
Table 4 Attribution of Adverse Events 
8.5 
REPORTING SERIOUS ADVERSE EVENTS 
8.5.1 Reporting SAEs to the IND Sponsor  
The following process for reporting an SAE ensures compliance with 21CFR 312 and ICH 
guidelines. After learning that a participant has experienced an SAE, the investigator or designee will 
report the SAE to the DAIT/NIAID, the IND sponsor for this protocol, via the electronic SAE report 
form (SAE CRF) within 24 hours of becoming aware of the event. The initial SAE CRF should 
include as much information as possible, but at a minimum must include the following: 
• AE term 
• Study drug treatment 
• Relationship to study medications 
• Reason why the event is serious 
• Supplementary CRF pages that must be current at the time of SAE reporting: medical history, 
concomitant medications, demographics, study drug administration, death.  
As additional details become available, the SAE CRF should be updated and submitted. Every time 
the SAE CRF is submitted, it should be electronically signed by the investigator or sub investigator.  
Code 
Descriptor 
Definition 
Unrelated Category  
1 
Unrelated 
The adverse event is clearly not related. 
Related Categories 
2 
Possible 
The adverse event has a reasonable possibility to be related; there is 
evidence to suggest a causal relationship. 
3 
Probable 
The adverse event is likely related. 
4 
Definite 
The adverse event is clearly related. 

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For additional information regarding SAE reporting, contact Rho Product Safety: 
Rho Product Safety  
6330 Quadrangle Drive, Suite 500 
Chapel Hill, NC  27517 
Toll-free (888) 746-7231 
SAE Fax Line: 1-888-746-3293 
Email: rho_productsafety@rhoworld.com 
8.5.2 Reporting SAEs to Health Authorities 
After the SAE has been reported by the site investigator and assessed by the IND sponsor 
(DAIT/NIAID Medical Monitor, and the DAIT/NIAID Office of Regulatory Affairs), the IND 
sponsor, must report the event to the FDA 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:  
o Serious, expected, suspected adverse reactions described in Sections 8.2.1, 8.2.4, and 8.2.5. 
o Serious and not a suspected adverse reaction described in Sections 8.2.1, 8.2.4, and 8.2.5. 
• 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 Sections 8.2.1, 8.2.4, 
and 8.2.5. 
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. (e.g., angioedema, hepatic injury, or Stevens-Johnson Syndrome); 
• 
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 (e.g., tendon 
rupture); 
o An aggregate analysis of specific 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 submitted by DAIT/NIAID to the FDA within 15 calendar days; fatal or 
immediately life-threatening, serious, unexpected, suspected adverse reactions must be reported 
within 7 calendar days.  
All site investigators must report SAEs to their respective IRBs as mandated by them. 

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8.5.3 Reporting SAEs to the DSMB 
The DAIT/NIAID will provide the DSMB with data of all SAEs on an ongoing basis as determined 
by the DAIT/NIAID Medical Monitor, including expedited reporting of SAEs that are also reported to 
the FDA (see Section 8.5.2), and annual safety reviews of all SAEs and as indicated in Section 3.4.1. 
8.5.4 Reporting SAEs to IRB/EC 
The DAIT/NIAID will notify all investigators of AE information. The investigator will ensure the 
timely dissemination of all AE information, including expedited reports, to the IRB/EC in accordance 
with all applicable regulations. All site investigators must report SAEs to their respective IRBs as 
mandated by their local IRB. 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
9.1 
ANALYSIS SAMPLES 
• 
Intent-to-treat (ITT) sample: All subjects who are randomly assigned to treatment or placebo will 
comprise the ITT sample.  
• 
Per-protocol sample for the primary endpoint: All ITT subjects who are also study-compliant 
through the maintenance phase and have an evaluable blinded OFC at the end of the maintenance 
phase. Compliance is defined as completion of the maintenance phase as described in Section 
6.7.4; than 3 occasions on which more than 3 consecutive home doses of study medication were 
missed; and less than 3 non-protocol specified ingestions of peanut-containing food within a year. 
• 
Per-protocol sample for the secondary endpoint: All participants included in the per protocol 
sample for the primary endpoint who are compliant with peanut avoidance during the avoidance 
phase and have an evaluable blinded OFC at the end of the avoidance phase. Compliance is 
defined as completion of the avoidance phase as described in Section 6.7.5 and less than 3 non-
protocol specified ingestions of peanut-containing food within a year. 
• 
 As-treated sample: All evaluable subjects, analyzed according to the amount of peanut therapy 
received, regardless of their randomized assignment.  
• 
Safety sample: All enrolled subjects who receive at least one dose of OIT or placebo. Participants 
in the safety sample will be analyzed according to the treatment they actually received, regardless 
of their randomized assignment. 
9.2 
ANALYSIS OF ENDPOINTS 
9.2.1 Overview 
Analysis of study data will be conducted to address all objectives of the trial and other 
interrelationships among all data elements of interest to the investigators and of relevance to the 
objectives of the study. Analyses of the primary and secondary endpoints will be conducted using the 
ITT sample described above. Additional analyses using the per-protocol and as-treated samples will 
serve to complement the main analysis by providing more homogeneous samples with respect to 
actual peanut consumption and allowing a close examination of the efficacy and mechanistic 
characteristics of peanut OIT. Subgroup and sensitivity analyses of primary interest will be specified 
a priori and in detail within the statistical analysis plan (SAP). All statistical tests will be two-sided at 
the alpha = 0.05 level of significance. 

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9.2.2 Primary Endpoint 
The primary endpoint is the proportion of participants desensitized to peanut after 134 weeks OIT. 
The definition of desensitization is in Section 3.3.1. Any randomized subject without an evaluable 
blinded OFC will be considered a treatment failure. The proportion of participants desensitized to 
peanut will be compared between arms using a multivariate logistic regression model with site, 
peanut specific IgE, and age as covariates in the model. 
In a secondary analysis, the interaction between each covariate and the treatment effect will be 
investigated. If no interaction is present, only the main effects and adjusted proportions and 
confidence intervals will be reported. Unadjusted proportions and odds ratios will also be presented 
with confidence intervals. All statistical analyses will be performed on each study sample specified in 
Section 9.1.  
9.2.3 Secondary Endpoints 
9.2.3.1 
 Efficacy 
1. Tolerance Endpoint 
 
This is the proportion of participants who pass the blinded OFC to 10 g peanut flour (5 g peanut 
protein) at week 160.  
 
The comparison of tolerance between the two randomized groups will be performed using a 
multivariate logistic regression model. The statistical methods specified for the primary endpoint 
in Section 9.2.1 and 9.2.2 will also be used for this endpoint. 
2. Transient Desensitization Endpoint 
 
This is the change in proportion of participants who pass the blinded OFC to 10 g peanut flour (5 
gram peanut protein) at week 134 and 160. This matched, pre/post peanut avoidance comparison 
allows for the exploration of mechanistic and immunologic differences between children who 
appear to be transiently desensitized compared to those who appear to be tolerant after 26 weeks 
of avoidance. If there is a statistically significant increase in the rate of peanut allergy from weeks 
134 and 160, this will be interpreted as evidence of transient desensitization. This within-group, 
paired comparison of proportions will be performed using a McNemar’s test at a 0.05 level of 
significance within the treatment arms of both the ITT and PP analysis samples.  
3. Highest Tolerated Cumulative Dose Endpoint 
The highest tolerated dose of peanut protein during each blinded OFC will be analyzed within 
and between both placebo and peanut OIT groups. This will allow the investigation of 
desensitization at 134 weeks, tolerance at 160 weeks, and possible changes between week 134 
and week 160. Each of these analyses will be performed in a similar manner as all other endpoint 
analyses. However, instead of a binary (pass or fail) blinded OFC outcome, the highest dose of 
peanut protein tolerated for each subject will be analyzed as a continuous outcome. Depending on 
the distribution of the data, parametric or non-parametric statistical methods may be performed. 
For example, a multivariate linear model could be used to test for desensitization at 134 weeks 
and tolerance at 160 weeks. A paired t-test could be used to test transient desensitization between 
134 weeks and 160 weeks within the peanut OIT or placebo groups. 
9.2.3.2 
Safety 
Safety will be analyzed through the reporting of AEs. All AEs will be classified by body system and 
preferred term according to MedDRA dictionary. The severity of AEs will be classified using the 

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specific grading scale for allergic reactions associated with study procedures related to administration 
of peanut flour or placebo which was adapted from the CoFAR3 protocol (DAIT/NIAID IND # 
13239). The NCI-CTCAE toxicity scale will be used for all other AEs. The total number of events 
and the number of participants experiencing AEs will be summarized by body system and preferred 
term for each treatment group and overall. Separate summaries will be provided for serious AEs, 
treatment-related AEs, and AEs leading to study discontinuation. Abnormal vital signs, physical 
examination results, and laboratory values that the investigator deems clinically significant will be 
graded according to the NCI-CTCAE toxicity scale and reported as AEs. Rates of withdrawal from 
therapy will be compared in the ITT, per protocol and safety samples. 
9.2.3.3 
Mechanistic 
The mechanistic analyses of endpoints described in Section 7 will be performed using a wide range of 
statistical methodologies. Generally, all statistical tests will be two-sided at the alpha = 0.05 level of 
significance. Normality can be assessed by a combination of methods including graphical analysis 
(e.g. normal probability plots, histograms, and quantile-quantile plots) and formal hypothesis tests 
(e.g. Kolmogorov-Simirnov test and Shapiro-Wilk test). Depending on the distributions of the data, 
parametric or non-parametric statistical methods may be performed. Transformation methods may 
also be used prior to fitting models where the normality assumption is required. 
T-tests (both paired and two-sample tests), ANOVA, and ANCOVA models can be used to compare 
mean values among groups of interest and across multiple time points. Pearson correlations 
coefficients can be used to compare continuous measurements when data are considered to be 
normally distributed. Analogous non-parametric methods such as the Wilcoxon Signed Rank Test, 
Mann-Whitney U Test, the Kruskal-Wallis Test, and Spearman’s rank correlation coefficient can be 
used if the data are considered non-normal.  
9.2.4 Missing Data 
Dropout in this study is anticipated to be ≤15% and equally distributed between the randomized 
groups. The main ITT analysis requires that missing data be imputed. As noted in Section 9.2.2, any 
randomized subject without an evaluable blinded OFC will be considered a treatment failure. Thus, 
up to about 15% of subjects could have results imputed and therefore be designated as not 
desensitized and not tolerant. 
If missing data are not equally distributed between groups, biases can be created. For example, if a 
significantly greater proportion of dropout occurs in the treatment arm, this arm will have a larger 
proportion of imputed treatment failures than the placebo arm. This imbalance could tend to 
underestimate a treatment effect. Conversely, if a significantly greater proportion of dropout occurs in 
the placebo arm, this could tend to overestimate a treatment effect. 
These opposing hypothetical biases will be investigated by examining the distribution of missing data 
as well as the factors associated with them in blinded and unblinded reviews. 
Optimistic and pessimistic imputation methods and sensitivity analyses data will be used to provide 
upper and lower bounds for potential bias. These will provide a measure of robustness of the 
treatment as it relates to the causes and consequences of missing data. More specific details of the 
imputation methods and sensitivity analyses will be specified in the SAP. Generally, a combination of 
Multiple Imputation methods for missing data will be used including for example: regression, 
propensity scoring, and/or Markov chain Monte Carlo methods. 

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9.2.5 Medical History 
Medical history—including the existence of current signs and symptoms—will be collected for each 
body system. 
9.2.6  Use of Medications 
All medications taken by or administered to study participants beginning 30 days before enrollment 
and continuing throughout the study will be collected. All medications used will be coded according 
to the WHO drug dictionary. The number and percentage of participants receiving prior and 
concomitant medications/therapies will be presented overall and by medication class. 
9.3 
SAMPLE SIZE  
Prior experience indicates that a high proportion of subjects in the group receiving peanut oral 
immunotherapy will achieve desensitization to peanut, whereas only a small proportion of those who 
receive placebo will outgrow their allergy and be considered desensitized. The effect sizes for the 
primary endpoint is thus likely to be large. 
A main aim of this trial, however, is also adequately to assess the secondary endpoint related to 
tolerance. In this case there is more limited prior experience. It is less well-known what proportion of 
the treated group will be considered tolerant when assessed after the avoidance phase, but it is 
certainly less than the proportion that are likely to be desensitized. To assess this endpoint adequately, 
the sample size needs to be larger than it would be for assessment of the primary endpoint alone. 
The drop-out rate in a previous peanut oral immunotherapy trial by Dr. Burks’ group was about 
25%.15 Adverse reactions in this trial were seen mainly during the dose escalation phase. Since then, 
the peanut escalation regimen has been completed over a longer duration. We therefore estimate that 
the overall drop-out rate in the current trial will be 15%. 
Sample size requirements were determined by calculating the total enrollment necessary to provide 
adequate power for the tolerance endpoint, allocating subjects to treatment and placebo arms in a ratio 
of 2:1. The power calculations were performed using a two-sample Pearson Chi-squared test of 
proportions at a two-sided 0.05 level of significance. 
Assumptions: 
• 
For subjects completing study therapy, the proportions in treatment and placebo arms achieving 
desensitization are estimated to be 0.90 and 0.15 respectively. 
• 
For subjects completing study therapy, the proportions in treatment and placebo arms achieving 
tolerance are estimated to be 0.40 and 0.15 respectively. 
• 
Overall dropout proportion, which is the total loss to follow-up, at any time from randomization 
to the 160-week blinded OFC, will be 0.15. 
• 
Under the intent-to-treat principle, subjects who discontinue study participation, but return to 
perform the 134-week or 160-week blinded OFC, will be evaluated as belonging to the arm to 
which they were randomly assigned. 
• 
Subjects who lack evaluable endpoint data will be considered treatment failures; that is, not 
desensitized and not tolerant. 
Combining these assumptions, we compute an as-analyzed expected rate of tolerance in the treatment 
arm of 0.40*(1-0.15) = 0.34, and in the placebo arm of 0.15*(1-0.15) = 0.1275. 

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We similarly compute an as-analyzed expected rate of desensitization in the treatment arm of 
0.90*(1-0.15) = 0.765, and in the placebo arm of 0.15*(1-0.15) = 0.1275. 
To provide 80% power for the tolerance endpoint with these assumptions and calculations requires a 
sample size of 144, which is 96 in the treatment arm and 48 in the placebo arm. A consequence of this 
sample size, combined with a large estimated effect size, is that the power for the primary endpoint is 
greater than 99%. 
9.4 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN 
The principal features of both the study design and the plan for statistical data analysis are outlined in 
this protocol and in the statistical analysis plan (SAP). Any change in these features requires either a 
protocol or an SAP amendment, which is subject to review by the IND Sponsor, DSMB, the study 
sponsor(s), and the FDA. These changes will be described in the final study report as appropriate. 
10. 
ACCESS TO SOURCE DATA/DOCUMENTS 
The investigational sites participating in this study will maintain the highest degree of confidentiality 
permitted for the clinical and research information obtained from participants in this clinical trial. 
Medical and research records should be maintained at each site in the strictest confidence. However, 
as a part of the quality assurance and legal responsibilities of an investigation, the investigational sites 
must permit authorized representatives of the ITN, IND Sponsor, and FDA to examine (and to copy 
when required by applicable law) clinical records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety and progress. Unless required by the laws permitting 
copying of records, only the coded identity associated with documents or other participant data may 
be copied (and any personally identifying information must be obscured). Authorized representatives 
as noted above are bound to maintain the strict confidentiality of medical and research information 
that may be linked to identified individuals. The investigational sites will normally be notified in 
advance of auditing visits. 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The investigator is required to keep accurate records to ensure that the conduct of the study is fully 
documented. The investigator is required to ensure that all CRFs are completed for every participant 
entered in the trial. 
The sponsor is responsible for regular inspection of the conduct of the trial, for verifying adherence to 
the protocol, and for confirming the completeness, consistency, and accuracy of all documented data. 
The CRFs will be completed online via a web-based electronic data capture (EDC) system that has 
been validated and is compliant with Part 11 Title 21 of the Code of Federal Regulations. Study staff 
at the site will enter information into the electronic CRFs, and the data will be stored remotely at a 
central database. Data quality will be ensured through the EDC system’s continuous monitoring of 
data and real-time detection and correction of errors. All elements of data entry (i.e., time, date, 
verbatim text, and the name of the person performing the data entry) will be recorded in an electronic 
audit trail to allow all changes in the database to be monitored and maintained in accordance with 
federal regulations.  

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12. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE 
12.1 
 STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, current Good Clinical Practice (GCP) 
guidelines — adopting the principles of the Declaration of Helsinki — and all applicable regulatory 
requirements. 
Prior to study initiation, the protocol and the informed consent documents will be reviewed and 
approved by the IND Sponsor and an appropriate ethics review committee or institutional review 
board (IRB). Any amendments to the protocol or consent materials must also be approved by the 
Sponsor, the IRB and submitted to FDA before they are implemented. 
12.2 
 INFORMED CONSENT 
The informed consent form is a means of providing information about the trial to a prospective 
participant and allows for an informed decision about participation in the study. All participants (or 
their legally acceptable representative) must read, sign, and date a consent form before participating 
in the study, taking the study drug, and/or undergoing any study-specific procedures. If a participant 
does not speak and read English, the consent materials must be translated into the appropriate 
language. 
The informed consent form must be updated or revised whenever important new safety information is 
available, whenever the protocol is amended, and/or whenever any new information becomes 
available that may affect participation in the trial. 
A copy of the informed consent form will be given to a prospective participant for review. The 
attending physician, or his/her designated study staff member, will review the consent and answer 
questions. The participant will be informed that participation is voluntary and that he/she may 
withdraw from the study at any time, for any reason. 
12.3 
PRIVACY AND CONFIDENTIALITY 
A participant’s privacy and confidentiality will be respected throughout the study. Each participant 
will be assigned a sequential identification number. This number, rather than the participant’s name, 
will be used to collect, store, and report participant information. 
13. 
PUBLICATION POLICY 
The ITN policy on publication of study results will apply to this study. Authorized participants may 
find details regarding the policy statement on the ITN internet website 
at http://www.immunetolerance.org.  
 

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14. 
REFERENCES 
 
1. 
Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of 
life. Pediatrics 1987;79:683-8. 
2. 
Sicherer SH, Muñoz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and 
sesame allergy: 11-year follow-up. J Allergy Clin Immunol 2010;125:1322-6. 
3. 
Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA. The natural history of 
peanut allergy. J Allergy Clin Immunol 2001;107:367-74. 
4. 
Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United 
States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010;126:S1-58. 
5. 
Bollinger ME, Dahlquist LM, Mudd K, Sonntag C, Dillinger L, McKenna K. The impact of food allergy on the 
daily activities of children and their families. Ann Allergy Asthma Immunol 2006;96:415-21. 
6. 
Cohen BL, Noone S, Muñoz-Furlong A, Sicherer SH. Development of a questionnaire to measure quality of life in 
families with a child with food allergy. J Allergy Clin Immunol 2004;114:1159-63. 
7. 
Springston EE, Smith B, Shulruff J, Pongracic J, Holl J, Gupta RS. Variations in quality of life among caregivers 
of food allergic children. Ann Allergy Asthma Immunol 2010;105:287-94. 
8. 
Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy 
with injections of aqueous peanut extract. J Allergy Clin Immunol 1997;99:744-51. 
9. 
Oppenheimer JJ, Nelson HS, Bock SA, Christensen F, Leung DY. Treatment of peanut allergy with rush 
immunotherapy. J Allergy Clin Immunol 1992;90:256-62. 
10. 
Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J 
Med 2003;348:986-93. 
11. 
Li XM, Srivastava K, Grishin A, et al. Persistent protective effect of heat-killed Escherichia coli producing 
"engineered," recombinant peanut proteins in a murine model of peanut allergy. J Allergy Clin Immunol 
2003;112:159-67. 
12. 
Srivastava KD, Kattan JD, Zou ZM, et al. The Chinese herbal medicine formula FAHF-2 completely blocks 
anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol 2005;115:171-8. 
13. 
Blumchen K, Ulbricht H, Staden U, et al. Oral peanut immunotherapy in children with peanut anaphylaxis. J 
Allergy Clin Immunol 2010;126:83-91.e1. 
14. 
Hofmann AM, Scurlock AM, Jones SM, et al. Safety of a peanut oral immunotherapy protocol in children with 
peanut allergy. J Allergy Clin Immunol 2009;124:286-91, 91.e1-6. 
15. 
Jones SM, Pons L, Roberts JL, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J 
Allergy Clin Immunol 2009;124:292-300,  e1-97. 
16. 
Varshney P, Jones SM, Scurlock AM, et al. A randomized controlled study of peanut oral immunotherapy: clinical 
desensitization and modulation of the allergic response. J Allergy Clin Immunol 2011;127:654-60. 
17. 
Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol 
2005;115:3-12; quiz 3. 
18. 
Patriarca G, Nucera E, Roncallo C, et al. Oral desensitizing treatment in food allergy: clinical and immunological 
results. Aliment Pharmacol Ther 2003;17:459-65. 
19. 
Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG. A protocol for oral desensitization in children 
with IgE-mediated cow's milk allergy. Allergy 2004;59:980-7. 
20. 
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs 
Th1 lineage commitment. Cell 2000;100:655-69. 
21. 
Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011;241:260-8. 
22. 
Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4+CD25+ regulatory T cells in children who have 
outgrown cow's milk allergy. J Exp Med 2004;199:1679-88. 
23. 
Shek LP SL, Ahlstedt S, Beyer K, Sampson HA. Determination of food specific IgE levels over time can predict 
the development of tolerance in cow's milk and hen's egg allergy. J Allergy Clin Immunol 2004;114:387-91. 
24. 
Vila L, Beyer K, Järvinen KM, Chatchatee P, Bardina L, Sampson HA. Role of conformational and linear epitopes 
in the achievement of tolerance in cow's milk allergy. Clin Exp Allergy 2001;31:1599-606. 
25. 
Järvinen KM, Beyer K, Vila L, Chatchatee P, Busse PJ, Sampson HA. B-cell epitopes as a screening instrument 
for persistent cow's milk allergy. J Allergy Clin Immunol 2002;110:293-7. 
26. 
Busse PJ, Järvinen KM, Vila L, Beyer K, Sampson HA. Identification of sequential IgE-binding epitopes on 
bovine alpha(s2)-casein in cow's milk allergic patients. Int Arch Allergy Immunol 2002;129:93-6. 
27. 
Flinterman AE, Knol EF, Lencer DA, et al. Peanut epitopes for IgE and IgG4 in peanut-sensitized children in 
relation to severity of peanut allergy. J Allergy Clin Immunol 2008;121:737-43.e10. 

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Peanut OIT in Children 
28. 
Lin J, Bruni FM, Fu Z, et al. A bioinformatics approach to identify patients with symptomatic peanut allergy using 
peptide microarray immunoassay. J Allergy Clin Immunol 2012;129:1321-8.e5. 
29. 
Burks W, Vickery B, Scurlock A, et al. Development of Clinical Tolerance after Peanut OIT. JACI 2012;129:AB 
66. 
30. 
Bock SA, Sampson HA, Atkins FM, et al. Double-blind, placebo-controlled food challenge (DBPCFC) as an 
office procedure: a manual. J Allergy Clin Immunol 1988;82:986-97. 
31. 
Perry TT, Matsui EC, Conover-Walker MK, Wood RA. Risk of oral food challenges. J Allergy Clin Immunol 
2004;114:1164-8. 
32. 
Nowak-Wegrzyn A, Assa'ad AH, Bahna SL, et al. Work Group report: oral food challenge testing. J Allergy Clin 
Immunol 2009;123:S365-83. 
33. 
Aceves SS, Newbury RO, Dohil MA, Bastian JF, Dohil R. A symptom scoring tool for identifying pediatric 
patients with eosinophilic esophagitis and correlating symptoms with inflammation. Ann Allergy Asthma 
Immunol 2009;103:401-6. 
34. 
Flinterman AE, Pasmans SG, den Hartog Jager CF, et al. T cell responses to major peanut allergens in children 
with and without peanut allergy. Clin Exp Allergy 2010;40:590-7. 
35. 
Turcanu V, Maleki SJ, Lack G. Characterization of lymphocyte responses to peanuts in normal children, peanut-
allergic children, and allergic children who acquired tolerance to peanuts. J Clin Invest 2003;111:1065-72. 
36. 
DeLong JH, Simpson KH, Wambre E, James EA, Robinson D, Kwok WW. Ara h 1-reactive T cells in individuals 
with peanut allergy. J Allergy Clin Immunol 2011;127:1211-8.e3. 
37. 
Wambre E, DeLong JH, James EA, LaFond RE, Robinson D, Kwok WW. Differentiation stage determines 
pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J Allergy Clin 
Immunol 2012;129:544-51, 51.e1-7. 
38. 
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;116:893-9. 
39. 
Ocmant A, Mulier S, Hanssens L, et al. Basophil activation tests for the diagnosis of food allergy in children. Clin 
Exp Allergy 2009;39:1234-45. 
40. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of 
anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-7. 
 
 

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Appendix 1. Schedule of Events: Screening, Initial Dose Escalation and Build-up 
Phase of trial 
 
 
IDE3 
Build-up 
Week 
-2 to -1 
0 
0 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 
Day 
-30 to -1 
0 
1 
14 
28 
42 
56 
70 
84 
98 
112 
126 
140 
154 
168 
182 
196 
Visit 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 
GENERAL ASSESSMENTS 
Informed Consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peanut Allergy History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Baseline GI Symptoms 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoing GI Symptoms 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Comprehensive Physical Exam 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Physical Exam 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADMINISTRATION OF STUDY MEDICATION 
Randomization 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial Dose Escalation 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OIT or Placebo 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
DISEASE-SPECIFIC ASSESSMENTS 
Diet and Allergy Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Skin Prick Test1  5 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.5 g Oral Food Challenge 4 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 g Oral Food Challenge4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOCAL LAB ASSESSMENTS 
CBC with differential  
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
 
MECHANISTIC ASSESSMENTS 
IgE to food allergens1 5 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgE to inhalant allergens1 5 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Basophil Activation Assay2 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cellular Assays 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
 
Plasma Assays 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
 
Stool & Saliva Assays 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¹ Please refer to visit windows in Section 6.1. 
2 Venous blood samples drawn at Stanford University will be assayed for basophil activation one day after the blood 
draw for comparison with samples from other sites that are shipped overnight to Stanford University. 
3 IDE:  Initial Dose Escalation (refer to Section 3). 
4 Amounts expressed in peanut protein. 
5   Please see complete list of allergens in Section 6.4.2. 
 

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Appendix 2. Schedule of Events: Maintenance, Avoidance and Post-Challenge (PC) 
Phase of trial 
Maintenance 
Avoidance 
PC 
 
 
Week 
30¹ 43 
56 
69 82 
95 
108 121 
134 
136 160 
16217 
 
 
Day 
210 
301 
392 
483 
574 
665 
756 
847 
938 
952 
1120 
1134 
 
Disco
ntinu
ation 
Visit 
16 
17 
18 
19 20 
21 
22 
23 
24 
25 
26 
27 
Un-
scheduled 
GENERAL ASSESSMENTS 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peanut Allergy History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Baseline GI Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoing GI Symptoms 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Comprehensive Physical  Exam 
 
 
 
 
 
 
x 
 
x 
 
x 
 
 
 
Brief Physical Exam 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
x 
x 
Vital Signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ADMINISTRATION OF STUDY MEDICATION 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial Dose Escalation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OIT or Placebo 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
DISEASE-SPECIFIC ASSESSMENTS 
 
Diet and Allergy Assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Skin Prick Test 5    
x 
 
 
 
x 
 
 
 
x 
 
x 
 
 
 
0.5 g Oral Food Challenge3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 g Oral Food Challenge3 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
Open Food Challenge 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
LOCAL LABORATORY ASSESSMENTS 
 
II:  CBC with differential 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
MECHANISTIC ASSESSMENTS 
 
IgE to food allergens 4 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
x 
IgE to inhalant allergens 4 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
Basophil Activation Assay2 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
 
 
Cellular Assays 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
Plasma Assays 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
Saliva &  Stool Assays 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x5 
x5 
HLA6 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
¹ Please refer to visit windows in Section 6.1. 
2Venous blood samples drawn at Stanford University will be assayed for basophil activation one day after the blood 
draw for comparison with samples from other sites that are shipped overnight to Stanford University. 
3 Amounts expressed in peanut protein. 
4   Please see complete list of allergens in Section6.4.2. 
5   Stool collection only, no saliva on Unscheduled visits or Discontiuation visits. 
6   Buccal swabs 
7 Only participants who tolerate peanut during the OpFC at the end of avoidance will return for Visit 27 
 

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Appendix 3: Anaphylaxis Staging System 
Anaphylaxis is a generalized allergic reaction that is rapid in onset and may progress to 
death.40  
Criteria for Diagnosis 
Anaphylaxis is likely when any one 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.” 
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 and 
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.