Challenging to Food With Escalating Thresholds for Reducing Food Allergy
Phase: PHASE2
Conditions: Food Allergy, Peanut Allergy
Sponsor: Scott Sicherer

Challenging to Food With Escalating Thresholds for Reducing Food Allergy 
Scott H Sicherer, M.D
NCT03907397
Document Date: 11/9/2021

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ASTHMA AND ALLERGIC DISEASES COOPERATIVE RESEARCH CENTERS  
PROTOCOL NUMBER AADCRC-ISMMS-03 
Immune Basis & Clinical Implications of Threshold-Based Phenotypes of Peanut Allergy  
Study Title: ChAllenging to Food with Escalating ThrEsholds for ReducIng Food Allergy (CAFETERIA) 
VERSION NUMBER 3.0/ VERSION DATE November 09, 2021 
NCT 03907397 
Study Sponsor(s): 
 
The National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding Mechanism: U19 AI 136053 
 
 
 
IND Sponsor/Number: Sicherer, 18399 
Study Drug Manufacturer/Provider:NA 
PROTOCOL CHAIR- SCOTT H SICHERER, 
MD 
Professor of Pediatrics  
Chief, Pediatric Allergy 
Icahn School of Medicine at  
Mount Sinai 
Div. of Pediatric Allergy 
One Gustave L. Levy Place, Box 1198 
New York, NY 10029, USA 
Phone: 212-241 5548 
Fax:212-426 1902 
E-mail:scott.sicherer@mssm.edu 
 
NIAID ADVISORY MEDICAL MONITOR-PATRICIA 
C. FULKERSON, MD, PHD 
Medical Officer, Food Allergy, Atopic 
Dermatitis & Allergic Mechanisms 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane 
Bethesda, MD 20892-9828, USA 
Phone: 301-761-6946   
E-mail:patricia.fulkerson@nih.gov  
BIOSTATISTICIAN-MAYTE SUAREZ-
FARINAS, PHD 
Research Professor 
Icahn SOM at Mount Sinai 
1425 Madison Avenue 
Floor 2, L2-70C, Box 1077 
New York, NY 10029, USA 
Phone:212-659-9678 
Fax:212-423-2998 
E-mail: 
mayte.suarezfarinas@mssm.edu 
 
PROTOCOL CO-CHAIR- JULIE WANG, MD 
Professor of Pediatrics  
Icahn School of Medicine at  
Mount Sinai 
Div. of Pediatric Allergy 
One Gustave L. Levy Place, Box 1198 
New York, NY 10029, USA 
Phone: 212-241 5548 
Fax:212-426 1902 
E-mail:julie.wang 
@mssm.edu 
 
PROJECT MANAGER-SUSAN PERRY, RN 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane 
Bethesda, MD 20892-9828, USA 
Phone:  240-669-2865 
E-mail:  susan.perry@nih.gov 
REGULATORY OFFICER-JULIA GOLDSTEIN, MD 
Office of Regulatory Affairs 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and 
Infectious Diseases 
5601 Fishers Lane 
Bethesda, MD 20892-9828, USA 
Phone:  240.669.5369 
E-mail: goldsteinj@niaid.nih.gov 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of the Protocol Chair, or 
the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases of the National Institutes of 
Health. 

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INVESTIGATOR SIGNATURE PAGE 
Protocol:    Immune Basis & Clinical implications of 
Threshold-Based Phenotypes of Peanut Allergy   
Version/Date: 3.0/ 
November 09, 2021 
Site Principal Investigator: Scott H Sicherer, MD  
  
Title:   ChAllenging to Food with Escalating ThrEsholds for ReducIng Food Allergy, 
CAFETERIA  
Study Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID) 
 
INSTRUCTIONS: The Principal Investigator should print, sign, and date at the indicated location below.  
The original should be kept for your records and a copy of the signature page sent to DAIT RMC.   
 
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 United States 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 site 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 the written permission of the 
IRB and NIAID. 
 
____________________________________     
Site Principal Investigator  (Print) 
 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                          Date 

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Protocol Synopsis 
Title 
CHALLENGING TO FOOD WITH ESCALATING THRESHOLDS FOR 
REDUCING FOOD ALLERGY 
Short Title 
CAFETERIA TRIAL 
Clinical Phase 
Phase II – Interventional 
Number of Sites 
Single (Icahn School of Medicine at Mount Sinai, New York, NY) 
 
IND Sponsor/Number   
18399 
Study Objectives 
The primary objective of this study is to determine whether 
allowing ingestion of sub-threshold amounts of peanut in those 
with a high threshold (tolerate at least 143 mg peanut protein on 
supervised double-blind, placebo-controlled oral food challenge 
[DBPCFC]) will be associated with attaining even higher thresholds 
over time in children with high threshold peanut allergy compared 
to those avoiding peanut. The secondary clinical objectives include 
assessing the development of sustained unresponsiveness (SU, a 
surrogate term for tolerance without daily ingestion), effects on 
quality of life, and safety compared to those avoiding peanut.  
Additionally, this study will phenotype the allergic response to 
peanut based on threshold and response to exposure.  Mechanistic 
study objectives will determine the immune and molecular basis of 
the high threshold endotype, identify predictors of response to 
exposure, and determine mechanisms and biomarkers of 
remission.    
Study Design 
Prospective two-arm, parallel-group, randomized (1:1) controlled 
open trial of a diet allowing ingestion of tolerated, home-
purchased, home-measurable quantities of peanut in children 
allergic to peanut in higher amounts.   
Primary Endpoint(s) 
The difference between the treatment and comparison 
(avoidance) groups in the percentage of children who by the 
endpoint DBPCFC tolerate a dose at least 2 steps higher than their 
baseline DBPCFC or 9043 mg of peanut protein. 
Secondary Endpoint(s)  
1. The percentage of children who achieve SU or natural tolerance 
during the study. 
2. Safety parameters (acute allergic reactions, including 
anaphylaxis, gastrointestinal side effects). 
3. Quality of life measures.  
4. Changes in SPT mean wheal size. 
5. Changes in Peanut-specific IgE and IgG4. 

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6. Mechanistic endpoints including change in frequency of peanut-
specific multi-Th2 cytokine effector cells and Tregs, basophil 
activation, peanut epitope binding, identification of a peripheral 
blood-based biomarker of desensitization potential, and 
identification of functional pathways underlying desensitization. 
Accrual Objective 
150-200 children undergoing DBPCFC to peanut to identify 72 with 
high threshold peanut allergy for trial randomization. 
Study Duration 
For each individual participant study participation may take up to 
120 weeks. 
Treatment Description  
Approximately one hundred fifty children with possible peanut 
allergy will undergo DBPCFC challenge to peanut per modified 
PRACTALL guidelines.  Those reactive to 143 mg or less, and those 
tolerant of 5043 mg or more, peanut protein will contribute 
biosamples for mechanistic studies but will not be randomized.  
Trial subjects, tolerating a cumulative DBPCFC dose of 143 mg but 
not 5043 mg peanut protein will be randomized to continue 
avoidance of peanut (comparison group, standard care) or to daily 
ingestion of a home measurable amount of peanut butter 
(intervention group) based upon their oral food challenge 
threshold. For initial home ingestion, store bought peanut butter 
will be used and measured with study-supplied kitchen measuring 
spoons.  Depending upon reaction threshold, participants may 
begin with different starting amounts of peanut butter (e.g., 1/8 
teaspoon [approximately 140 mg peanut protein], ¼  teaspoon, 3/8 
teaspoon, 1 teaspoon).  Depending on preference, when having 
exceeded 3/8 teaspoon of peanut butter, participants may 
substitute specific amounts of other peanut products (Bamba, 
peanut candy, etc.). Every 8 weeks, participants will return for 
attempting to ingest a higher amount of peanut along a ladder of 
1/8 tsp, ¼ tsp, 3/8 tsp, ½ tsp, ¾ tsp, 1 tsp, 1.5 tsp, 2 tsp, 3 tsp.  
A  repeat DBPCFC will be performed 8 weeks after reaching 1 
tablespoon (or equivalent) in the intervention group, or at 72 
weeks. A repeat DBPCFC will be performed in the control group at 
a time point determined by an algorithm matching controls to the 
intervention participants.  Subjects tolerating the full challenge 
amount will add peanut to the diet for 16 weeks and then avoid 
peanut for 8 weeks, followed by a DBPCFC to assess for sustained 
unresponsiveness [SU] (remission during avoidance).    
Inclusion Criteria 
Subject and/or parent guardian must be able to understand and 
provide informed consent. 
Inclusion criteria for screening DBPCFC: Age 4-14 years, either sex, 
any race, any ethnicity who are enrolled while strictly avoiding 
peanut and have a history of sensitization (detectable peanut IgE 
>0.35 kUA/L). 
Inclusion criteria for randomization: On screening DBPCFC are able 
to ingest >= 143 mg peanut protein but < 5043 mg peanut protein.  

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All children will have documented consent and assent as is 
appropriate for age. 
Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for 
enrollment as study participants: 
1. Inability or unwillingness of a participant to give written 
informed consent or comply with study protocol 
2. Serum peanut-specific IgE antibody level > 50  kUA/L   
3. Recent (within the past 2 years) life-threatening (grade 3) 
anaphylactic reaction to peanut. 
4. Any disorder in which epinephrine is contraindicated such as 
known hypertension or cardia rhythm disorders. 
5. History of chronic disease requiring therapy (other than asthma, 
atopic dermatitis, rhinitis). 
6. On a build-up phase of any allergen immunotherapy. 
7. For those with a history of asthma, the following are assessed 
and any of the following is an exclusion (markers of current 
uncontrolled or moderate to severe asthma):   
A. FEV1 value <80% predicted (only for participants age 7 
years or older and are able to perform spirometry)* 
B. ACT or cACT < 20 
C. >Step 3 controller therapy as defined for children 0-4,  5-
11 and >=12 years of age by EPR-3 tables 
D. Use of steroid medications in the following manners:  
a. history of daily oral steroid dosing for >1 month 
during the past year,  
b. having 1 burst or steroid course within the past 6 
months, or  
c. having >1 burst oral steroid course within the past 
12 months.  
E. Asthma requiring >1 hospitalization in the past year for 
asthma or >1 ED visit in the past 6 months for asthma, or 
any prior intubation/mechanical ventilation for 
asthma/wheezing. 
*When COVID related institutional restrictions on 
spirometry are in effect, spirometry will be not performed 
and peak flow will be used with 80% predicted as the cut-
off. 
8. Gastrointestinal 
eosinophilic 
disorders, 
esophagitis, 
gastroenteritis.  
9. Use of short-acting antihistamines (diphenhydramine, etc.) 
more than one time within 3 days prior to DBPCFC or skin 
testing.* 

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10. Use of medium-acting antihistamines (hydroxyzine, loratadine, 
etc.) more than one time within 7 days of DBPCFC or skin 
testing.* 
11. Use of systemic steroid medications (IV, IM or oral) for 
indications other than asthma for > 3 weeks within the past 6 
months 
12. Use of beta-blockers (oral), (ACE) inhibitors, angiotensin-
receptor blockers or calcium channel blockers. 
13. Participation in any trials of therapeutic interventions for food 
allergy in the past year. 
14. Therapy with anti-IgE or other biologics, including within 1 year 
of enrollment.  
15. Use of investigational drugs within 52 weeks of participation. 
16. Allergy to all of the following: oat, rice, corn, tapioca. 
17. Pregnancy 
18. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, 
which, in the opinion of the investigator, may pose additional 
risks from participation in the study, may interfere with the 
participant’s ability to comply with study requirements or that 
may impact the quality or interpretation of the data obtained 
from the study. 
*Any subject meeting these criteria during the visits can be 
rescheduled for the oral food challenge or prick skin testing. 
Study Stopping Rules 
The study will be temporarily suspended pending DSMB review if 
any of the following occurs 
• Any death possibly related to study participation . 
• 2 subjects requiring more than 1 injection of epinephrine for at 
home study-allowed ingestion of peanut. 
• 3 subjects diagnosed with eosinophilic esophagitis  
Participant Stopping Rules 
Participants may be prematurely terminated from the study for the 
following reasons: 
 
The participant elects to withdraw consent form 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. 
 
The participant dies. 
 
The Investigator no longer believes participation is in the best 
interest of the participant. This includes subjects who refuse to 
come for the Desensitization DBPCFC visit.  

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 
Subjects who fail to adhere to the request to stop the study 
intervention per section 6.5 will be considered for premature 
termination. 
 
Pregnancy 
 
Diagnosis of eosinophilic esophagitis   
Premature Discontinuation of 
Investigational Agent 
Study therapy may be prematurely discontinued for any 
participant for any of the following reasons: 
 
Severe (grade 3) anaphylaxis secondary to any DBPCFC or 
ingestion of the measured dose of peanut. 
 
Significant worsening or persistent activation of atopic 
dermatitis, allergic rhinitis or asthma believed to be related to 
participation in the study. 
 
Any subject deemed to have severe allergic and/or GI 
symptoms and receiving aggressive therapy. 
 
Inability or unwillingness to comply with study procedures (re-
education can be provided at the discretion of the PI/Co-I to 
allow continuation) as evidenced by 
o Excessive missed days i.e., > 7 consecutive days missed 
on 3 occasions. 
o failure to report if they have more than mild 
symptoms;  
o do not ingest the designated amount of peanut for 
over 10 consecutive days;  
o attempt to increase amounts without supervision; 
o  or experience symptoms judged by the PI/Co-I to 
warrant withdrawal from ingestion 
 
Study therapy may also be prematurely discontinued for any 
participant if the investigator believes that the study treatment is 
no longer in the best interest of the participant. 
 
 
 
 

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Study Contacts: Core Laboratories 
 
 
 
 
CO-PD/PI 
Cecilia Berin, Ph.D. 
Mount Sinai School of Medicine 
Jaffe Food Allergy Laboratory 
Div. of Pediatric Allergy & Immunology 
One Gustave L. Levy Place, Box 1198 
New York, NY 10029, USA 
Phone: 212-659-8442 
Fax:212-426 1902 
Email: cecilia.berin@mssm.edu 
CO-I 
Supinda Bunyavanich, M.D., M.P.H. 
Mount Sinai School of Medicine 
Jaffe Food Allergy Laboratory 
Div. of Pediatric Allergy & Immunology 
One Gustave L. Levy Place, Box 1198 
New York, NY 10029, USA 
Phone: 212-659-8262 
Fax:212-426 -1902 
Email: 
supinda.bunyavanich@mssm.edu  
CO-I 
Hugh A. Sampson, M.D. 
Mount Sinai School of Medicine 
Jaffe Food Allergy Laboratory 
Div. of Pediatric Allergy & Immunology 
One Gustave L. Levy Place, Box 1198 
New York, NY 10029, USA 
Phone: 212-659-9426 
Fax:212-426-1902 
Email: hugh.sampson@mssm.edu  
 
 
 
 
 
 
 
 
 

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Table of Contents 
Glossary of Abbreviations ..................................................................................................................................................... 13 
Study Definitions Page .......................................................................................................................................................... 14 
1. 
Background and Rationale ............................................................................................................................................ 16 
1.1. 
Background and Scientific Rationale ..................................................................................................................... 16 
1.2. 
Rationale for Selection of Investigational Product or Intervention ...................................................................... 17 
1.3. 
Preclinical Experience ........................................................................................................................................... 19 
1.4. 
Clinical Studies ...................................................................................................................................................... 19 
2. 
Study Hypotheses/Objectives ....................................................................................................................................... 19 
2.1. 
Hypotheses............................................................................................................................................................ 20 
2.2. 
Primary Objective(s) .............................................................................................................................................. 20 
2.3. 
Secondary Objective(s) ......................................................................................................................................... 20 
3. 
Study Design .................................................................................................................................................................. 21 
3.1. 
Description of Study Design .................................................................................................................................. 21 
3.2. 
Primary Endpoint(s)/Outcome(s) .......................................................................................................................... 23 
3.3. 
Secondary Endpoint(s)/Outcome(s) ...................................................................................................................... 24 
3.4. 
Exploratory Endpoint(s)/Outcome(s) ....................................................................... Error! Bookmark not defined. 
3.5. 
Stratification, Randomization, and Blinding/Masking .......................................................................................... 24 
3.5.1. 
Procedure for Unblinding/Unmasking .............................................................................................................. 25 
4. 
Selection of Participants and Clinical Sites/Laboratories.............................................................................................. 25 
4.1. 
Rationale for Study Population ............................................................................................................................. 25 
4.2. 
Inclusion Criteria ................................................................................................................................................... 25 
4.3. 
Exclusion Criteria ................................................................................................................................................... 25 
4.4. 
Selection of Clinical Sites/Labs .............................................................................................................................. 26 
5. 
Known and Potential Risks and Benefits to Participants .............................................................................................. 27 
5.1 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert................. 27 
5.2 
Risks of Investigational Product or Intervention cited in Medical Literature ....................................................... 27 
5.3 
Risks of Other Protocol Specified Medications ..................................................................................................... 28 
5.4 
Risks of Study Procedures ..................................................................................................................................... 28 
5.5 
Potential Benefits .................................................................................................................................................. 29 
6. 
Investigational Agent /Device/Intervention ................................................................................................................. 29 
6.1 
Investigational Agents/Devices/Interventions ...................................................................................................... 29 
6.1.1 
Investigational Agent #1 ............................................................................................................................... 30 

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6.1.1.1 
Formulation, Packaging, and Labeling .......................................................................................................... 30 
6.1.1.2 
Dosage, Preparation, and Administration ..................................................................................................... 30 
6.1.2 
Investigational Agent #2 ................................................................................................................................... 30 
6.1.2.1 
Formulation, Packaging, and Labeling .......................................................................................................... 30 
6.1.2.2 
Dosage, Preparation, and Administration ..................................................................................................... 30 
6.2 
Drug Accountability ............................................................................................................................................... 30 
6.3 
Assessment of Participant Compliance with Investigational Agent ..................................................................... 30 
6.4 
Toxicity Prevention and Management .................................................................................................................. 30 
6.5 
Premature Discontinuation of Investigational Agent ........................................................................................... 30 
7. 
Other Medications ........................................................................................................................................................ 31 
7.1 
Concomitant Medications ..................................................................................................................................... 31 
7.2 
Prophylactic Medications ...................................................................................................................................... 31 
7.3 
Prohibited Medications ......................................................................................................................................... 31 
7.4 
Rescue Medications .............................................................................................................................................. 31 
8. 
Study Procedures .......................................................................................................................................................... 31 
8.1 
Enrollment ............................................................................................................................................................. 31 
8.2 
Screening/Baseline Visit ........................................................................................................................................ 31 
8.3 
Study Visits or Study Assessments ........................................................................................................................ 32 
8.4 
Unscheduled Visits ................................................................................................................................................ 34 
8.5 
Visit Windows ....................................................................................................................................................... 36 
9. 
Mechanistic Assays ....................................................................................................................................................... 38 
10. 
Biospecimen Storage................................................................................................................................................. 38 
11. 
Criteria for Participant and Study Completion and Premature Study Termination.................................................. 39 
11.1 
Participant Completion ......................................................................................................................................... 39 
11.2 
Participant Stopping Rules and Withdrawal Criteria ............................................................................................ 39 
11.3 
Participant Replacement ....................................................................................................................................... 39 
11.4 
Follow-up after Early Study Withdrawal ............................................................................................................... 39 
12. 
Safety Monitoring and Reporting ............................................................................................................................. 40 
12.1 Overview ................................................................................................................................................................... 40 
12.2 Definitions ................................................................................................................................................................. 40 
12.2.1 Adverse Event (AE) ............................................................................................................................................. 40 
12.2.2 Unexpected Adverse Event ................................................................................................................................ 40 
12.2.3 Serious Adverse Event (SAE) .............................................................................................................................. 40 

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12.3 Grading and Attribution of Adverse Events .............................................................................................................. 41 
12.3.1 Grading Criteria .................................................................................................................................................. 41 
12.3.2 Attribution Definitions ....................................................................................................................................... 41 
12.4 Collection and Recording of Adverse Events ............................................................................................................ 42 
12.4.1 Collection Period ................................................................................................................................................ 42 
12.4.2 Collecting Adverse Events .................................................................................................................................. 42 
12.4.3 Recording Adverse Events .................................................................................................................................. 42 
12.5 Reporting of Serious Adverse Events and Adverse Events ....................................................................................... 42 
12.5.1 Reporting of Serious Adverse Events to Sponsor, DAIT/NIAID .......................................................................... 43 
12.5.2 Reporting to Health Authority ........................................................................................................................... 43 
12.5.3 Reporting of Adverse Events to IRBs/IECs ......................................................................................................... 44 
12.6   
Pregnancy Reporting ......................................................................................................................................... 44 
12.7 Reporting of Other Safety Information ..................................................................................................................... 45 
12.8 Review of Safety Information ................................................................................................................................... 45 
12.8.1 Medical Monitor Review .................................................................................................................................... 45 
12.8.2 DSMB Review ..................................................................................................................................................... 45 
13. 
Statistical Considerations and Analytical Plan .......................................................................................................... 46 
13.1 
Overview ............................................................................................................................................................... 46 
13.2 
Endpoints .............................................................................................................................................................. 46 
13.4 
Analysis Plan .......................................................................................................................................................... 48 
13.4.1 
Analysis Populations. .................................................................................................................................... 48 
13.4.2 
Primary Analysis of Primary Endpoint(s)/Outcome(s) .................................................................................. 48 
13.4.3 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s) ...................................................................... 48 
13.4.4 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) ......................................................................... 49 
13.4.5 
Analyses of Exploratory Endpoint(s)/Outcome(s)......................................................................................... 49 
13.4.6 
Descriptive Analyses ..................................................................................................................................... 49 
13.5 
Interim Analyses .................................................................................................................................................... 49 
13.5.1 
Interim Analysis of Efficacy Data-NA ................................................................................................................. 50 
13.5.2 
Interim Analysis of Safety Data-NA ................................................................................................................... 50 
13.5.3 
Futility Analysis-NA ........................................................................................................................................... 50 
13.6 
Statistical Hypotheses ........................................................................................................................................... 50 
13.7 
Sample Size Considerations .................................................................................................................................. 50 
14. 
Identification and Access to Source Data ................................................................................................................. 50 

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14.1 
Source Data ........................................................................................................................................................... 50 
14.2 
Access to Source Data ........................................................................................................................................... 51 
15. 
Protocol Deviations ................................................................................................................................................... 51 
15.1 
Protocol Deviation Definitions .............................................................................................................................. 51 
15.2 
Reporting and Managing Protocol Deviations ...................................................................................................... 51 
16. 
Ethical Considerations and Compliance with Good Clinical Practice ........................................................................ 51 
16.1 
Statement of Compliance ..................................................................................................................................... 51 
16.2 
Informed Consent Process .................................................................................................................................... 51 
16.3 
Privacy and Confidentiality ................................................................................................................................... 52 
17. 
Publication Policy ...................................................................................................................................................... 52 
18. 
References ................................................................................................................................................................ 52 
 
 

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Glossary of Abbreviations 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DBPCFC 
Double-blind, placebo-controlled oral food challenge 
DSMB 
Data Safety Monitoring Board 
EoE 
Eosinophilic esophagitis 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HT 
High threshold peanut allergy 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LT 
Low threshold peanut allergy 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases 
NPA 
Not peanut allergic (tolerant) 
OFC 
Oral food challenge 
PI 
[Site] Principal Investigator 
PBMC 
Peripheral blood mononuclear cells 
PST 
Prick skin test 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SOP 
Standard Operating Procedure 
SU 
Sustained unresponsiveness 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
 

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Study Definitions Page  
1. Anaphylaxis 
 
 
2. Criteria for 
anaphylaxis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anaphylaxis is a generalized allergic reaction that is rapid in onset and may 
progress to death.1  
 
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 a likely 
 
allergen for that patient (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 known allergen for that patient (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. 
 
 
 
 
 
 

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3. Anaphylaxis grading 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tolerant or tolerate 
 
 
 
Tolerance 
Grading System of Severity of Anaphylaxis 
Grade 
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; SOB, wheezing & 
retractions; crampy abdominal 
pain, recurrent vomiting and/or 
diarrhea; and/or mild dizziness 
3. Severe (hypoxia, 
hypotension, or neurological 
compromise) 
Cyanosis or SpO2 < 92% at any 
stage, hypotension, confusion, 
collapse, loss of consciousness; 
or incontinence 
4. Life-threatening 
The above, and cardiac or 
respiratory arrest  
5. Death 
 
 
 
 
Ability to ingest an allergenic food without evidence of allergic symptoms; 
does not infer concomitant long-lasting change in the individual’s 
immunologic response to food; may reflect “desensitization” or “tolerance” 
 
Long-lasting change in an individual’s immunologic response to a food 
allergen in conjunction with the ability of the individual to ingest the food 
without evidence of allergic symptoms. Induced tolerance refers to having an 
active intervention resulting in tolerance. Natural tolerance refers to 
attaining tolerance without an intervention (i.e., outgrowing an allergy). 
Sponsor- Medical Monitor 
A physician administratively independent of the Sponsor-Investigator who is 
familiar with clinical trials who will oversee the safety of the participants on 
behalf of the Sponsor-Investigator 
 
 
 
 
 
 
 

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1. Background and Rationale  
1.1. Background and Scientific Rationale 
Food allergy affects up to 5% of adults and 4-8% of young children in the US, an estimated 15 million Americans.1,2  Food 
allergy carries a significant cost, and a negative impact on nutrition and quality of life.3-6  Peanut allergy affects nearly 2% 
of children, is often severe, and life-long.7  The current standard for food allergy management relies on strict avoidance 
of the offending food.  Children are monitored for resolution of food allergy with periodic oral food challenges (OFC), 
which are performed when diagnostic tests and the medical history suggest a possibility that the allergy has resolved.  
An OFC involves gradually feeding increasing amounts of the food under medical supervision until a “meal-sized” portion 
is ingested, unless there are symptoms requiring cessation of dosing.  These tests are performed by allergists for clinical 
diagnosis when they suspect resolution of peanut allergy or sensitization without reactivity, using office-measured foods 
such as peanut butter, peanut flour, or Bamba, in amounts measured by common kitchen materials such as spoons.8  A 
child who reacts at any dose during an OFC, even at the top dose, even with mild symptoms, is considered allergic and 
advised to continue strict avoidance until the next OFC is performed, typically not less than a year later.4,9-11   
However, the paradigm of strict avoidance of a food as therapy for food allergy is changing.  Our research group 
fundamentally changed the paradigm for egg and milk allergy in children without exquisite sensitivity to these allergens.  
We showed that approximately 70% of children with milk or egg allergy tolerated extensively heated forms (bakery 
goods); allowing them to eat these forms facilitated allergy recovery (including evidence of immune modulation and, for 
some, eventual tolerance of unheated, full servings of these foods) and was safe.12-20  
For those with low threshold food allergy, oral (OIT), sublingual (SLIT), and epicutaneous (EPIT) immunotherapy, as well 
as combination therapy using OIT and omalizumab have all shown some promise to improve treatment.13,21-23 However, 
studies of these immunotherapies typically exclude persons with high thresholds of reactivity, those who react at doses 
higher than 100 or 300 mg of peanut protein.  While this is understandable given the needs of those with severe 
allergies (low threshold, serious symptoms at low doses), a large proportion of the allergic community have a high 
threshold of reactivity and yet they are instructed to avoid the allergen.  A large proportion of individuals are not 
exquisitely sensitive and exhibit a high threshold phenotype.  Therefore, current immunotherapeutic treatment 
approaches are likely focusing on less than half of the affected population, potentially neglecting millions of people with 
food allergy. There is an unmet need to provide approaches for people with high threshold food allergy, the majority of 
the food-allergic population. 
We believe that the next logical step is a simple and cost-effective approach of allowing children with high threshold 
peanut allergy to ingest tolerated amounts of peanut.  The approach is based in part on our prior success with allowing 
children to ingest milk and egg in tolerated forms, and the promise seen in OIT studies.  
Currently, allergists perform OFCs in the office setting by feeding supermarket forms of peanut measured with simple 
kitchen materials often using foods brought in by the patient.  We propose that allowing children with high threshold 
peanut allergy to ingest tolerated, sub-threshold amounts of peanut, using home-purchased, home-measured foods 
based on the results of an OFC, may be associated with benefits such as further increased threshold with time and 
potentially sustained unresponsiveness (SU, remission off daily ingestion), should be safe, and result in improved quality 
of life.  This approach may become a prototype for studying additional foods. Additionally, we will undertake 
immunologic genomic, and transcriptomic characterization of a high threshold endotype of peanut allergy to inform 
identification of biomarkers and mechanisms of threshold, response to therapy, reaction severity, and 
SU/tolerance/remission.    

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1.2. Rationale for Selection of Investigational Product or Intervention 
The intervention is to allow children with a threshold greater than or equal to 143 mg peanut protein but less than 5043 
mg peanut protein to ingest, if tolerated, a daily home-purchased, home-measured amount of peanut.  The rationale to 
this practical approach is that allowing ingestion of sub-threshold amounts of food allergens will induce changes in the 
immune response that will allow ingestion of larger amounts of the food over time (increased threshold).  We anticipate 
that introduction and periodic increase of the sub-threshold amounts of peanut will induce desensitization and over 
time will lead to SU.  
The background for the rationale and intervention has 3 themes: 1) moderate allergy is common (significant unmet 
need), 2) ingestion of tolerated amounts of allergen is generally safe and can be achieved using “regular food” at home 
(inexpensive, simple), and has been an acceptable approach, and 3) ingesting allergen may result in increasing 
desensitization and possibly, with time and increased quantities, maintaining a high threshold despite discontinued daily 
ingestion (sustained unresponsiveness, SU, a surrogate term for tolerance or remission) indicating a health benefit of 
this approach. 
1) There is a large unmet need for those with high threshold food allergy.  Prior studies  suggest that overall, during 
oral food challenges approximately 75% of the reactions occur at doses over 100 mg of food protein, and 55% of 
reactions occur at cumulative doses over 250 mg, with over 30% at doses over ~1.5 grams,24-31 as summarized in Table 1.  
 
Table 1: Selected studies reporting threshold doses during diagnostic oral food challenges in food allergy practices 
Study/Food/N of subjects 
Median age  
Cumulative threshold, 
mg food protein 
Ballmer Weber JACI 201525 
Peanut, Hazelnut Celeriac, Fish; N=224 
Overall 24.2 years; peanut-10.4 
years; fish-14.2 years 
75% reacted at or above 
100 mg  
Taylor S et al, Food and Chemical Toxicology, 
201026; Peanut; N=286 
7 years 
75% reacted above 100 mg 
peanut 
Osterballe et al, JACI, 200327; Egg, N=56 
2.2 years 
Median threshold was 2.2 
g whole egg 
Moneret-Vautrin, 1998, Clin Exp Allergy28 
Peanut, egg; N=90 
Children 
Peanut: 75% reacted above 
100 mg; 63% reacted at 
100-1000 mg 
Egg: 70%-reacted above 
100 mg; 30% reacted at 
100-1000 mg 
Sicherer et al, JACI 200024 
Milk, egg, peanut, wheat, soy and fish 
N=196 
 
5 years 9 mo 
Overall 56% of the ofc 
were to the cumulative 
doses over 500 mg of food 
(protein is generally <25% 
of the whole food): egg-
51%, milk-45%, peanut-
74%, fish-83%, soy-72%, 
wheat-75%; 75% of 
children reacted to milk at 
>100 mg [starting dose]; 
89% of children reacted to 
egg at >100 mg [starting 
dose]. 
Blumchen et al, JACI, 201430; Peanut; N=63 
5.5 years (3.2-17.8) 
50% reacted above 100 mg  
Allen KJ, et al, JACI 201331;  
Peanut, milk; N=400 
Children and adults 
Peanut: 60% react above 
100 mg 
Milk: 70% react above 100 
mg 
Zhu J, et al, Food and Chemical Toxicology, 
201532; Peanut, N=257; Milk, N=167 
Children 
Peanut: 55% reacted above 
100 mg 
Milk: 75% reacted above 
100 mg 
 

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2) Ingestion of tolerated amounts of food, below a threshold of reaction, is generally safe and for those with high 
threshold peanut allergy, can be achieved using foods measured at home. The notion that allergens must be strictly 
avoided has come under scrutiny.  In a series of studies conducted at Mount Sinai, children allergic to milk or egg but 
tolerant of baked forms were permitted to ingest these forms.  The approach was noted to be safe, improved outcomes 
and is now a worldwide accepted approach.12,13,17,19,33,34  In these trials, children who incorporated baked milk had 
improved growth and caregiver-reported improvement in the quality of life compared to those who could have but did 
not incorporate the food, highlighting additional benefits of introducing tolerated amounts of food allergens to the diet. 
Indeed, there are other examples where persons with a food allergy are “permitted” to ingest a potential allergen with 
specific stipulations.   OIT, currently under study in phase III trials, is another example of a change in approach where 
ingestion of a known allergen is permitted.  OIT consists of introduction of the food allergen starting from minimal 
doses, usually in the subjects with exquisite allergy who react to a cumulative dose of 143 mg food protein or less (i.e., 
react at the single 100 mg dose given during a PRACTALL OFC).35-43  Following an initial dose escalation day, the dose of 
food is ingested daily and the treated subjects return every 2 weeks for dose escalations followed by a prolonged period 
of maintenance dosing.21,44 OIT, although often beneficial, carries a known adverse effect profile, with about 20% unable 
to progress.45  However, severe systemic reactions occur infrequently during OIT clinical trials; estimated rates of 
anaphylaxis are about 0.01% of all doses across various studies on peanut and milk OIT. Both severe and mild adverse 
events are more common during the initial dose escalation and in the early stages of build-up phase when dosing is 
being escalated from milligram doses every 2 weeks.46,47 Therefore, patients with high threshold food allergy as defined 
previously are anticipated to experience fewer reactions from being allowed to ingest sub-threshold amounts of the 
allergen, as we intend to study.  In a study of 39 children with peanut allergy undergoing OIT aiming for a 4 gram 
maintenance dose, 26 who successfully attained this dose continued long term ingestion with few adverse events and 
no withdrawals. 48   Their higher threshold therefore appears to be stable.   
The concept that an individual has a threshold of reaction that is generally stable (repeated oral food challenge 
performed yearly do not vary widely spontaneously) is central to all studies of food allergy therapy (the oral food 
challenge threshold is the relied-upon endpoint).  Specifically, in interventional studies, DBPCFCs are repeated at 
intervals to determine if the intervention is having an effect. Although there is a “placebo” effect of treatment, studies 
suggest that control groups do not vary significantly (it is unusual to see control participants vary from low threshold to 
high threshold). 39,46-49 In a recent peanut OIT trial, no participants in the control group (entry reaction <143 mg peanut 
protein) tolerated 600 mg on re-challenge.50 In a recent trial of peanut EPIT, only 3/25 children in the placebo group 
changed their threshold from <500 mg to > 500 mg.51 In a trial that was unusual in performing DBPCFCs just a few 
months apart, the procedures reproducibility was noted.52  In the current study, participants randomized to ingest 
peanut will have a medically supervised ingestion of the amount to be ingested at home (separate from the study 
DBPCFC) to be sure it is tolerated.    
Regarding the use of home measured and home purchased foods, our approach is akin to our prior baked milk/baked 
egg studies, where a tolerated amount of the food is permitted for feeding.   Oral food challenges are performed with 
store bought foods (peanut flour, peanut butter, Bamba™, etc.) measured by teaspoon measures (1/8 etc.) as routine 
clinical practice.8    Importantly, OIT studies have allowed home measurement of food once larger amounts are safely 
attained (data not shown, NCT01980992)39 Various store bought peanut foods (peanut butter, Bamba™, peanut flour ) 
have also been recommended for oral food challenge testing and prevention therapies.8,53  Allowing persons to eat a 
food despite having reactions to higher amounts or with exercise is also accepted practice with regard to food-
associated, exercise-induced anaphylaxis.54,55   
3) Ingesting allergen may result in increasing the threshold (desensitization, temporary hypo-responsiveness 

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dependent upon regular ingestion) and possibly, with time and increased quantities, maintaining a high threshold 
despite discontinued daily ingestion, termed sustained unresponsiveness, SU (indicating a health benefit of this 
approach). The success of OIT for the majority treated has intrinsically dispelled the notion that strict avoidance is the 
only option, but has also informed potential benefits of the approach we will test. In OIT, approximately 75% of the 
actively treated subjects become desensitized and reach the daily maintenance dose.35-37,39,42,48,50 The reported rates of 
SU following OIT treatment are significantly lower, but are highest for those able to ingest larger doses daily for long 
periods of time, like those we are targeting for study.39,48  Lower pre-OIT serum peanut-specific IgE antibody levels, more 
in line with levels we will see in this study,  are associated with SU following peanut (and egg) OIT.48,56-58   
In summary, there are millions of children with high threshold food allergy who are strictly avoiding foods; currently 
emerging therapeutics are not targeting these children.  These individuals may be able to safely ingest sub-threshold 
amounts of allergen.  The amounts they could ingest are easily measurable as “real food” at home just like these foods 
are used during OFCs in physician offices or used at home for prevention.  Based on OIT studies and our baked milk/egg 
studies, allowing these children to ingest the amount of food that does not trigger reactions, and performing 
intermittent OFCs to determine if increasingly more food can be ingested without reactions, has a high chance to induce 
increasing desensitization and possibly SU.  This dietary approach uses “regular food” and no medical products, making 
it practical and inexpensive.  This study will carefully assess this approach to inform safety and outcomes for potential 
utilization by allergists. Studying the proposed approach with peanut will provide a prototype for studies of additional 
foods.      
1.3. Preclinical Experience 
Not applicable. 
1.4. Clinical Studies 
The reader is referred to studies mentioned above (section 1.2) regarding the number of peanut allergic individuals with 
high threshold allergy, the safety of ingestion of home-prepared foods, and the immunotherapeutic potential of 
ingestion exposure.  There are two small case series exploring the notion of allowing children to ingest tolerated 
amounts of a food based upon the results of OFC.  Garvey et al59 permitted children with mild reaction to high doses of 
peanut to ingest 1 peanut at home daily, increasing while still at home to an amount under their OFC reaction threshold.  
After 6 months, 9/10 tolerated the OFC and 8/10 showed SU.  Yanagida et al60 described their clinical experience in 
Japan in which children undergo egg, milk or wheat OFCs by trying single dose challenges of increasing amounts several 
months apart and are allowed to ingest up to the amount they tolerated at home at each step (3 steps).  Although the 
study (n=760) did not evaluate the benefit of ingesting a tolerated amount with regard to outcomes, they demonstrated 
safety of allowing the ingestion of subthreshold amounts measured at home with natural foods. We recently offered to 
allow 6 children who failed peanut oral food challenges at higher amounts to undertake lower dose ingestion under 
supervision on an IRB-approved observational protocol.  The children, 2 male, 4 female (ages 2, 2, 3, 10, 12, 14 yrs), had 
mild symptoms (urticaria, abdominal pain, pruritus) on doses from 5/8th to 3 teaspoons of peanut flour/butter during 
OFCs. With informed consent, repeat oral food challenges to a lower dose were performed (single starting dose 1/8 
teaspoon for 3, ¼ teaspoon for 2, 3/8 teaspoon for 1) and was tolerated.  Periodic visits with OFC for higher amounts 
resulted over a mean follow up of 10 months with 5 on 3 teaspoons and one on 2 teaspoons without symptoms.           
2. Study Hypotheses/Objectives 
 
 

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2.1. Hypotheses 
Clinical hypothesis and research question 
The research question we will address: Is there a benefit to allowing children with high threshold peanut allergy to 
ingest home measured amounts of peanut below their threshold, as compared to standard care avoidance?     
We hypothesize that for persons with high threshold peanut allergy, ingesting sub-threshold amounts of the allergen 
(amounts not causing symptoms) will result in an ability to ingest higher amounts with time (desensitization) and 
potentially sustained unresponsiveness (SU).  
We also hypothesize that the approach will be safe and improve quality of life compared to avoidance.   
We base these hypotheses in part on observations from studies of OIT in low threshold subjects as described in 1.2 
above. 
Mechanistic hypothesis 
We hypothesize that ingestion of sub-threshold amounts of peanut protein will be associated with peanut-specific 
immunomodulation, consistent with the development of desensitization and sustained unresponsiveness. Specifically, 
we hypothesize that ingestion of peanut will be associated with changes in peanut-specific humoral immunity, with a 
decrease in anaphylaxis-promoting IgE antibodies and an increase in blocking antibodies, and a modulation of the 
peanut-specific T cell response consistent with immune tolerance. We anticipate that individuals’ potential for 
desensitization via the ingestion of subthreshold amounts of peanut protein will be detectable as early IgE and IgG4 
epitope-specific and transcriptional signatures in peripheral blood, and that data-driven selection of these signatures will 
yield a clinically useful biomarker of desensitization potential. Further, these transcriptional signatures will elucidate 
functional pathways underlying desensitization success.  
2.2. Primary Objective(s) 
Primary clinical objective 
The primary objective of this study is to determine whether allowing ingestion of sub-threshold amounts of peanut in 
subjects with a high threshold (those who tolerate at least 143 mg peanut protein on supervised double-blind, placebo-
controlled oral food challenge [DBPCFC]) will be associated with attaining even higher thresholds over time compared to 
those avoiding peanut. Primary mechanistic objectives 
The primary mechanistic objectives are to elucidate immune mechanisms induced by daily ingestion of sub-threshold 
amounts of peanut, and to identify biomarkers of and functional pathways underlying desensitization potential. We will 
test if peanut ingestion is associated with the following immune and transcriptomic processes: 
 
Suppression of serum peanut-specific IgE  
 
Increase in serum peanut-specific IgG and IgG4 
 
Change in peanut IgE and IgG4 epitope binding scores 
 
Decrease in basophil activation tests 
 
Decrease in peanut-specific multifunctional Th2 cells 
 
Increase in peanut-specific regulatory T cells 
 
Change in peripheral blood transcriptional signatures 
 
Up and downregulation of distinct gene ontology pathways 
 
2.3. Secondary Objective(s) 
Secondary clinical objectives 

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The secondary clinical objectives of this study are to determine whether ingesting sub-threshold amounts of peanut in 
children with high threshold peanut allergy, compared to avoidance, will: 
 
A) Result in increased rates of sustained unresponsiveness. 
 
B) Have positive effects on quality of life. 
 
C) Be a safe approach. 
 
Secondary mechanistic objectives 
Secondary mechanistic objectives are to: 
A) Determine if immune and transcriptomic measures obtained early in the course of ingestion exposure can 
predict development of desensitization or sustained unresponsiveness.  
B) Identify immune and genomic biomarkers of the high threshold phenotype. 
C) Identify early-appearing functional pathways underlying a successful desensitization course (exploratory). 
3. Study Design 
3.1. Description of Study Design  
This is a prospective, two-arm parallel-group, randomized (1:1; 36 per group), controlled, open label  trial of peanut 
ingestion and dose escalation (versus avoidance) in children age 4 to less than 15 years at enrollment who have high 
threshold peanut allergy (tolerate  ≥143 mg but not 5043 mg cumulative peanut protein) based on DBPCFC. It is 
anticipated that approximately 150-200 subjects undergoing DBPCFCs will be needed to identify 72 participants for 
randomization. 
3.1.1 Screening DBPCFC to determine threshold and identify subjects for randomization 
Subject fulfilling inclusion/exclusion criteria will undergo an initial DBPCFC according to modified PRACTALL guidelines.61 
Dosing is 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 3000 mg, 4000 mg peanut protein.  The dosing interval 
is 20-30 minutes except the final dose, 4000 mg, will be given 60 minutes after the 3000 mg dose. This baseline DBPCFC 
will phenotype participants as having LT peanut allergy, HT peanut allergy or no peanut allergy (Figure 1). Blood samples 
will be obtained in association with screening DBPCFC for mechanistic studies associated with peanut allergy endotypes. 
Those tolerating 9043 mg (approximately 8 teaspoons of peanut butter or equivalent)will be permitted to add peanut to 
the diet. 
 
 
    
Figure 1. Initial screening DBPCFC to phenotype threshold, obtain biosamples, and identify those qualified for 
randomization. 

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3.1.2. Overview of trial scheme 
Children with HT peanut allergy will be randomized to continue avoidance (control) or to ingest a home measured 
amount of peanut daily (intervention) based on their threshold. Subjects in the intervention group return to the 
research unit for re-challenge to increased amounts of peanut at 8 week intervals and are instructed to ingest the larger 
amount if tolerated.  A repeat DBPCFC will be performed 8 weeks after reaching 1 tablespoon (or equivalent) in the 
intervention group, or at 72 weeks. A repeat DBPCFC will be performed in the control group at a time calculated 
according to a surveillance algorithm to ensure similar lengths between initial and desensitization DPBCFC between the 
two groups (see Section 13.3).    Subjects in the intervention arm tolerating the full challenge amount will add peanut to 
the diet for 16 weeks and then avoid peanut for 8 weeks, followed by a DBPCFC to assess for sustained 
unresponsiveness [SU] (ability to consume without reaction after a period of avoidance).    The study scheme is shown in 
Figure 2. 
 
 
Figure 2. Randomized Intervention Study scheme 
3.1.3 Intervention Arm Procedures 
Children randomized to the active arm will return for an observed administration of the highest amount of peanut they 
should tolerate with no or minimal (oral) symptoms based on their baseline DBPCFC.  The starting amount of peanut 
butter will be 1/8th teaspoon [approximately 140 mg peanut protein] if they reacted at 443 mg cumulative dose on 
DBPCFC, ¼ teaspoon [approximately 280 mg peanut protein], if they reacted at 1043 mg cumulative dose on DBPCFC,  
3/8 teaspoon [approximately 430 mg peanut protein] for a reaction at 2043 mg cumulative dose) or 1 teaspoon 
[approximately 1140 mg] for a reaction at 5043 mg cumulative dose. To continue on daily peanut, the 1/8th  teaspoon 
supervised feeding post food challenge must be tolerated. Study participants/families will be given detailed instructions 

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specifying the types and amounts of the commercial foods allowed for home ingestion. They also will be required to 
strictly avoid the food allergen other than the amount under the study. They will return every 8 weeks to attempt a 
supervised feeding of the next higher amount, as shown in Figure 2. If successfully consumed, they will continue the one 
step higher amount daily. When participants have exceeded 3/8 teaspoon of peanut butter, alternative forms (Bamba™, 
candies)62,63 can be substituted but such substitutions will be performed as observed feedings. (Table available in the 
MOP.)  If subjects have symptoms at 1/8 teaspoon peanut butter during the study, they will be permitted to trial 1/16th 
teaspoon under observed feeding, but this will be the lowest amount allowed in the study.  
 
3.1.4 Control Arm Procedures 
Children randomized to the control arm will follow standard care of strict avoidance of peanut.  They will have a repeat 
DBPCFC to peanut at a time determined by a surveillance algorithm as described in Section 13.3, to match the 
distribution of DBPCFC to those of the intervention group.   Based on the outcome of the DBPCFC, they will either be 
considered no longer allergic (naturally tolerant, NT) if they tolerate the full dose of the challenge (9043 mg) or will 
continue strict avoidance under clinical care off of the study. 
 
3.1.5 Desensitization DBPCFC in intervention arm 
(a) Children in the active arm who react at or below the full dose of 9043 mg peanut protein on the second DBPCFC will 
be considered not fully desensitized and will pursue clinical care off of the study.   
(b) Children in the active arm, who are able to ingest the full dose of the DBPCFC (9043 mg) will be considered fully 
desensitized and will go to a more open diet, with no upper limit to the amount they may eat, but they must eat at least 
one serving (equivalent of approximately 2 tablespoons or approximately 6800 mg) of peanut per week for 16 weeks. 
3.1.6 Sustained unresponsiveness (SU) DBPCFC (Intervention group) 
To determine SU, children in the active arm after 16 weeks of the open diet described in 3.1.5, will strictly avoid peanut 
for 8 weeks followed by the repeated SU DBPCFC to the full dose of peanut. Those who tolerated the full dose of peanut 
(9043 mg) after the 8 weeks of strict avoidance will be considered to have achieved SU (TS-SU) and will add peanut to 
their diet without restrictions other than the recommendation that they continue to have at least one serving every 
week and will pursue clinical care off of the study. Those who react at the SU OFC following the 8-week avoidance period 
will be considered desensitized but not achieving SU (TS-D) and will  be followed clinically off study. 
3.1.7 Study timelines 
Participation for individual subjects is up to 120 weeks.   
 
 
3.2. Primary Endpoint(s)/Outcome(s) 
3.2.1 Primary Clinical Endpoints 

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The difference between the treatment and comparison (avoidance) groups in the percentage of children who by the 
desensitization endpoint DBPCFC tolerate a dose at least 2 steps higher than their baseline DBPCFC or the full dose 
(9043 mg) of peanut protein. 
3.2.2 Primary Mechanistic Endpoints 
1. Change in peanut and Ara h 2-specific IgE from baseline as measured by ImmunoCAP assay 
2. Change in peanut and Ara h 2-specific IgG4 from baseline as measured by ImmunoCAP assay 
3. Change in peanut epitope-specific IgE and IgG4 binding score from baseline 
4. Change in basophil activation from baseline, as measured by %CD63+ basophil by flow cytometry/mass 
cytometry 
5. Change in frequency of peanut-specific Th2 cells, as measured by CD154 and cytokine co-expression after in 
vitro stimulation with peanut. 
6. Change in frequency of peanut-specific T cells expressing CD137 and regulatory markers or producing IL-10 after 
in vitro stimulation with peanut. 
7. Change in peripheral blood transcriptional signature. 
 
3.3. Secondary Endpoint(s)/Outcome(s) 
3.3.1 Secondary Clinical Endpoints 
1. The percentage of children who achieve SU or natural tolerance during the study. 
2. Safety parameters (acute allergic reactions, including anaphylaxis, gastrointestinal side effects). 
3. Quality of life (QOL) measures (the QOL instrument will not administered to participants who do not speak English 
because it is not validated in languages other than English).  
4. SPT mean wheal size changes. 
3.3.2 Secondary Mechanistic Endpoints 
1. Immune and transcriptomic measures obtained early in the course of ingestion exposure that predict development 
of desensitization or sustained unresponsiveness.  
2. Immune and genomic biomarkers of the high threshold phenotype. 
3. (Exploratory) Early-appearing functional pathways underlying a successful desensitization course. 
 
3.4.1. Additional samples for future/ancillary studies.   
Saliva and stool samples will be collected at specified visits (see Table 2) and stored for anticipated microbiome studies. 
3.4. Stratification, Randomization, and Blinding/Masking 
This is a prospective two-arm parallel-group, randomized (1:1) controlled open trial. The data and statistical coordinating 
center (DSCC) will maintain control of stratification and randomization, described in Section 13.3. 
Neither the children nor the investigators will be blinded to randomization assignment. The study staff conducting the 
DBPCFCs, however, will be blinded to the participant randomization status.  

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3.4.1. Procedure for Unblinding/Unmasking 
Not applicable.  
 
4. Selection of Participants and Clinical Sites/Laboratories 
4.1. Rationale for Study Population 
The screening eligibility for the study population are those age 4-14 years strictly avoiding peanut and having a history of 
sensitization (detectable peanut IgE >0.35 kUA/L). These children must also be generally healthy and able to undergo 
study procedures (see Section 4.3).   
Children with peanut IgE levels over 50 kUA/L are excluded because it is unlikely they will be high threshold.64 The study 
inclusion criteria are those with high threshold peanut allergy who are likely to safely ingest sub-threshold amounts of 
peanut and may benefit by doing so as described in Section 1 of this Protocol. Those with high threshold peanut allergy 
have no current therapeutic or standard of care options other than avoidance and allowing ingestion of subthreshold 
amounts of peanut for this population has not been studied and equipoise exists.  
The age range of 4 through age 14 years was chosen because there is less chance of spontaneous resolution compared 
to younger peanut-allergic children65-67, the home-measured amounts and foods would not be significantly varied on a 
per kg basis compared to including infants or older teenagers, subjective side effects would be easier to monitor with 
verbal participants (itchy mouth), and adherence may be maximized compared to including older adolescents or 
adults.41,68  
4.2. Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study participants:  
1. Subject and/or parent guardian must be able to understand and provide informed consent. 
2. Inclusion criteria for screening DBPCFC:  Age 4-14 years, either sex, any race, any ethnicity who are enrolled while 
strictly avoiding peanut and have a history of sensitization (detectable peanut IgE >0.35 kUA/L).   
3. Inclusion criteria for randomization (post screening): On screening DBPCFC are able to ingest >=143 mg peanut 
protein but <5043 mg peanut protein. 
 
4.3. Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study participants: [Suggested 
line items are included in italics; modify, add or remove as needed; line items #1, 10 and 11 should be 
included without modification]  
1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol 
2. Serum peanut-specific IgE antibody level > 50 kUA/L   
3. Recent (within the past 2 years) life-threatening (grade 3) anaphylactic reaction to peanut. 
4. Any disorder in which epinephrine is contraindicated such as known hypertension or cardia rhythm disorders. 
5. History of chronic disease requiring therapy (other than asthma, atopic dermatitis, rhinitis). 
6. On a build-up phase of any allergen immunotherapy. 

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7. For those with a history of asthma, the following are assessed and any of the following is an exclusion (markers of 
current uncontrolled or moderate to severe asthma):   
A. FEV1 value <80% predicted (only for participants age 7 years or older and are able to perform spirometry*).   
B. ACT or cACT < 20  
C. >Step 3 controller therapy as defined for children 0-4, 5-11 and >=12 years of age by EPR-3 tables 
D. Use of steroid medications in the following manners:  
a. history of daily oral steroid dosing for >1 month during the past year,  
b. having 1 burst or steroid course within the past 6 months, or  
c. having >1 burst oral steroid course within the past 12 months.  
E.  Asthma requiring >1 hospitalization in the past year for asthma or >1 ED visit in the past 6 months for asthma, 
or any prior intubation/mechanical ventilation for asthma/wheezing. 
F. *When COVID related institutional restrictions on spirometry are in effect, spirometry will be not performed and 
peak flow will be used with 80% predicted as the cut-off. 
 
8. Gastrointestinal eosinophilic disorders, esophagitis, gastroenteritis.  
9. Use of short-acting antihistamines (diphenhydramine, etc.) more than one time within 3 days prior to DBPCFC or 
skin testing.* 
10. Use of medium-acting antihistamines (hydroxyzine, loratadine, etc.) more than one time within 7 days of DBPCFC or 
skin testing.* 
11. Use of systemic steroid medications (IV, IM or oral) for indications other than asthma for > 3 weeks within the past 6 
months 
12. Use of beta-blockers (oral), (ACE) inhibitors, angiotensin-receptor blockers or calcium channel blockers. 
13. Participation in any trials of therapeutic interventions for food allergy in the past year. 
14. Therapy with anti-IgE or other biologics, including within 1 year of enrollment.  
15. Use of investigational drugs within 52 weeks of participation. 
16. Allergy to all of the following: oat, rice, corn, tapioca. 
17. Pregnancy 
18. Past or current medical problems or findings from physical examination or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
*Any subject meeting these criteria during the visits can be rescheduled for the oral food challenge or prick skin testing. 
4.4. Selection of Clinical Sites/Labs 
The study will be performed at the Icahn School of Medicine, Mount Sinai, NY, NY.  Based on our clinical experience with 
patient inquiries regarding threshold food challenges (to determine the degree of allergy) and overall high level of 
interest in approaches enhancing desensitization and tolerance, we anticipate that the proposed approach will be 
extremely attractive to the food-allergic children and their caregivers. This study offers all potential participants an 
insight into their degree of sensitivity to peanut, thereby providing a uniform benefit.  The enrollment criteria may 
represent the majority of children presenting to allergy practices with peanut allergy, and at Mount Sinai we evaluate 
over 6500 children with food allergies each year, about half with peanut allergy. We also have >4000 families registered 
for our research newsletter, demonstrating the large base of interested, potential participants. We assume this study, 

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like many of our others, will require a lottery system to choose potential participants because of the attractiveness of 
the study.    We are not aware of any other trials with a similar approach that would compete. Regarding retention, with 
our experienced, multi-disciplinary staff, we are able to establish trusting relationships with our subjects and their family 
members and ensure open lines of communication at every stage. In addition, we have developed a variety of other 
novel approaches to further enhance retention in our clinical trials, including newsletters, periodic “rewards” (e.g. 
stickers, birthday cards, or milestone achievement awards), and involving child life services to make study visits a 
positive experience for our pediatric subjects. The timing of the tests is not intrusive, and the various controls would 
likely be having allergy tests yearly for clinical purposes. We already have protocols for food challenges and have 
successfully undertaken the general aspects needed for this study (sample acquisition and processing, monitoring, study 
procedure forms, dosing, etc.) in many other studies. 
5 Known and Potential Risks and Benefits to Participants 
5.1 Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert 
The investigational product is a food commercially available at retail stores so there is no package insert. Because the 
protocol will be conducted at one site  there is no investigator’s brochure (see also Section 6.1).   
 
5.2 Risks of Investigational Product or Intervention cited in Medical Literature 
For several foods, allowing ingestion of tolerated amounts that could trigger reactions in circumstances of higher 
ingestion amounts or different forms is already accepted practice (e.g., baked milk in milk allergy, baked egg in egg 
allergy, heated cheese in milk allergy, wheat in tolerated quantities or without exercise in wheat allergy/food-associated 
exercise induced anaphylaxis, various foods causing food-associated exercise-induced anaphylaxis).13,54,55 Recent studies 
suggest the safety of this approach (children permitted to ingest subthreshold amounts based on OFC).59,60  
The risk of ingestion of allergen (DBPCFC and home ingestion). The potential risks are those associated with allergen 
ingestion, including those observed in food challenges8,69  Oral food challenges (gradual feeding of the allergic food, or 
providing an amount somewhat higher than previously tolerated) are performed to determine if the food allergy exists 
or has resolved and to determine the threshold dose at which symptoms of an immediate allergic reaction appear. 
Symptoms can include itchy skin rash (urticaria, flare of atopic dermatitis, angioedema), nausea, stomach pain, vomiting, 
and/or diarrhea, rhinitis (stuffy “runny” nose and sneezing) and/or wheezing.  The major risks involved include severe 
breathing difficulties and rarely a drop in blood pressure. There is a single reported fatality.  To date, the investigators 
have performed more than 30,000 oral food challenges without a serious life-threatening anaphylactic reaction. The 
procedure is performed under direct medical supervision according to guidelines and dosing is stopped for persistent 
subjective or objective symptoms.61  The procedure is performed with full treatment available, as per guidelines.70   
Details of the DBPCFC procedure (preparation, dosing, stopping, observations times, etc.), are detailed in the Manual of 
Procedures.  
Home ingestion of an allergenic food that has been ingested safely under supervision during food challenges could cause 
an allergic response, although it is standard of care to permit ingestion of a food after an observed “negative” OFC.69 
Allowing ingestion of a tolerated amount that is below a known threshold is the novel aspect of this intervention 
(although there are examples of doing so as stated above). Extrapolating potential risks from studies of peanut oral 
immunotherapy to the current intervention may not be applicable for the following reasons:  1) peanut OIT studies 
target low threshold peanut allergic children who may be more reactive than the current study population; 2) OIT 

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regimens induce desensitization purposefully in an escalation phase rather than providing ingestion amounts known to 
be tolerated at presentation, and 3) permit dosing despite chronic symptoms. If extrapolation is accepted nonetheless, 
then the intervention (allowance of home ingestion of a tolerated amount) could be considered similar to the 
“maintenance phase” of peanut OIT. Most reactions to peanut OIT occur in the “escalation” or “build-up” phases.46,47 
However, anaphylaxis rates are 0.01% across studies.46,47  In a representative study,71 the risk of dosing symptoms to  
peanut was 93% during the escalation day, 46% during build-up, but only 3.5% for final home dosing. Most of those 
symptoms were upper respiratory (1.2%), skin (1.1%) and abdominal (0.9%) with 0.3% affecting the chest (mild in 0.2%, 
moderate in 0.06%, none severe). These observations speak to the stability of a threshold even for those with a low 
peanut allergy threshold. 
Having food allergy is a risk for eosinophilic esophagitis (EoE)72 and ingestion of ostensibly tolerated foods (i.e., no acute 
reaction) can be a trigger (most common triggers are milk and wheat).  The risk that OIT can trigger EoE has been 
estimated at up to 2.7%.73 This risk will also be communicated to potential participants.  Participants will be monitored 
for new onset of persistent gastrointestinal symptoms and or weight loss and if EoE is suspected they will be instructed 
to discuss this with their allergist or pediatrician for potential referral to a pediatric gastroenterologist for evaluation 
outside of the study, if necessary. Therapy will be stopped in case of new onset EoE; pre-existing EoE is an exclusion 
criterion.   
To minimize risk of allergic reaction to home ingested peanut, specific instructions are provided, e.g., eating the 
measured amount of peanut at the same time of the day following or with a full meal, avoidance of exercise for 2 hours 
following ingestion and temporary suspension of eating peanut during febrile illness, gastroenteritis or asthma 
exacerbation, which are known factors that may precipitate reactions to previously tolerated amounts.74 Guidance is 
also provided regarding products and their measurement (details in the MOP).  Participants will be advised on 
purchasing any of a number of commercially available peanut butters; these have remarkably similar peanut protein 
characteristics.62 Participants will receive close monitoring regarding any allergic reactions (telephone follow-up and 
monitoring of any symptoms). We do not anticipate severe symptoms to suddenly appear without warning.  Written 
emergency plans will be provided which include instructions on initial emergency treatment and calling 911 in the event 
of an acute allergic reaction. Subjects will be prescribed epinephrine autoinjectors and trained in their use. 
5.3 Risks of Other Protocol Specified Medications 
Not applicable. 
5.4 Risks of Study Procedures  
Blood draw: Blood drawing may aggravate a pre-existing anemic condition, but this risk is negligible since blood is drawn 
per NIH guidelines (not to exceed 5cc/kg on a single day or 9.5ml/kg over any eight-week period). Other risks are those 
attendant to any needle puncture, including slight bruising, local infection, or the possibility of the subject fainting.  The 
discomfort involved is minimal. 
Prick skin test: Skin prick tests will be performed utilizing the bifurcated nedle; this will cause minimal discomfort (the 
sensation of a prick and a pruritic, transient hive may result).  Such tests could theoretically induce a systemic allergic 
reaction, but this is exceedingly rare (<.01%).75 
Questionnaires: Parents will complete demographic surveys,  diaries, diet questionnaires, and quality of life 
questionnaire (FAQOL-PB76). There should be no significant risk.  Privacy wil be guarded through locking paper files and 
having password protected databases with protection of personal health information. 

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Collection of saliva and stool: These samples will be collected and stored (see Table 2) for anticipated ancillary 
microbiome studies.  No risks are anticipated.  
5.5 Potential Benefits 
There may be no benefit to participating.  The typical instructions are allergen avoidance, which should pose no added 
risk of a reaction to the control group.  There may be a benefit to society to understand if children with peanut allergy, 
able to tolerate home-measured, home-purchased amounts of peanut below an amount that causes symptoms, are 
better for doing so compared to those following avoidance.  
The benefits of undergoing a DBPCFC to peanut can include understanding the threshold of reactivity, determining that 
there is low threshold allergy which may allow referral for emerging/available treatment options, or identification of 
tolerance to peanut with allowing dietary inclusion of peanut. 
The benefits of the intervention may include: 1) Increased threshold of ingestion (able to eat a larger amount without 
symptoms than before) after a time eating a tolerated amount of the food, 2) ability to eat full servings of peanut even 
after not having a daily amount for a period of 2 months, 3) better quality of life.   
Mechanistic (laboratory) studies associated with this clinical trial will provide information on:  
1. Mechanisms of (A) high threshold reactions; (B) development of desensitization in response to sub-threshold 
peanut ingestion; (C) development of sustained unresponsiveness in response to sub-threshold peanut ingestion;  
2. Predictive biomarkers of response to dietary treatment. 
 
These mechanistic outcomes will allow for personalized treatment approaches and will identify novel pathways for 
refinement of treatment strategies. 
 
 
6 Investigational Agent /Device/Intervention  
6.1 Investigational Agents/Devices/Interventions 
The intervention allows ingestion of home-purchased, home-measured amounts of peanut (initially in the form of 
peanut butter).  The instructions and measurements (e.g., 1/8 teaspoon peanut butter, 8 pieces of Bamba™, etc.) are 
similar to guidelines used for office-based food challenges and parental instructions for home feeding of peanut for 
prevention of peanut allergy, even for infants.8,53 
Although there is no formal standardization of the peanut products that children will eat at home, several strategies 
have been employed to address this issue: 
1. Parents will be provided with informational sheets describing the amounts to give and the foods they could 
purchase, including pictures.  
2. For teaspoon measurements, parents will be given a set of spoons and will be instructed and observed 
(teaching) in their use for proper measurement. 
3. Peanut butter, which is easily obtainable, measured, and can be mixed easily into foods the child enjoys will be a 
preferred product and used at least until the 1/2 teaspoon of peanut butter is the amount given.  Transition to 
alternative products (peanut, Bamba, various candies) will be done under a supervised feeding.    
4. Although there is some variation in home measured amounts (this also applies to office-based oral food 
challenges that use a variety of peanut products), the observed feeding of the amount and product that will be 

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given at home will use the highest amount measured by an analytical scale as tested during piloting the use of 
kitchen spoons (result of 10 measures each). 
 
6.1.1 
Investigational Agent #1 
Not applicable, see 6.1. 
6.1.1.1 
Formulation, Packaging, and Labeling 
NA 
6.1.1.2 Dosage, Preparation, and Administration 
NA  
6.1.2 
Investigational Agent #2 
NA 
6.1.2.1 Formulation, Packaging, and Labeling 
6.1.2.2 Dosage, Preparation, and Administration 
6.2 Drug Accountability 
Not applicable 
6.3 Assessment of Participant Compliance with Investigational Agent 
All participants will be instructed to avoid peanut, except for the subthreshold amount allowed for ingestion by those 
randomized to the intervention.  Symptom diaries will be monitored and all allergic reactions reported.  Serum peanut-
specific IgG will be measured as a potential marker of exposure which will be queried further if noted in the avoidance 
arm (i.e., drop-in to intervention).   
6.4 Toxicity Prevention and Management 
Not applicable 
6.5 Premature Discontinuation of Investigational Agent 
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
 
Severe (grade 3) anaphylaxis secondary to any DBPCFC or ingestion of the measured dose of peanut. 
 
Significant worsening or persistent activation of atopic dermatitis, allergic rhinitis or asthma believed to be related 
to participation in the study. 
 
Any subject deemed to have severe allergic and/or GI symptoms and receiving aggressive therapy. 
 
Inability or unwillingness to comply with study procedures (re-education can be provided at the discretion of the 
PI/Co-I to allow continuation) as evidenced by subject: 
o Excessively missed days of PB ingestion; i.e., > 7 consecutive days missed on 3 occasions. 
o fails to report if they have more than mild symptoms;  
o does not ingest the designated amount of peanut for over 10 consecutive days;  
o attempts to increase amounts without supervision; or 
o experiences symptoms that the PI/Co-I considers warrant withdrawal from ingestion 
 
Study therapy may also be prematurely discontinued for any participant if the investigator believes that the study 
treatment is no longer in the best interest of the participant. 

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Those discontinuing peanut for the above reasons will continue with other study procedures (e.g., monthly calls, AE 
monitoring, SU DBPCFC). 
7 Other Medications 
7.1 Concomitant Medications 
 
All subjects may continue their usual medications, including those taken for asthma, allergic rhinitis and atopic 
dermatitis, during the study.  They must, however, be able to discontinue antihistamines prior to skin testing and OFCs. 
Regular topical steroids use is permitted at the time of skin testing. 
 
7.1.1 
Protocol-mandated concomitant medications 
Participants must have been prescribed epinephrine autoinjectors, see 7.4. 
7.1.2 
 Other permitted concomitant medications 
Not applicable. 
7.2 Prophylactic Medications 
Participants may receive routine vaccines during the study.  
7.3 Prohibited Medications 
Treatment with biologic therapies will not be allowed during the participation in this study. Other therapeutic 
interventions for food allergy (e.g. desensitization protocols) will not be allowed. Medications that interfere 
with treatment of allergic reactions are not allowed (see Exclusion Criteria). 
 
7.4 Rescue Medications  
 
Treatment of individual allergic reactions should be with either an H1 and/or H2 antihistamine and/or epinephrine, 
along with IV fluids, albuterol and steroids as indicated.  Subjects and parents will be trained in proper use of an 
epinephrine autoinjector and will be able to demonstrate proper technique. 
  
8 Study Procedures 
8.1 Enrollment 
The research study will be explained in lay terms to each potential research participant. The potential participant will 
sign an informed consent form before undergoing any study procedures.  Once the consent form is signed, the 
participant will be considered enrolled and will be assigned a unique participant number. 
8.2 Screening/Baseline Visit 
The purpose of the screening period is to confirm eligibility to continue in the study. The procedures involved in the 
screening/baseline visit will determine if the participant can be randomized to the study intervention or will be 
characterized as low threshold (LT) peanut allergy or not peanut allergic (NPA).  Those who are LT or NPA will participate 
for mechanistic studies but will not continue to the randomized trial.  

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The following procedures, assessments, and laboratory measures (windows for sample collection are detailed in the 
MOP as applicable) will be conducted, some of which to determine participant eligibility for the randomized trial: 
 
Physical exam, vital signs, complete medical history 
 
Spirometry (or peak flow under age 7 or if spirometry not allowed per COVID protocols) 
 
DBPCFC to peanut per modified PRACTALL (and associated examinations) 
 
Skin prick test to peanut 
 
Blood samples (before DBPCFC commences and 2 and 4 hours after starting; not to exceed 5cc/kg on a single 
day or 9.5ml/kg over any eight-week period per NIH guidelines). A saline lock may be placed to facilitate blood 
sampling at this and other visits where periodic samples are obtained. 
 
Quality of life survey, diet questionnaire, demographics   
 
Urine pregnancy if child bearing potential 
 
Saliva and stool collection 
 
Screening takes place over 3 days (with one DBPCFC per day for 2 days). Each day is 4-8 hours. 
If a participant reacts during the placebo arm of a DBPCFC, the DBPCFC may be repeated once.  If a determination of 
reaction cannot be made due to unwillingness to repeat the DBPCFC or repeated placebo reactions, participation will 
end and any associated data will not be included in the analyses.  
8.3 Study Visits or Study Assessments  
 
Intervention Arm 
For those with high threshold peanut allergy randomized to ingestion. 
Participants in the intervention arm will receive monthly telephone follow up (unless they have a visit on that month) 
and reporting of any allergic reactions, including reporting accidental exposure to peanut, and will keep a diary.  The 
diary will be accessed for the following issues: missed dose, ate peanut outside of the study dose, and any reaction, 
symptoms or illnesses. These will be confirmed/reviewed monthly by telephone, email (printout as source) or in person 
visit to evaluate that the entries match what the experience is.  This will be documented on an eCRF (or email print out) 
and the clinical team will add any diary entries if needed. 
 
Visit 1. Initial feeding challenge with subthreshold amount of peanut (visit length 2-3 hours) 
 
Physical exam, vital signs, medical history 
 
Spirometry (or peak flow under age 7, or if spirometry not allowed per COVID protocols) 
 
Open oral food challenge to amount determined by DBPCFC (Section 3.1.3) to confirm tolerance of threshold (if 
failed, can return for repeated Visit 1 with next lower dose if not already at 1/8 teaspoon).  
 
Training on measuring amounts for home use 
 
Provision of diaries and contact instructions 
 
 
Escalation Visits (3-8 visits depending upon starting point and progress) 

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Visits 2 (week 8), 3 (week 16), 4 (week 24), 5 (week 32), 6 (week 40), 7(week 48), 8 (week 56), 9 (week 64) for increasing 
amounts of peanut (visit length 2-3 hours). These visits stop at week 64 or when 1 Tablespoon (equivalent) is reached. 
Attempt to increase daily ingestion by open oral food challenge to next amount higher.  Maximum amount is 3 
teaspoons/equivalent. 
 
Physical exam, vital signs, medical history 
 
Blood samples, Visit 3, week 16 (before feeding challenge commences; not to exceed 5cc/kg on a single day or 
9.5ml/kg over any eight-week period per NIH guidelines) 
 
Spirometry or peak flow (optional under age 7) 
 
Open oral food challenge to amount determined by DBPCFC (Section 3.1.3) unless at top amount 
 
Training/review on measuring amounts for home use 
 
Collection/Provision of diaries and contact instructions 
 
Saliva and stool collection (visit 3) 
 
Quality of life survey, diet questionnaire   (visit 3) 
 
Desensitization  DBPCFC visit,  (week 72 or 8 weeks after reaching 1 Tablespoon or equivalent. Visit length 4-8 hours 
each of 2 days. 
 
Physical exam, vital signs, medical history 
 
Blood samples (before feeding challenge commences and 2 and 4 hours after starting;  not to exceed 5cc/kg on 
a single day or 9.5ml/kg over any eight-week period per NIH guidelines) 
 
Spirometry or peak flow (optional under age 7) 
 
DBPCFC to peanut per modified PRACTALL (and associated examinations) 
 
Skin prick test to peanut 
 
Quality of life survey, diet questionnaire   
 
Urine pregnancy if child bearing potential 
 
Saliva and stool collection 
This is the end of study visit for those not tolerating the DBPCFC and they will transfer to clinical management off of the 
study.  Those tolerating the DBPCFC  will proceed to the SU visit. 
Additional visits for evaluation of Sustained Unresponsiveness in Intervention Arm 
Sustained unresponsiveness visit  for DBPCFC  following 16 weeks of “ad lib” peanut (no upper limit but at least 2 
Tablespoons peanut butter or equivalent per week) and then 8 weeks peanut avoidance following the desensitization  
DBPCFC (visit length 4-8 hours each of 2 days).   
If the desensitization DBPCFC is passed , the subject will be instructed to incorporate peanut into the diet for 16 weeks. 
If this is tolerated, peanut will then be avoided for 8 weeks at which time the following procedure will be performed: 
 
Physical exam, vital signs, medical history 
 
Blood samples (before feeding challenge commences and 2 and 4 hours after starting ; not to exceed 5cc/kg on 
a single day or 9.5ml/kg over any eight-week period per NIH guidelines) 
 
Spirometry (or peak flow under age 7, or if spirometry not allowed per COVID protocols) 
 
DBPCFC to peanut per modified PRACTALL (and associated examinations) 
 
Skin Prick Test to peanut 
 
Saliva and stool collection 
 
Urine pregnancy if child bearing potential 
 
Diet questionnaire, Quality of life survey 

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If this DBPCFC is tolerated, the subject will eat peanut “ad lib” but with at least one weekly serving recommended 
(serving is about 2 Tablespoons peanut butter or equivalent).  If this DBPCFC is not tolerated, the subject will undertake 
clinical management off of the study.     
Control Arm 
Participants in the control arm will receive monthly telephone follow up and reporting of any allergic reactions, including 
reporting accidental exposure to peanut, and will keep a diary.  The diary will be accessed for the following issues:  ate 
peanut, and any reaction, symptoms or illnesses. These will be confirmed/reviewed monthly by telephone, email 
(printout as source) or in person visit to evaluate that the entries match what the experience is.  This will be 
documented on an eCRF (or email print out) and the clinical team will add any diary entries if needed. They will have a 
visit 16 weeks following the initial DBPCFC for review of avoidance instructions and collection of a blood sample, saliva 
and stool for mechanistic studies, and QoL and diet questionnaires. The control arm subjects will undergo a DBPCFC and 
procedures listed under desensitization  DBPCFC (above) are performed at a time determined by a surveillance 
algorithm  (see Section 13.3).  Control arm participants do not require follow up for SU. Those unable to tolerate the 
DBPCFC  will pursue clinical management off of the study, those who tolerate the full feeding may add peanut to the 
diet “ad lib” but with at least one weekly serving recommended and pursue clinical care off of the study. 
8.4 Unscheduled Visits  
If disease activity increases or other concerns arise between regularly scheduled visits, participants will be instructed to 
contact study personnel and may be asked to return to the study site for an “unscheduled” visit. If the participant 
becomes/is unable to ingest at least 1/8 teaspoon of peanut butter, they will undergo a supervised feeding of 1/16th 
teaspoon, which is the lowest amount permitted and may become the daily amount if tolerated.  If the participant 
cannot ingest 1/16th teaspoon of peanut butter they will be considered a treatment failure and will stop any daily 
ingestion, but will undergo the endpoint DBPCFCs at 72 weeks. 
The following circumstances may lead to unscheduled visits (active arm): 
1. Concern regarding peanut ingestion triggering increased chronic symptoms (e.g., increased eczema, gastrointestinal 
symptoms).  
Procedures (1-8 hour visit): 
 
Physical exam, vital signs, medical history 
 
Spirometry (or peak flow under age 7, or if spirometry not allowed per COVID protocols) 
 
DBPCFC to the amount being ingested on a daily basis, or supervised open feeding of the amount ingested on a 
daily basis, or supervised feeding of a lower amount, as deemed necessary for full evaluation 
The PI/Investigator and family will determine whether to continue daily ingestion, reduce the daily amount, or follow off 
intervention, and/or refer for additional medical evaluation (i.e., endoscopy). 
2. Concern regarding acute symptoms from home ingestion.  
Participants will be instructed to contact the PI/Investigator/study team for acute allergic symptoms (with the exception 
of oral pruritus, mild transient abdominal discomfort, or perioral redness/hives). The investigator will determine the best 
course of action, with possible actions being the following:  

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1. Continue with daily home dosing 
2. Return for an observed ingestion of the same amount 
3. Return for an observed ingestion of a step lower amount. 
4. Discontinuation of ingestion 
 
The following process algorithm will be applied regarding symptoms associated with the daily ingestion. 
If the subject only experiences oral/pharyngeal pruritus, or perioral redness/hives, or mild transient abdominal 
discomfort, the daily ingestion may continue.  Instructions about eating peanut with meals will be reviewed. If the 
symptoms are bothersome or persistent, procedures per #1 above (chronic symptoms) will be followed. 
 
If the subject experiences mild symptoms, defined as: 
o Skin – non-perioral hives/swelling, skin flushing or pruritus 
o Respiratory – rhinorrhea/sneezing, nasal congestion, occasional cough, throat discomfort 
o GI – abdominal pain that is more than mild transient/minor episode of vomit 
 
The action should be either to repeat the daily amount at home, or a reduced amount, or to have the subject 
return to the site for a repeat of the ingested amount or to trial a step lower amount (at the physician’s discretion).  
If the amount is tolerated, then the subject will continue on that amount until the next scheduled visit.  If the 
ingestion again causes mild symptoms, then the subject may return to the site to trial a lower amount, as possible.  
 
If the subject experiences moderate symptoms, defined as: 
o Skin – systemic hives/swelling 
o Respiratory – throat tightness without hoarseness, persistent cough, wheezing without dyspnea 
o GI – persistent moderate abdominal pain/cramping/nausea, increased vomiting 
The action should be to have the subject return to trial a lower amount, as possible and with physician discretion. 
If this amount is tolerated, it will be continued as the daily home ingestion amount until the next scheduled visit.  
If the amount is not tolerated, then a discussion with the Study PI or Co-PI will ensue to make a decision about 
whether to continue the subject on active ingestion in the study. 
 
If the subject experiences severe symptoms, defined as: 
o Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea  
o GI – significant severe abdominal pain/cramping/repetitive vomiting 
o Neurological – change in mental status 
o Circulatory – hypotension 
 
The action should be to treat the subject, and at the physician’s discretion either 1) have them return to the site 
for trial of a 2 step lower (at least) amount under observation or 2) discontinue them from the active arm.  If the 
subject tolerates the reduction, then they will remain on that amount until the next scheduled visit.  A discussion 
with the Study PI or Co-PI may ensue to make a decision about whether to continue the subject on active 
treatment in the study. 
For a completed ingestion visit with no symptoms, subjects should be observed for 30 minutes.  For mild 
symptoms, subjects should have a 1-2 hours post ingestion observation period.  For moderate to severe 

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symptoms, the observation period should be at least 4 hours and up to 24 hours based on symptoms and 
treatment regimen needed to stabilize. 
3. Excessive days without ingestion of peanut. 
Participants will be instructed to skip days ingesting peanut for illness.  However, if more than 5 consecutive 
days are missed, at the discretion of the PI, a visit for observed feeding may be undertaken versus allowing 
continuation at home. 
4. Early withdrawal. 
If the PI/Co-I or participant wishes to discontinue participation in the study, they will be asked to attend an early 
withdrawal visit for review of their diet, collection of diaries, blood, stool and saliva for mechanistic studies and 
completion of a QOL survey and diet questionnaire.   
8.5 Visit Windows 
Study visits should take place within the time limits specified as follows:  
The visit window between the screening DBPCFC and Visit 1 is 14 days.  The visit window for Visits 1-9  and SU visit is -7 
to +14 days.  The visit window for the Desensitization  DBPCFC visit is -7 days to 6 months. Due to the uncertainty of the 
COVID-19 pandemic and the challenges with in-person visits, a large window is necessary to provide sufficient 
opportunity for subjects to return for the primary endpoint visit.  For participants who pass this 6 month window by the 
time this version of the protocol has been approved, an extension of the window will be applied. If a visit window is 
missed for visits 2-9, the escalation will be skipped and addressed at the next scheduled escalation visit.  An exception is 
for visits 2-9 that cannot be undertaken for study pause for COVID or similar reasons in which case the visit window is 
not considered and the study visits resume when possible in the planned sequence. When face to face visits resume 
after a pause, the visit window period to resume an in-person visit from approval to restart is extended to 8 weeks to 
allow safe scheduling and ramp-up study restart. After the 8 week period, windows resume.  
 
Table 2. Table of Events (does not include unscheduled visits)  
Procedures  
Screening
/Baseline 
DBPCFC 
week 0, 3 
days 
Visit #1. Initial 
feeding with 
sub-threshold 
amount, week 
1  
Visit 2-9, 
evaluate to 
increase 
threshold, 
week 
8,16, 24, 32, 
40, 48, 56, 64 
(all visits may 
not be 
needed 
depending 
upon 
escalation 
progress)  
DBPCFC for 
desensitizatio
n (active) or 
follow up 
(controls) 
Week 32, 56, 
64 or 72 
SU DBPCFC (24 weeks after 
desensitization DBPCFC for 
those on active peanut 
Informed consent, 
screening, complete 
All  
 
 
 
 

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Procedures  
Screening
/Baseline 
DBPCFC 
week 0, 3 
days 
Visit #1. Initial 
feeding with 
sub-threshold 
amount, week 
1  
Visit 2-9, 
evaluate to 
increase 
threshold, 
week 
8,16, 24, 32, 
40, 48, 56, 64 
(all visits may 
not be 
needed 
depending 
upon 
escalation 
progress)  
DBPCFC for 
desensitizatio
n (active) or 
follow up 
(controls) 
Week 32, 56, 
64 or 72 
SU DBPCFC (24 weeks after 
desensitization DBPCFC for 
those on active peanut 
medical history, 
demographic 
questions  
Physical 
assessment, vital 
signs, spirometry, 
interval medical 
assessment 
All  
Intervention 
group 
Intervention 
group 
All 
Intervention group passing 
desensitization 
Pregnancy test 
(urine) for females 
of child bearing 
potential 
All  
 
 
All 
Intervention group passing 
desensitization 
DBPCFC as per 
PRACTALL protocol, 
up to cumulative 
dose 9043 
All  
 
 
All 
Intervention group passing 
desensitization  
Open peanut 
feeding for 
threshold  
 
Intervention 
group 
Intervention 
group 
 
 
Skin prick testing 
All  
 
 
All  
Intervention group passing 
desensitization  
Blood sample , stool 
and saliva collection  
All  
 
All, week 16 
All  
Intervention group passing 
desensitization  
Quality of life 
questionnaire, diet 
survey 
All  
 
All week 16 
All  
Intervention group passing 
desensitization  
Review adverse 
events and home 
food  
administration 
diary, report all 
 
 
All (including 
monthly call 
[monthly 
review call 
not 
All 
Intervention group passing 
desensitization  

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Procedures  
Screening
/Baseline 
DBPCFC 
week 0, 3 
days 
Visit #1. Initial 
feeding with 
sub-threshold 
amount, week 
1  
Visit 2-9, 
evaluate to 
increase 
threshold, 
week 
8,16, 24, 32, 
40, 48, 56, 64 
(all visits may 
not be 
needed 
depending 
upon 
escalation 
progress)  
DBPCFC for 
desensitizatio
n (active) or 
follow up 
(controls) 
Week 32, 56, 
64 or 72 
SU DBPCFC (24 weeks after 
desensitization DBPCFC for 
those on active peanut 
food allergic 
reactions (both 
randomized groups) 
performed if 
an in-person 
visit occurs; 
monthly calls 
continue until 
last study 
visit]). 
 
9 Mechanistic Assays 
Peripheral blood will be collected in sodium heparin tubes to obtain whole blood, plasma, and cells.  A whole blood 
aliquot will be stored at -80C, tubes will then be centrifuged to obtained plasma, and the remaining cellular fraction 
used for basophil activation and T cell assays. For biomarker identification, additional blood will be obtained in Tempus 
tubes for RNA isolation. This will be followed by library preparation and RNA sequencing. DNA may be isolated from 
selected whole blood aliquots for genotype determination by array. 
Plasma will be aliquoted and stored in cryovials at -80 C until use. An aliquot of blood (1 ml) will be used fresh for 
basophil activation tests. Briefly, whole blood will be stimulated with peanut extract or anti-IgE or fMLP as positive 
controls. Blood will be stained, fixed, and acquired by flow cytometry. Additional blood will be stimulated and 
cryopreserved for mass cytometry.  
The remaining cellular fraction will undergo ficoll separation for purification of PBMCs, which will be cryopreserved until 
use in batched stimulations.  
To assess T cell frequency and phenotype, PBMCs will be thawed, rested overnight, and stimulated with peanut antigen 
in the presence of Brefeldin A. After 6h, cells will be harvested. Peanut-responsive cells will be identified by upregulation 
of CD154 and CD137. Intracellular cytokines and surface markers will be used to identify T cell subsets.  
10 Biospecimen Storage 
Whole blood aliquots, plasma and Tempus tubes will be stored at -80 until use. Freezers are on emergency backup 
power and monitored by alarm system that alerts lab staff by phone call. 

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Cryopreserved PBMCs will be stored in alarm-monitored liquid nitrogen tank. 
 
 
11 Criteria for Participant and Study Completion and Premature Study Termination 
11.1 
Participant Completion 
Participants will be considered to have completed the protocol  if they completed the desensitization DBPCFC visit, or if 
they were in the active arm and tolerated peanut at desensitization DBPCFC and underwent evaluation for SU at final 
study visit .   
The statistical analysis plan allows for inclusion of non-completers (Section 13). 
11.2 
Participant Stopping Rules  
Participants may be prematurely terminated from the study for the following reasons: 
1. The participant elects to withdraw consent from all future study activities, including follow-up. 
2. 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).  
3. The participant dies.  
4. The Investigator no longer believes participation is in the best interest of the participant. This includes subjecs 
who refuse to come for the Desensitization  DBPCFC visit. 
5. Pregnancy 
6. Subjects who fail to adhere to the request to stop the study intervention per section 6.5 will be considered for 
premature termination.  Development of eosinophilic esophagitis 
  
11.3 
Participant Replacement 
Participants who withdraw or are withdrawn will not be replaced and will be part of the ITT analysis. 
11.4 
Follow-up after Early Study Withdrawal 
See section 8.4.    
11.5.  Study Stopping Rules 
There are no pre-specified study stopping rules, but study procedures and dosing will be temporarily suspended 
pending DSMB review (see 12.8.2.2.1) for the following reasons: 
 
Any death possibly related to study participation. 
 
2 subjects requiring more than 1 injection of epinephrine during  at-home, ingestion of study-allowed peanut. 
 
3 subjects diagnosed with eosinophilic esophagitis 
 

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12 Safety Monitoring and Reporting 
12.1 Overview 
 
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for 
appropriately collecting, grading, recording, and reporting those data. Adverse events that are classified as serious 
according to the definition of health authorities must be reported promptly (per Section 12.5, Reporting of Serious 
Adverse Events and Adverse Events) to the Sponsor-investigator, NIAID medical monitor, and Sponsor medical monitor.  
Appropriate notifications will also be made to site principal investigators, Institutional Review Boards (IRBs), and health 
authorities.  
Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical Practice, 21CFR Parts 312 and 320, and applies the 
standards set forth in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0 : http://ctep.cancer.gov/reporting/ctc.html. 
12.2 Definitions 
12.2.1 Adverse Event (AE) 
 
Any untoward or unfavorable medical occurrence associated with the subject’s participation in the research, whether or 
not considered related to the subject’s participation in the research (modified from the definition of adverse events in 
the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice) (from OHRP "Guidance 
on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events 
(1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2 )  
 
For this study, any adverse event will  be assessed for relationship during the following times frames with:   
 
Study therapy regimen: Ingestion of sub-threshold amounts of home-measured, home-purchased peanut.  AEs 
will be collected until study completion or withdrawal.  
 
Study mandated procedures: AEs associated with DBPCFC, blood draw, observed feedings, skin prick tests will 
be monitored for 24 hours after the procedure.  
 
12.2.1.1 Suspected Adverse Reaction (SAR) 
 
Any adverse event for which there is a reasonable possibility that the investigational drug [or 
investigational study therapy regimen] 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 event. 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)). 
 
12.2.2 Unexpected Adverse Event  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the protocol, or 
Informed Consent Forms or is not listed at the specificity, severity or rate of occurrence that has been observed; 
or, is not consistent with the risk information described in the general investigational plan or elsewhere. 
12.2.3 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator 
or Sponsor-Investigator, it results in any of the following outcomes (21 CFR 312.32(a)): 

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1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the 
investigator or Sponsor-Investigator its occurrence places the subject at immediate risk of death. It does not 
include an AE or SAR that had it occurred in a more severe form, might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
12.3 Grading and Attribution of Adverse Events 
12.3.1 Grading Criteria 
The study site will grade the severity of adverse events experienced by the study subjects according to the 
criteria set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE, 
5.0), with the exception of anaphylaxis which will be graded according to the scale included in the definition 
section  This document (referred to herein as the NCI-CTCAE manual) provides a common language to describe 
levels of severity, to analyze and interpret data, and to articulate the clinical significance of all adverse events. 
The NCI-CTCAE has been reviewed by the PI/Co-I and has been deemed appropriate for the subject population 
to be studied in this protocol.  
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 event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
Only events grade 2 or higher and SAEs will be recorded on the appropriate AE case report form for this study. 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not limited to, a 
radiograph, an ultrasound, an electrocardiogram etc.), a treatment-emergent adverse event is defined as an 
increase in grade from baseline or from the last post-baseline value that doesn’t meet grading criteria. Changes 
in grade from screening to baseline will also be recorded as adverse events, but are not treatment-emergent. If 
a specific event or result from a given clinical or laboratory evaluation is not included in the NCI-CTCAE manual, 
then an abnormal result would be considered an adverse event if changes in study therapy or monitoring are 
implemented as a result of the event. For additional information and a printable version of the NCI-CTCAE 
manual, consult the NCI-CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html. 
 
 
12.3.2 Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study procedure(s) will 
initially be determined by the site investigator or Sponsor-investigator and recorded on the appropriate AE 
eCRF.  Final determination of attribution for safety reporting will be determined by the Sponsor-Investigator.  
The relationship of an adverse event to study therapy regimen or procedures will be determined using the 
descriptors and definitions provided in Table 12.3.2.  

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Table 12.3.2 Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to primary investigational product 
and/or other concurrent mandated study therapy or 
study procedure) 
UNRELATED CATEGORY 
1 
Unrelated 
The adverse event is clearly not related:  there is 
insufficient evidence to suggest a causal relationship. 
 RELATED CATEGORIES 
2 
Possible 
The adverse event has a reasonable possibility to be 
related; there is evidence to suggest a causal 
relationship. 
3 
Definite 
The adverse event is clearly related. 
 
 
12.4 Collection and Recording of Adverse Events 
12.4.1 Collection Period 
Adverse events will be collected from the time of the onset of the event until a subject completes study 
participation or until 30 days after he/she prematurely discontinues (without withdrawing consent) or is 
withdrawn from the study by the investigator.  
12.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the subject. 
• 
Interviewing the subject [e.g., using a checklist, structured questioning, diary, etc.]  . 
• 
Receiving an unsolicited complaint from the subject. 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an adverse 
event, as defined in Section 12.3, Grading and Attribution of Adverse Events. 
12.4.3 Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse events as described 
previously (Section 12.2, Definitions) on the AE/SAE eCRF regardless of the relationship to study therapy 
regimen or study procedure.  
The investigator will treat subjects experiencing AEs appropriately and observes them at suitable intervals until 
their symptoms resolve or stabilize.  Once recorded, an AE/SAE will be followed until it resolves with or without 
sequelae, or until the end of study participation, or until 30 days after the subject prematurely withdraws 
(without withdrawing consent)/or is withdrawn from the study, whichever occurs first. 
 
12.5 Reporting of Serious Adverse Events and Adverse Events 

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12.5.1 Reporting of Serious Adverse Events 
This section describes the responsibilities of the Sponsor- investigator to report serious adverse events.  Timely 
reporting of adverse events is required by 21 CFR and ICH E6 guidelines.  
Site investigators will report all serious adverse events to the Sponsor-Investigator (see Section 12.2.3, Serious 
Adverse Event), regardless of relationship or expectedness within 24 hours of discovering the event. The Sponsor 
investigator will inform the DAIT NIAID Medical Monitor and Sponsor Medical Monitor in real time 
For serious adverse events, all requested information on the AE/SAE CRF will be provided.  However, unavailable 
details of the event will not delay submission of the known information.  As additional details become available, 
the AE/SAE CRF will be updated and reported. 
12.5.2 Reporting to Health Authority 
The Sponsor-Investigator of the IND  has the responsibility of reporting all AEs and SAEs to the FDA within the 
reporting time limits set forth by the FDA. It is the Sponsor-investigator’s responsibility to report any serious 
adverse event to the Sponsor Medical Monitor at his site and to the NIAID Medical Monitor within 24 hours of 
becoming aware of the event.  
After an adverse event requiring 24-hour reporting (per Section 12.5.1, Reporting of Serious Adverse Events to 
Sponsor) is reported  by the site investigator and assessed by Sponsor-Investigator, there are two options for 
reporting the adverse event to the  FDA: 
12.5.2.1 Annual Reporting 
The Sponsor-Investigator will report  in the annual study report to FDA  all adverse events classified as: 
o Serious, expected, suspected adverse reactions (see Section 12.2.1.1, Suspected Adverse Reaction, 
and Section 12.2.2, Unexpected Adverse Event). 
o Serious , and not a suspected adverse reaction (see Section 12.2.1.1, Suspected Adverse Reaction). 
o Pregnancies. 
Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the Annual 
IND Report. 
12.5.2.2 Expedited Safety Reporting  
This option, with 2 possible categories, applies if the adverse event is classified as one of the following: 
Category 1:  Serious, unexpected and suspected adverse reaction [SUSAR] (see Section 12.2.1.1, 
Suspected Adverse Reaction and Section 12.2, Unexpected Adverse Event).  
The sponsor shall report any suspected adverse reaction that is both serious and unexpected.  
The sponsor shall 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: 
1. 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); 
2. 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); 

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3. An aggregate analysis of specific 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. 
 
 
Category 2: Any findings from studies that suggests a significant human risk  
 
The sponsor shall report any findings from other epidemiological studies, analyses of adverse 
events within the current study or pooled analysis across clinical studies or animal or in vitro 
testing (e.g. mutagenicity, teratogenicity, carcinogenicity) that suggest a significant risk in 
humans exposed to the drug that would result in a safety-related change in the protocol, 
informed consent, investigator brochure or package insert or other aspects of the overall 
conduct of the study.   
 
The IND Sponsor-Investigator shall notify the appropriate FDA and all participating sub investigators of 
expedited safety reports within 15 calendar days; unexpected fatal or immediately life-threatening 
suspected adverse reaction(s) shall be reported as soon as possible or within 7 calendar days.  
12.5.3 Reporting of Adverse Events to IRBs/IECs 
All investigators shall report adverse events, including expedited reports, in a timely fashion to their 
respective IRBs/IECs in accordance with applicable regulations and guidelines. All reports shall be distributed 
by DAIT/NIAID or designee to all participating institutions for site IRB/IEC submission.  
   12.6   Pregnancy Reporting 
 
The females in this study will largely be pre-menarche.  If a participant reports the onset of menarche, they will 
be counseled to use birth control if participating in sexual activity. The investigator shall be informed 
immediately of any pregnancy in a study subject.   A pregnant subject shall be instructed to stop taking study 
intervention.  The investigator shall counsel the subject and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. Monitoring of the pregnant subject shall continue until the conclusion of 
the pregnancy.   There are no reasons to think there would be an adverse effect on the pregnancy of a female 
partner of a male participant, and therefore, these pregnancies will not be followed. 
The investigator or Sponsor-investigator shall report to the DAIT/NIAID Medical Monitor and the Sponsor 
Medical Monitor all participant pregnancies within 1 business day of becoming aware of the event using the 
Pregnancy eCRF.  All participant pregnancies identified during the study shall be followed to conclusion and the 
outcome of each must be reported.  The Pregnancy eCRF shall be updated and submitted to the SACCC and 
DAIT/NIAID when details about the outcome are available.   
Information requested about the delivery shall include: 
o 
Gestational age at delivery 
o 
Birth weight, length, and head circumference 
o 
Gender 
o 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, and 24 hours 
after birth, if available 

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o 
Any abnormalities. 
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and medically 
indicated abortion - an SAE shall be submitted to the SACCC and DAIT/NIAID using the SAE reporting procedures 
described above.   
12.7 Reporting of Other Safety Information 
An investigator or Sponsor-investigator shall promptly notify the site IRB as well as DAIT/NIAID Medical Monitor 
and the Sponsor Medical Monitor by telephone or email  when an “unanticipated problem involving risks to 
subjects or others” is identified, which is not otherwise reportable as an adverse event. 
12.8 Review of Safety Information 
12.8.1 Medical Monitor Review 
The Sponsor Medical Monitor and the DAIT/NIAID Medical Monitor shall receive monthly line listing reports 
from the site compiling new and accumulating information on AEs, SAEs, and pregnancies recorded by the study 
site on appropriate eCRFs. 
In addition, the DAIT/NIAID Medical Monitor shall review and recommend on the disposition of  SAE and 
pregnancy reports received by the Sponsor-Investigator (See Sections 12.5.1, Reporting of Serious Adverse 
Events to Sponsor, and 12.6, Pregnancy Reporting).   
12.8.2 DSMB Review 
 
12.8.2.1 Planned DSMB Reviews  
The Data and Safety Monitoring Board (DSMB) shall review safety data at least yearly during planned 
DSMB Data Review Meetings. Data for the planned safety reviews will include, at a minimum, a listing of 
all reported AEs and SAEs.   
The DSMB will be informed of an Expedited Safety Report in a timely manner.   
12.8.2.2 Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called 
upon for ad hoc reviews. The DSMB will  review any event that potentially impacts safety at the request 
of the protocol chair or DAIT/NIAID. In addition, the following events will trigger an ad hoc 
comprehensive DSMB Safety Review: Meeting study stopping rules (Section 11.5) 
After review of the data, the DSMB will make recommendations regarding study conduct and/or 
continuation. 
12.8.2.2.1 Temporary Suspension of enrollment, dosing and study procedures (skin tests, 
DBPCFC)  for ad hoc DSMB Safety Review  
A temporary halt in enrollment, DBPCFC, SPT and daily ingestion will be implemented if an ad 
hoc NIAID DSMB safety review is required.  
A safety related suspension of enrollment will occur, pending expedited review of all pertinent 
data by the institutional review board (IRB), the National Institute of Allergy and Infectious 

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Diseases (NIAID) Medical Monitor, and the NIAID Data Safety Monitoring Board (DSMB) based 
on the following:  
• 
Any death possibly related to study participation  
• 
2 subjects requiring more than 1 injection of epinephrine during for at-home, study-
allowed ingestion of study-allowed peanut. 
• 
3 subjects diagnosed with eosinophilic esophagitis. 
13 Statistical Considerations and Analytical Plan 
13.1 
Overview  
The primary objective of this study is to test a simple peanut feeding protocol in children with a high threshold 
form of peanut allergy, allowing them to ingest a tolerated amount of peanut and to periodically try larger 
amounts under medical supervision, to determine whether allowing ingestion of sub-threshold amounts of 
peanut will be associated with increasing their threshold with time. The secondary clinical objectives include 
assessing for the development of sustained unresponsiveness (SU, a surrogate term for tolerance without daily 
ingestion), effects on quality of life, and safety.  Additionally, this study will result in phenotyping the allergic 
response to peanut based on threshold and response to exposure.  Mechanistic study objectives will determine 
immune characteristics of the high threshold endotype and predict response to exposure and determine 
mechanisms of remission.  Mechanistic studies/biomarker studies will also identify genes that are differentially 
expressed in the resting state of peanut allergic subjects with high and low threshold reactivity, those associated 
with severity, and response to exposure.   
This is a randomized, two-arm parallel-group, controlled open trial.  The study randomizes (1:1) children age 4-
14 years with high threshold peanut allergy to ingest a sub-threshold amount of peanut daily or to follow 
avoidance.   
13.2 
Endpoints  
 
The clinical endpoints are: 
Primary endpoint:  The difference in the percentage of children who by the desensitization DBPCFC tolerate a 
dose at least 2 steps higher than their baseline DBPCFC or the full dose (9043 mg) of peanut protein in the two 
HT groups. 
Secondary endpoints: The following secondary clinical endpoints will be compared between subjects in the 
intervention and control arm 
1. The percentage of children who achieve SU or natural tolerance during the study. 
2. Safety parameters (acute allergic reactions, including anaphylaxis, gastrointestinal side effects). 
3. Quality of life measures.  
4. SPT mean wheal size changes. 

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The mechanistic endpoints are: 
1.Peanut and Ara h 2-specific IgE. 
2. Peanut and Ara h 2-specific IgG4 
3. Epitope binding score for IgE and IgG4. 
4. Basophil activation measured by flow cytometry after peanut activation 
5. Frequency of peanut-specific Th2 cells 
6. Frequency of peanut-specific Tregs 
7.Data-driven identification of functional pathways (derived from transcriptional data) underlying successful 
desensitization. 
Secondary mechanistic endpoints: 
1. Baseline mechanistic measures 1-7 from primary endpoints will be used to test prediction of desensitization or 
sustained unresponsiveness.  
2. Baseline mechanistic measures 1-7 from primary endpoints will be used to test prediction of the high threshold 
phenotype. 
3. (Exploratory) Early-appearing functional pathways (derived from transcriptional data) underlying a successful 
desensitization course. 
 
13.3 
Measures to Minimize Bias  
Although this is an open trial, DBPCFCs will be performed by staff blinded to randomization assignment.  
Randomization will be stratified by age (4-<10 years vs. 10-14 years) and reaction dose at the initial DBPCFC, 
balanced by blocks of 4 and 6. This will guarantee that both treatment arms have similar distribution of those 
covariates without pre-specifying a number of patients per strata, which will limit enrollment. Clinical samples 
for mechanistic studies will be received by the laboratory personnel in coded fashion without indication of 
intervention allocation. 
 
Defining the timing for the DBPCFC in the control group: Time from randomization to the DBPCFC will be dictated 
by the  achievement of 1 tbsp threshold in children in the intervention group. In order to ensure that the two 
trial arms will have the same time to DBPCFC on average, we will develop an  adaptive algorithm to assign a time 
to DBPCFC in avoiders that matches that of the consumers.  After the baseline DBPCFC, patients in the avoider 
group will be assigned a ‘time to the second DBPCFC’ as a value randomly selected from the distribution of the 
consumer patients with the same baseline reactive dose. Initial distributions for time to DBPCFC will be assumed 
to follow a uniform distribution centered on the treatment expectations anticipated by the clinicians based on 
initial DBPCFC (i.e. ~32 weeks for those who fail at 3000 mg, ~72 weeks for those who fail at 300 mg) plus minus 

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3 weeks. After the recruitment of every 10 patients, the time to OFC distribution for each baseline reactive dose 
will be updated as a uniform distribution derived from the time to OFC of consumer patients if 2 or more 
observations are available, otherwise we will keep the initial uniform distribution for that baseline reactive dose. 
The statistician will receive an email from RedCap alerting them that 10 new patients had been accrued; and will 
update the timing distributions. Once a patient is randomized to the Avoider group, the unblinded statistician 
will send the timing of the second  DBPCFC to the study coordinator, who will enter the assigned time into 
RedCap. For monitoring and data checking purposes, the unblinded statistician will maintain their own records. 
Inconsistencies will be identified and resolved in a timely manner within the monitoring process when producing 
data inconsistencies and data completeness reports.  
 
13.4 
Analysis Plan 
13.4.1 Analysis Populations. 
 
 
An intention-to-treat (ITT) analysis will be performed for the primary analysis and for selected secondary 
 
 
analyses. All hypothesis tests will be two-sided and performed at the 5% significance level. Baseline  
 
 
characteristics will be summarized for all of the patients in the ITT population.  
13.4.2 Primary Analysis of Primary Endpoint(s)/Outcome(s)   
 
 
The primary endpoint of this study is the ability to tolerate a dose at least 2 steps higher than the one 
tolerated at baseline or 9043 mg of peanut protein by the desensitization  DBPCFC.  The proportion of subjects in the 
intervention and the control group meeting the primary outcome will be compared using a continuity corrected chi-
squared test at the 0.05 significance level. As the intent-to-treat principle includes all randomized subjects in the primary 
analysis, patients who are missing the trial’s primary endpoint will have their outcome imputed using multiple 
imputation techniques.  Missing data in the primary endpoint will be assumed to depend only on the observed values, 
i.e., data are missing at random (MAR). Data imputation under this assumption will be performed using the proposed 
multiple imputation method by Rubin.77 Covariates in the imputation model will include treatment assignment, gender, 
age and baseline reactive dose strata, clinical severity during DBPCFC as well as peanut-specific IgE levels at baseline and 
week 16. 
 
13.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s)  
Sensitivity analyses will be performed to assess the sensitivity of the primary analysis results to choice of statistical test 
and missing imputation procedure as well as departures of the MAR assumption and to treatment cross-overs. 
Sensitivity analysis include:  
a) Stratified Chi-square test (by baseline reactive dose and age strata) 
b) Fisher’s exact test under 5 ad-hoc imputation strategies: i) all are failures, ii) are all failures except the highest dose at 
baseline which are successes, iii) all are failures except highest two doses at baseline, iv) all are successes except lowest 
dose at baseline, and v) all are successes.  That is, the first and last of the five are the least conservative, respectively, 
and the others are in between but use the baseline dose as a means of an intermediate approach, which also 
incorporates a possible difference in distribution of baseline doses between the groups. 

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c) If the MAR assumption is not tenable, statistical methods that assume missing not at random (MNAR) such as pattern 
mixture models for non-ignorable missing data will be considered. 
d) When cross-over rates are high, the ITT effect of being assigned to treatment may differ from the effect of actually 
receiving treatment.  As a sensitivity analysis, we will perform an instrumental variable (IV) analysis to obtain an 
unbiased estimate of the treatment effect, using randomization assignment as the instrument. 
e) Given the potential impact of COVID-19 pandemic on subject’s return for the Desensitization  DBPCFC visit, we will 
perform a sensitivity analysis that examines the effect of intervention on primary endpoint success adjusting for time 
from randomization to Desensitization  DBPCFC visit and whether patients were randomized prior to study pause in 
March 2020 using logistic regression modelling. 
 
13.4.4 Analyses of Secondary and Other Endpoint(s)/Outcome(s) 
 
Sustained unresponsiveness or natural tolerance: The proportion of children who 
experience SU in the active arm of the HT group will be compared to the proportion of children who achieve natural 
tolerance  in the control arm in an intent-to-treat analysis using a continuity corrected chi-squared test, similar to the 
plan detailed for the primary endpoint.  
 
Immunological parameters: Changes in skin prick test mean wheal diameter will be 
compared between randomization groups using linear mixed effects models for data collected at baseline and 
desensitization DBPCFC.  The linear mixed effects model has the advantage that the estimation of the model parameters 
will be unbiased even in the presence of missing outcomes, assuming that the missing values depend only on the 
observed values (MAR). If the MAR assumption is not plausible, pattern-mixture modeling (which stratifies subjects by 
their pattern of missing data) will be used.  
 
Quality of life: Changes in quality of life over the study as measured by The Food 
Allergy Quality of Life-Parental Burden76 will be compared between randomization groups and analyzed using linear 
mixed effects models as described previously (Immunological parameters, above).  
 
Adverse Events: Adverse events (AEs) will be coded using the CTCAE, Common 
Terminology Criteria for AE, V4.0. Individual adverse events will be summarized as the number (%) of events and number 
(%) of patients with the event in each group.  Adverse events will be modelled using Poisson regression and the rate of 
individual adverse events will compared between randomization arms over the study period.  Long-term adverse events 
will be evaluated with data up to 96 weeks for those in the active group who are tested for SU following a 
desensitization DBPCFC. 
13.4.5 Analyses of Exploratory Endpoint(s)/Outcome(s) 
 
 
Not applicable. 
13.4.6 Descriptive Analyses  
 
Descriptive analysis will be used to describe patient variables such as age, sex, race/ethnicity, atopic conditions,  
 
use of medications, allergic reactions, and study completion.  
13.5 
Interim Analyses  
Not applicable. 

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13.5.1 Interim Analysis of Efficacy Data-NA 
13.5.2 Interim Analysis of Safety Data-NA 
13.5.3 Futility Analysis-NA 
13.6 
Statistical Hypotheses  
We hypothesize that for persons with high threshold peanut allergy, ingesting sub-threshold amounts of the allergen 
(amounts not causing symptoms) will result in an ability to ingest higher amounts with time (desensitization) and 
potentially sustained unresponsiveness (SU). We also hypothesize that the approach will be safe and improve quality of 
life compared to avoidance.   
Section 13.7 describes the statistical considerations for these differences. 
13.7 
Sample Size Considerations  
The primary objective of this study is to compare the proportion of children who at the desensitization  DBPCFC tolerate 
an amount at least 2 steps higher than the baseline amount or who tolerate the full dose (9043 mg) of peanut protein 
between the active and the control arm in the HT group.  Secondary clinical outcomes of this study include sustained 
unresponsiveness, skin prick test mean wheal diameters, quality of life, and adverse events.  For sample size 
calculations, we assume a conservative estimate for the proportion of spontaneous tolerance in the control group of 
10%. We believe that an additional absolute increase of 45 percentage points under the intervention is feasible and 
clinically meaningful (55% vs. 10%).  We also assume a drop-in rate (avoiders to consumers) and drop-out rate 
(consumers discontinuing study treatment) of 5%and 20%, respectively. This results in an attenuated effect size of 
33.75% percentage points (46% vs. 12.25%.  A total of 72 children randomized with equal probability to the active or 
control arm (36per group) provides approximately 85% power to detect a difference of 33.75% (46% versus 12.25%) in 
the proportion of children who tolerate at least 2 steps higher amount from baseline or the full amount of peanut 
protein by the desensitization DBPCFC, based on a 0.05 level continuity corrected chi-squared test. We believe the drop-
in rate will be kept at a minimum since parents and children will likely not attempt dose escalation on their own. The 
drop-out rate is conservative, based on our prior experience, which reported a drop-out rate of 15%.  
We do not anticipate many families becoming “drop-in” doing this because those randomized to avoidance will not have 
their tolerance of a specific measured amount confirmed under supervision and there is generally a concern of allergic 
reactions from ingestion. More importantly, we believe this concern will be easily addressed because there are true 
issues of equipoise.  It may be that those randomized to ingestion will have more allergic reactions than controls,45 or 
develop side effects such as eosinophilic esophagitis,73 or not be able to progress on the large steps outlined in the 
PRACTALL modified dosing.  If families on avoidance are non-adherent, we can detect this.  We will monitor peanut-
specific IgG levels in all participants and those with rising peanut-specific IgG from ingestion could be identified. The 
statistical analysis plan includes a sensitivity analysis that uses instrumental variable methods to obtain an unbiased 
estimate of the treatment effect in the presence of cross-overs.   
14 Identification and Access to Source Data 
14.1 
Source Data 
Source documents and source data are considered to be the original documentation where subject information, visits 
consultations, examinations and other information are recorded.   Documentation of source data is necessary for the 
reconstruction, evaluation and validation of clinical findings, observations and other activities during a clinical trial. 

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14.2 
Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID staff, as well as to relevant 
health authorities.  Authorized representatives as noted above are bound to maintain the strict confidentiality of 
medical and research information that may be linked to identified individuals. 
15 Protocol Deviations 
15.1 
Protocol Deviation Definitions 
Protocol Deviation – The investigators and site staff will conduct the study in accordance to the protocol; no deviations 
from the protocol are permitted.  Any change, divergence, or departure from the study design or procedures constitutes 
a protocol deviation.  As a result of any deviation, corrective actions will be developed by the site and implemented 
promptly. 
 
Major Protocol Deviation (Protocol Violation) - A Protocol Violation is a deviation from the IRB approved protocol that 
may affect the subject's rights, safety, or well-being and/or the completeness, accuracy and reliability of the study data.  
In addition, protocol violations include willful or knowing breaches of human subject protection regulations, or policies, 
any action that is inconsistent with the NIH Human Research Protection Program’s research, medical, and ethical 
principles, and a serious or continuing noncompliance with federal, state, local or institutional human subject protection 
regulations, policies, or procedures.  
 
Non-Major Protocol Deviation - A non-major protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that does not have a major impact on the subject's rights, safety or well-
being, or the completeness, accuracy and reliability of the study data. 
15.2 
Reporting and Managing Protocol Deviations 
The study site principal investigator has the responsibility to identify, document and report protocol deviations as 
directed by the study Sponsor.  However, protocol deviations may also be identified during site monitoring visits or 
during other forms of study conduct review. Upon determination that a protocol deviation has occurred, the staff will a) 
notify the Principal Investigator, b) notify the NIAID Project Manager and c) will begin completing the Protocol Deviation 
CRF.  The PI will be responsible for providing NIAID with listings of all protocol deviations periodically.  NIAID may 
request discussion with the Principal Investigator and the Independent Medical Monitor to determine the effect of the 
protocol deviation on the study. 
16 Ethical Considerations and Compliance with Good Clinical Practice 
16.1 
Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance, and according to the criteria specified in this study protocol.  Before study 
initiation, the protocol and the informed consent documents will be reviewed and approved by the [select: IRB, Ethics 
Committee].  Any amendments to the protocol or to the consent materials will also be approved by the [select: IRB, 
Ethics Committee] before they are implemented. 
16.2 
Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will allow adequate time 
for review and discussion prior to his/her decision.  The principal investigator or designee listed on the Investigator of 

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Record form will review the consent and answer questions. Study staff approved by the Investigator and IRB as qualified 
may also obtain consent.  The prospective participant/parent will be told that being in the trial is voluntary and that he 
or she may withdraw from the study at any time, for any reason.  All participants (or their legally acceptable 
representative) will read, sign, and date a consent form before undergoing any study procedures.  Consent materials will 
be presented in participants’ primary language. A copy of the signed consent form will be given to the participant.  
 
The consent process will be ongoing with verbal review of the nature of the study at least yearly.  The consent form will 
be revised when important new safety information is available, the protocol is amended, and/or new information 
becomes available that may affect participation in the study.   
16.3 
Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant will be assigned a 
unique identification number and these numbers rather than names will be used to collect, store, and report participant 
information.  Site personnel will not transmit documents containing personal health identifiers (PHI) to the study 
sponsor or their representatives. 
17 Publication Policy 
The NIH policy on the publication of study results will apply to this trial. 
18 References 
 
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List of Tables- 
Table 1: Selected studies reporting threshold doses during diagnostic oral food challenges in food allergy practices 
Table 2. Table of Events (does not include sustained unresponsiveness visits)  
Table 12.3.2 Attribution of Adverse Events 
List of Figures- 
Figure 1. Initial screening DBPCFC to phenotype threshold, obtain biosamples, and identify those qualified for 
randomization. 
Figure 2. Randomized Intervention Study scheme 

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List of Appendices- NA