T Cell Reagent Research for Monitoring T Cells in Food Allergy (MOTIF) Phase 2 Study Using Food Allergen Oral Immunotherapy for Shrimp or Cashew Allergies
Phase: PHASE2
Conditions: Allergy;Food, Allergy to Shrimp, Allergy to Cashew Nut (Disorder)
Sponsor: Sayantani B. Sindher

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OIT in Shrimp or Cashew allergy (MOTIF protocol)  Version 4.0 26MAY2022  
 
 
 
 
    PROTOCOL NUMBER: UO1-STAN-003 
T Cell Reagent Research for Monitoring T Cells in Food Allergy (MOTIF) 
Phase 2 study using food Allergen Oral Immunotherapy for Shrimp or Cashew allergies 
VERSION NUMBER / VERSION DATE: 4.0 / 26MAY2022 
IND
 (with cross reference to IND
 & 
) 
NIAID Funding Mechanism: UO1 RFA-AI-16-027 NCT#: 03504774 
 
 
IND Sponsor:  Stanford (Sayantani Sindher, MD)  
Study Drug Manufacturer/Provider: Sean N. Parker Center for Food Allergy and Asthma Research (SNP)-
Clinical Research Unit (
) and cGMP Facility (
) Stanford 
Packard El Camino Hospital, Mountain View, CA. 
 
 
PROTOCOL PI-  
Kari C. Nadeau, MD, PhD 
Stanford University 
240 Pasteur Drive, 
  
Palo Alto, CA 94304 
Phone: 
 
Fax: 
 
E-mail: knadeau@stanford.edu 
 
MEDICAL MONITOR- 
, MD, MPH 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and 
Infectious Diseases 
5601 Fishers Lane 
Bethesda, MD 20892-9828, USA 
Phone: 
 
E-mail: 
 
 
Independent Medical Monitor - 
, MD 
875 Blake Wilbur Drive, 
 
Stanford, CA 94305 
Phone: 
 
Fax: 
 
 
CO-PI-  
Sharon Chinthrajah, MD 
Stanford University 
240 Pasteur Drive, BMI  1700  
Palo Alto, CA 94304 
Phone: 650 521 7237 
Fax: 650-724 0198 
E-mail: schinths@stanford.edu 
 
SITE_PI 
Sayantani B. Sindher, MD 
Stanford University 
LPCH El Camino Hospital 
2500 Grant Road, Room 4C347 
Mountain View, CA 94040 
Phone: 650-521 7237 
Fax: 650-724 0198 
E-mail: tina.sindher@stanford.edu 
 
PROJECT MANAGER- 
, RN, BSN 
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  
BIOINFORMATICIAN- 
, PhD 
Stanford University 
1070 Arastradero Road, 
 
Palo Alto, CA 94304 
Phone: 
 
Fax: 
 
E-mail: 
 
 
REGULATORY OFFICER- 
, PHD 
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: 
 
E-mail:  
 
 
BIOSTATISTICIAN-  
, MSc 
Stanford University 
240 Pasteur Drive, 
  
 Palo Alto, CA 94304 
Phone: 
 
Fax: 
 
E-mail: 
 
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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OIT in Shrimp or Cashew allergy (MOTIF protocol)  Version 4.0 26MAY2022  
 
 
 
 
 
 
 
 
 
 
INVESTIGATOR SIGNATURE PAGE 
Protocol:  
U01-STAN-003  
Version/Date:  
V4.0 / 26MAY2022  
Site Principal Investigator:  Sayantani Sindher, MD 
Title: T Cell Reagent Research for Monitoring T Cells in Food Allergy 
Phase II Study using food Allergen Oral Immunotherapy for Shrimp or Cashew allergies   
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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OIT in Shrimp or Cashew allergy (MOTIF protocol)  Version 4.0 26MAY2022  
 
Protocol Synopsis 
Title 
T Cell Reagent Research for Monitoring T Cells in Food Allergy 
Phase 2 study using Food Allergen Oral Immunotherapy for Shrimp 
or Cashew Allergies 
Short Title 
Monitoring T cells in Food Allergy (MOTIF) 
Clinical Phase 
Phase II 
Number of Sites 
1 
 
IND Sponsor/Number   
Sayantani Sindher, MD
 
Study Objectives 
Primary Objective: 
To determine T cell, immune-based mechanisms of food allergy 
(FA) and to optimize T cell reagent discovery and validation by 
obtaining blood samples from FA participants undergoing oral 
immunotherapy (OIT), and simultaneously, develop diagnostic, 
prognostic, and mechanistic tools based on the T cell reagents 
developed during the course of OIT.  
 
Secondary Objectives: 
• 
Identify, characterize, and validate new T cell epitopes for 
important food allergens (cashew, shrimp) 
• 
Track the numbers and functions of epitope-specific T cells 
during stages of FA OIT 
• 
Associate these parameters with phenotype and endotype 
characterizations in food-allergic individuals 
• 
Determine whether immune monitoring measurements 
reflecting these underlying mechanisms can be used to 
predict responses to OIT 
Exploratory Clinical objectives: 
• 
To evaluate desensitization protocols for cashew and shrimp 
in allergic individuals 
Determine whether the achievement of sustained 
unresponsiveness is different between cashew, or shrimp food 
allergy participants after a period of withdrawal from OIT 
Study Design 
A prospective Phase 2, single-center, single-allergen OIT of cashew 
or shrimp in participants with proven allergies to either cashew or 
shrimp, respectively. We intend to treat 72 participants, ages 7 to 
55 years with an allergy to either cashew, or shrimp determined by 
Double Blind-Placebo Controlled-Food Challenges (DBPCFC), 
allergy history, clinical symptoms, food-allergen (FA)-specific IgE 
levels, and skin prick test (SPT). Enrolled participants must be 

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OIT in Shrimp or Cashew allergy (MOTIF protocol)  Version 4.0 26MAY2022  
positive at or before the 300 mg (443 mg cumulative) dosing level 
of FA protein. OIT treatment groups will be cashew or shrimp.  
All cohorts will undergo an updosing regimen starting at 5 mg 
allergen, with dose escalation every 2 weeks to reach a 1,000 mg 
dose at week 28, after which they will be maintained at that dose 
for 24 weeks. At the conclusion of the maintenance phase (Week 
52), participants will undergo DBPCFC. Participants that pass their 
food challenge with no or mild objective reactions to up to a 
cumulative 2043 mg of the FA allergen in their OIT at the end of 
this phase (primary outcome) will be considered desensitized and 
have successfully met the primary endpoint.  
All participants then will continue in the study by undergoing a 
withdrawal from OIT for 6 weeks to examine mechanisms 
underlying sustained responsiveness (SU) which will be defined as 
a participant’s passing DBPCFC with no or mild objective reaction 
to up to a cumulative 2043 mg of the FA allergen in their DBPCFC 
at week 58. Those participants who pass the Week 58 challenge up 
to a cumulative of 2043 mg will be given the option to continue 
the withdrawal phase up to Week 64 which will be end of study. 
Week 58 will be end of study for those who do not opt for this 
continuation of withdrawal.  
Primary Endpoint(s) 
Change in expression of CD28 in the CD4+ allergen specific 
(CD154+) T-cells at 52 weeks relative to baseline values between 
those who do and do not tolerate a cumulative of 2043 mg in the 
DBPCFC at week 52.  
Secondary Endpoint(s)  
 
 
 
• 
Compare changes in expression of CD28+ allergen specific 
(CD154+ ) T-cells over multiple time points from baseline to 
week 58 and week 64 between those with sustained 
unresponsiveness (SU) vs those desensitized but SU failures 
vs those who did not pass the desensitization DBPCFC 
• 
Compare changes in the following measures in CD4+CD28+ 
allergen specific (CD154+ ) T-cells at week 52 and week 58 
between those who achieved sustained unresponsiveness 
(SU) vs those desensitized but SU failures vs those who did 
not pass the desensitization DBPCFC at week 52. 
o Levels of IFN-gamma 
o Levels of IL-4  
o Receptor diversity in allergen specific T cell CDR3b as 
compared to non-specific T cells 
o Levels of IL-10  
o Levels of TGF beta 
o Levels of GPR15 
o Levels of CCR4+ 
o Levels of CRTh2 

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Exploratory Clinical Objectives 
Comparing the proportion of participants who become 
desensitized vs all others (i.e. treatment failures) at week 52 
DBPCFC. 
Comparing the proportion of participants who reach SU vs 
desensitized but SU failures at week 58 DBPCFC. 
Comparing changes in the transcriptomes and phenotypes of 
tetramer+ T cells from baseline to 52 weeks, 58 weeks, and to 64 
weeks. 
Safety Endpoints 
The proportion of participants with only mild AEs during the course 
of the study. 
 
The proportion of participants with respiratory or abdominal 
severe AEs during the course of the study. 
 
The proportion of participants who successfully pass a DBPCFC 
with no or mild objective reactions to a cumulative 2043 mg of the 
FA allergen at the end of OIT (desensitization, week 52). 
 
The proportion of participants who successfully pass a DBPCFC 
with no or mild objective reactions to a cumulative 2043 mg of the 
FA allergen after 6 weeks off OIT (sustained unresponsiveness, 
week 58) and the subsequent optional DBPCFC at Week 64 (please 
see Appendix 2). 
Accrual Objective 
72 
Study Duration 
Participants will be in an active phase of the protocol for about 16 
months (see Appendix 1 for individual subject timeline) 
Treatment Description  
Subjects will undergo an initial dose day for consumption of a 
maximum single dose of 5 mg food allergen (cashew, or shrimp) 
protein. They will consume this dose at home for two weeks and 
document reactions. Upon returning to the SNP-CRU (Sean N 
Parker-Clinical Research Unit) two weeks later, a dose escalation 
will be attempted. This escalation will continue until the subject 
reaches a maximum dose of 1,000 mg protein daily at week 28.   
Participants then will continue that maintenance dose until Week 
52 from baseline before they undergo DBPCFC, which will mark the 
end of treatment intervention. 
Inclusion Criteria 
• 
Subject and/or parent guardian must be able to understand 
and provide informed consent 
• 
Age 7 through 55 years (inclusive) 
• 
Clinical history of allergy to cashew or shrimp-containing foods 

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OIT in Shrimp or Cashew allergy (MOTIF protocol)  Version 4.0 26MAY2022  
• 
Serum IgE to cashew or shrimp of ≥0.35 kUA/L [determined by 
UniCAPTM within the past 12 months] and/or a SPT to   
cashew or shrimp ≥3 mm compared to control 
• 
Experience dose-limiting symptoms at or before the 300 mg 
challenge dose of FA protein on Screening DBPCFC conducted 
in accordance with PRACTALL guidelines 
• 
Written informed consent from adult participants 
• 
Written informed consent from parent/guardian for minor 
participants 
• 
Written assent from minor participants as appropriate (e.g., 
above the age of 7 years or the applicable age per local 
regulatory requirements) 
• 
All female subjects of child-bearing potential will be required 
to provide a blood or urine sample for pregnancy testing that 
must be negative one week before being allowed to 
participate in the study. 
• 
Use of effective birth control by female participants of child-
bearing potential 
Exclusion Criteria 
• 
Inability or unwillingness of a participant to give written 
informed consent or comply with study protocol 
• 
History of uncontrolled cardiovascular disease, including 
uncontrolled hypertension 
• 
History of other chronic disease (other than asthma, atopic 
dermatitis, or allergic rhinitis) requiring therapy (e.g., heart 
disease, diabetes) that is, or is at significant risk of becoming 
unstable or requiring a change in chronic therapeutic regimen 
and, in the opinion of the Principal Investigator, would 
represent a risk to the subject’s health or safety in this study or 
the subject’s ability to comply with the study protocol. 
• 
History of eosinophilic esophagitis (EoE), other eosinophilic 
gastrointestinal disease, chronic, recurrent, or severe 
gastroesophageal reflux disease (GERD) grade 3 according to 
CTCAE version 5.0, symptoms of dysphagia (e.g., difficulty 
swallowing, food “getting stuck”), or recurrent gastrointestinal 
symptoms of undiagnosed etiology 
• 
Current participation in any other interventional study 
• 
Subject is currently in the build-up phase of immunotherapy to 
another allergen and is on maintenance immunotherapy dose 
for any allergen related to cashew or shrimp 
• 
Severe asthma (NAEPP EPR-3 Medication Criteria Steps 5 or 6)  
• 
Mild or moderate asthma (NAEPP EPR-3 Medication Criteria 
Steps 1-4), if not controlled as indicated by an ACT<19 
• 
A hospitalization for asthma in the past 6 months  
• 
ER visit for asthma within the past 6 months 
• 
Burst or steroid course for asthma in the past 6 months 
• 
Use of omalizumab or biologic therapy (e.g., infliximab, 
rituximab, etc.) within the past 6 months 
• 
Use of complementary and alternative medicine (CAM) 
treatment modalities (e.g., herbal remedies) for atopic and /or 

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non-atopic disease within 90 days preceding Initial Dose 
Escalation Day (IDED) or at any time after the IDED 
• 
Use of beta-blockers (oral) 
• 
Pregnancy or lactation 
• 
Allergy to oat  
• 
History of severe anaphylaxis to cashew or shrimp with 
symptoms including hypotension requiring fluid resuscitation 
and/or the need for mechanical ventilation within the last year 
• 
Use of investigational drugs within 12 weeks of participation 
• 
Past or current medical problems or findings from physical 
assessment 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 
Study Stopping Rules 
During the study, if the investigator or the NIAID Medical Officer 
discovers conditions that indicate that the study should be 
discontinued, an appropriate procedure for stopping the study 
pending DSMB review will be instituted. 
If any of the stopping rules listed below are met, study enrollment 
will be suspended, the Initial dose day will be suspended, dose 
escalation during Build-up will be stopped, and all enrolled 
participants will remain on their current dose pending expedited 
review of all pertinent data by the Data Safety Monitoring Board: 
• 
Any death related to cashew or shrimp OIT dosing 
• 
More than 3 cases of CoFAR Grade 4 AE related to food 
allergen dosing or to oral food challenge. 
• 
More than 3 participants require more than 2 injections of 
epinephrine during a single dosing of cashew or shrimp OIT 
investigational product  
• 
More than 3 of the following events: 
o Severe adverse event, other than anaphylaxis, 
related to investigational product 
o Eosinophilic esophagitis 
Participant Stopping Rules 
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. 
5. Individual safety stopping rules:  
a. Anaphylaxis resulting in hypotension, neurological 
compromise or mechanical ventilation secondary to OIT 
dosing or food challenge 

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b. Any subject deemed to have severe allergic reactions and 
who receives aggressive therapy (e.g., hypotension with IV 
fluid resuscitation, mechanical ventilation, more than 2 
doses of epinephrine for a life-threatening reaction) at any 
time should be discontinued from further therapy   
c. Other circumstances including, but not limited to, the 
following: 
o Severe adverse event, other than anaphylaxis, 
related to investigational product 
o Pregnancy 
Premature Discontinuation of 
Investigational Agent 
• 
Poor control or persistent activation of secondary atopic 
disease (e.g., AD, asthma), at the discretion of the investigator  
• 
Started on beta-blockers, or other prohibited medications, 
with no alternative medications available per the prescribing 
physician 
• 
Non-adherence with home OIT dosing protocol (excessive 
missed days more than 20 days) without consulting with study 
staff would be a safety issue warranting discontinuation 
• 
The subject develops biopsy-documented eosinophilic 
esophagitis (EoE) with synchronous clinical symptoms or other 
eosinophilic gastrointestinal disease 
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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Table of Contents 
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 ...................................................................... 16 
1.3. 
Preclinical Experience ........................................................................................................................................... 16 
1.4. 
Clinical Studies ...................................................................................................................................................... 17 
2. 
Study Hypotheses/Objectives ................................................................................................................................... 17 
2.1. 
Primary Objective(s) .............................................................................................................................................. 18 
2.2. 
Secondary Objective(s) ......................................................................................................................................... 18 
2.3. 
Exploratory Clinical objectives: ............................................................................................................................. 18 
2.4.  Safety Objectives ....................................................................................................................................................... 18 
3. 
Study Design .............................................................................................................................................................. 18 
3.1. 
Description of Study Design .................................................................................................................................. 18 
3.2. 
Primary Endpoint(s)/Outcome(s) .......................................................................................................................... 21 
3.3. 
Secondary Endpoint(s)/Outcome(s) ...................................................................................................................... 21 
3.4. 
Exploratory Clinical Objectives .............................................................................................................................. 22 
3.5. 
Safety Endpoints ................................................................................................................................................... 22 
3.6. 
Stratification, Randomization, and Blinding/Masking .......................................................................................... 22 
4. 
Selection of Participants and Clinical Sites/Laboratories.......................................................................................... 22 
4.1. 
Rationale for Study Population ............................................................................................................................. 22 
4.2. 
Inclusion Criteria ................................................................................................................................................... 23 
4.3. 
Exclusion Criteria ................................................................................................................................................... 23 
4.4. 
Selection of Clinical Sites/Labs .............................................................................................................................. 24 
5. 
Known and Potential Risks and Benefits to Participants .......................................................................................... 24 
5.1. 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert................. 24 
5.2  Risks of Investigational Product or Intervention cited in Medical Literature ............................................................ 24 
5.2. 
Risks of Other Protocol Specified Medications ..................................................................................................... 25 
5.3. 
Risks of Study Procedures ..................................................................................................................................... 25 
5.4. 
Potential Benefits .................................................................................................................................................. 26 
6. 
Investigational Agents ............................................................................................................................................... 26 
6.1. 
Cashew Flour or Shrimp Powder for OIT............................................................................................................... 26 
6.2. 
Drug Accountability ............................................................................................................................................... 27 

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6.3. 
Assessment of Participant Compliance with Investigational Agent ..................................................................... 27 
6.4. 
Toxicity Prevention and  Management (CoFAR guidelines will be used at all times unless specified otherwise) 27 
6.4.1 Reactions to OIT During Initial Dose Day ............................................................................................................. 27 
6.4.2 Reactions to OIT During build-up or Maintenance Phase .................................................................................... 27 
6.4.3 Treatment for reactions during the Build-up and Maintenance Phase ............................................................... 28 
6.5. 
Premature Discontinuation of Investigational Agent ........................................................................................... 29 
7. 
Other Medications .................................................................................................................................................... 29 
7.1. 
Concomitant Medications ..................................................................................................................................... 29 
7.2. 
Prophylactic Medications ...................................................................................................................................... 30 
7.3. 
Prohibited Medications ......................................................................................................................................... 30 
7.4. 
Rescue Medications .............................................................................................................................................. 30 
8. 
Study Procedures ...................................................................................................................................................... 30 
8.1. 
Enrollment ............................................................................................................................................................. 30 
8.2. 
Screening/Baseline Visit ........................................................................................................................................ 30 
8.3. 
Study Visits or Study Assessments ........................................................................................................................ 31 
Allergen-Specific OIT Treatment Overview ....................................................................................................................... 31 
Allergen-Specific OIT: ........................................................................................................................................................ 32 
8.4. 
Unscheduled Visits ................................................................................................................................................ 34 
8.5. 
Visit Windows ....................................................................................................................................................... 34 
9. 
Mechanistic Assays ................................................................................................................................................... 35 
10. 
Biospecimen Storage................................................................................................................................................. 37 
11. 
Criteria for Participant and Study Completion and Premature Study Termination.................................................. 37 
11.1. Participant Completion ......................................................................................................................................... 37 
11.2. Participant Stopping Rules and Withdrawal Criteria ............................................................................................ 37 
11.3. Participant Replacement ....................................................................................................................................... 38 
11.4. Follow-up after Early Study Withdrawal ............................................................................................................... 38 
12. 
Safety Monitoring and Reporting ............................................................................................................................. 38 
12.1 Overview ................................................................................................................................................................... 38 
12.2 Definitions ................................................................................................................................................................. 38 
12.2.1 Adverse Event (AE) ............................................................................................................................................. 38 
12.2.2 Unexpected Adverse Event ................................................................................................................................ 39 
12.2.3 Serious Adverse Event (SAE) .............................................................................................................................. 39 
12.3 Grading and Attribution of Adverse Events .............................................................................................................. 40 

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12.3.1 Grading Criteria .................................................................................................................................................. 40 
12.3.2 Attribution Definitions ....................................................................................................................................... 44 
12.4 Collection and Recording of Adverse Events ............................................................................................................ 45 
12.4.1 Collection Period ................................................................................................................................................ 45 
12.4.2 Collecting Adverse Events .................................................................................................................................. 45 
12.4.3 Recording Adverse Events .................................................................................................................................. 45 
12.5 Reporting of Serious Adverse Events and Adverse Events ....................................................................................... 45 
12.5.1 Reporting of Serious Adverse Events to DAIT/NIAID ......................................................................................... 45 
12.5.2 Reporting to Health Authority ........................................................................................................................... 46 
12.5.3 Reporting of Adverse Events to IRBs/IECs ......................................................................................................... 47 
12.6  Pregnancy Reporting ................................................................................................................................................ 47 
12.7 Reporting of Other Safety Information ..................................................................................................................... 47 
12.8 Review of Safety Information ................................................................................................................................... 47 
12.8.1 Medical Monitor Review .................................................................................................................................... 47 
12.8.2 DSMB Review ..................................................................................................................................................... 48 
13. 
Statistical Considerations and Analytical Plan .......................................................................................................... 48 
13.1 
Overview ............................................................................................................................................................... 48 
13.2 
Endpoints and anticipated results ........................................................................................................................ 49 
13.2.1 Primary Endpoint(s)/Outcome(s) ....................................................................................................................... 49 
13.2.2 Secondary Endpoint(s)/Outcome(s)................................................................................................................... 49 
13.3 
Measures to Minimize Bias ................................................................................................................................... 50 
13.4 
Analysis Plan .......................................................................................................................................................... 50 
13.4.1 
Analysis Populations. .................................................................................................................................... 50 
13.4.2 
Primary Analysis of Primary Endpoint(s)/Outcome(s) .................................................................................. 51 
13.4.3 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s) ...................................................................... 51 
13.4.4 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) ......................................................................... 51 
13.4.5 
Analyses of Exploratory Endpoint(s)/Outcome(s)......................................................................................... 51 
13.4.6 
Descriptive Analyses ..................................................................................................................................... 51 
13.5 
Interim Analyses .................................................................................................................................................... 52 
13.5.1 
Interim Analysis of Efficacy Data ................................................................................................................... 52 
13.5.2 
Interim Analysis of Safety Data ..................................................................................................................... 52 
13.5.3 
Futility Analysis ............................................................................................................................................. 52 
13.6 
Statistical Hypotheses ........................................................................................................................................... 52 

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13.7 
Sample Size Considerations .................................................................................................................................. 52 
14. 
Identification and Access to Source Data ................................................................................................................. 53 
14.1. Source Data ........................................................................................................................................................... 53 
14.2. Access to Source Data ........................................................................................................................................... 54 
15. 
Protocol Deviations ................................................................................................................................................... 54 
15.1. Protocol Deviation Definitions .............................................................................................................................. 54 
15.2. Reporting and Managing Protocol Deviations ...................................................................................................... 54 
16. 
Ethical Considerations and Compliance with Good Clinical Practice ........................................................................ 54 
16.1. Statement of Compliance ..................................................................................................................................... 54 
16.2. Informed Consent Process .................................................................................................................................... 55 
16.3. Privacy and Confidentiality ................................................................................................................................... 55 
17. 
Publication Policy ...................................................................................................................................................... 55 
18. 
References ................................................................................................................................................................ 55 
Appendix 1. Schedule of Events ........................................................................................................................................ 57 
Appendix 2: Participant Disposition .................................................................................................................................. 58 
Appendix 3: Dose Limiting Symptoms (CoFAR guidelines) ............................................................................................... 58 
Appendix 4 Sample Serious Adverse Event Form ............................................................................................................. 59 
Appendix 5: Sample Deviation Report Form ..................................................................................................................... 61 
Appendix 6: Epinephrine device Training Form ................................................................................................................ 63 
Appendix 7: Evaluation of Asthma .................................................................................................................................... 65 
 
 
 
 
 
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 Food Challenges 
DSMB 
Data Safety Monitoring Board 
EOS 
End Of Study 
FA 
Food Allergen 
FDA 
Food and Drug Administration 

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GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IDD 
Initial dose day 
IEC 
Institutional Ethics Committee 
IMM 
Independent Medical Monitor 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases 
PC 
Protocol Chair 
PI 
Principal Investigator 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SMC 
Safety Monitoring Committee 
SNP-CRU 
Sean N Parker-Clinical Research Unit 
SOP 
Standard Operating Procedure 
SU 
Sustained Unresponsiveness 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 

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Study Definitions Page  
Desensitization 
Participants that pass their food challenge with no or mild objective 
reactions to up to a cumulative 2043 mg of the food allergen in their OIT at 
end of maintenance phase (week 52) will be considered desensitized. 
Desensitization Failure 
Participants who tolerate OIT but do not tolerate at least 2043 mg of food 
allergen at week 52. 
Double blind placebo 
controlled food 
challenge 
A graded challenge of suspect allergenic or placebo food product where 
neither the patient nor the supervising physician is aware of which product 
the patient is ingesting. 
Independent Medical 
Monitor 
This a physician experienced in clinical trials who is administratively 
independent of the investigative team.  They serve as a contact who is able 
to review the situation at the site for the DAIT team in the event of any 
occurrence of concern. 
Lost to Follow-up 
Lost to follow-up refers to patients who at one point in time were actively 
participating in a clinical research trial but have become lost (either by 
error in a computer tracking system or by being unreachable) at the point 
of follow-up in the trial. 
Maintenance Failure 
Participants who cannot tolerate 1000 mg but are not withdrawn due to 
unacceptable side effects. 
NAEPP EPR-3 
The EPR 3 Guidelines on Asthma was developed by an expert panel 
commissioned by the National Asthma Education and Prevention Program 
(NAEPP) Coordinating Committee (CC), coordinated by the National Heart, 
Lung, and Blood Institute (NHLBI) of the National Institutes of Health. 
Using the 1997 EPR 2 guidelines and the 2004 update of EPR 2 as the 
framework, the expert panel organized the literature review and final 
guidelines report around four essential components of asthma care, 
namely: assessment and monitoring, patient education, control of factors 
contributing to asthma severity, and pharmacologic treatment. Subtopics 
were developed for each of these four broad categories. 
(https://www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-
management-of-asthma) 
Natural tolerance 
Naturally tolerant individuals are defined as individuals who had clinically 
diagnosed food allergies by oral food challenge (OFC) who then lost those 
food allergies over time without treatment and have a verified negative 
OFC for that food allergen. 
Non-adherence 
Non-adherence with home OIT dosing protocol (excessive missed days 
more than 20 days) without consulting with study staff would be a safety 
issue warranting discontinuation 
 
PRACTALL guidelines 
The PRACTALL program is a common initiative of EAACI and the American 
Academy of Allergy, Asthma and Immunology. It focuses on practical 
aspects of allergy to deliver updated and evidence-based 
recommendations for clinicians. 
DOI: https://doi.org/10.1016/j.jaci.2012.10.017 

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Principal Investigator 
A person responsible and accountable for conducting the clinical trial and 
for the rights, health and welfare of the subjects in the trial. The principle 
investigator assumes full responsibility for the evaluation of human 
subjects, and for the integrity of the research data and results. 
Protocol Mandated 
Procedures 
Procedures mandatory per protocol. 
Site Principal 
Investigator 
Site Principal Investigator is the Principal Investigator at the lead research 
site and has responsibility over the conduct of a clinical study at that site. 
Site Study Coordinator 
A Clinical Research Coordinator (CRC) is a person responsible for 
conducting clinical trials using good clinical practice (GCP) under the 
auspices of a Principal Investigator (PI). 
Study Termination 
Permanent cessation of all research activities. 
Study Therapy 
Specific intervention according to the research plan or protocol created by 
the investigator. 
Sustained 
unresponsiveness 
Sustained unresponsiveness corresponds to the effects of OIT and will be 
defined as a participant’s passing a Double-blind Placebo-controlled Food 
challenge (DBPCFC) with no or mild objective reaction to up to a 
cumulative 2043 mg of the FA allergen in their OIT at week 58. 
Sustained 
unresponsiveness 
Failure 
Participants who tolerate at least 2043 mg cumulative protein at the week 
52 DBPCFC with no or mild objective reactions, but who can no longer 
tolerate at least this dose at the week 58 DBPCFC 
T cell epitopes 
A peptide sequence that can bind to a specific T cell receptor when 
presented in the context of MHC 
Tetramers 
A group of 4 engineered defined, soluble MHC/peptide multimers capable 
of engaging more than one copy of the TCR on the surface of a T cell to 
identify antigen-specific T cells by flow cytometry, even those present at 
low frequencies in fresh populations of lymphocytes sampled directly ex 
vivo.  
Tolerance (immune) 
Long term sustained unresponsiveness: this is a similar definition as 
sustained unresponsiveness but instead of week 58, will be determined in 
long term follow up under a different protocol at 5 years after study start 
for each participant. 
Treatment Failure 
Treatment failures will be defined as those participants who withdraw or 
are withdrawn due to unacceptable side effects of OIT  
Withdrawal from 
Therapy 
Therapy is stopped as directed per protocol, participant’s decision or per 
study withdrawal criteria. 
 
 
 
 
 
 

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1. Background and Rationale  
1.1. Background and Scientific Rationale 
Food allergy (FA) is now recognized to be a major health concern affecting about 8% of the US population and costing 
the healthcare system and families about $24.8 billion per year. About 40% of children with food allergy have 
experienced a severe, life-threatening allergic reaction, and 30% report allergies to multiple foods. There is an unmet 
need for new therapies in food allergy as many patients with food allergies are at risk for accidental reactions, especially 
those with cashew, and shrimp allergies. Current OIT remains associated with refractory vs. successfully treated 
populations due to a number of cellular and molecular mechanisms, with a predominance of cellular changes occurring 
in food allergen-specific (FS) T cells.1-4 There is an unmet need for new therapies in FA, since many patients in OIT trials 
continue to have side effects that can hinder their compliance and the overall efficacy of OIT. Current OIT is not 
universally effective.  A significant portion of food allergic patients fall into the refractory or fail-to-treat populations, 
likely due to variability of cellular and molecular endotypes and clinical phenotypes.5,6 To address these challenges and 
to test the ability to desensitize to cashew, or shrimp, we propose a Phase 2 clinical trial using OIT for cashew or shrimp 
allergies in participants with proven allergies to either cashew or shrimp, respectively, to link clinical outcomes with food 
allergen-specific T cell studies and epitope discovery and validation. For our clinical research hypotheses, we will test the 
safety and efficacy of cashew or shrimp allergen desensitization using validated and standardized endpoints. For our 
mechanistic hypotheses, we hypothesize that T cell epitopes and TCR repertoire/targeted RNA-Seq in participants 
achieving clinical success at 52 weeks will change significantly as compared to baseline. As a corollary, we hypothesize 
that T cell epitopes and TCR repertoire/targeted RNA-Seq in participants achieving clinical success at desensitization vs. 
sustained unresponsiveness (SU) will differ as compared to baseline.  
 
1.2. Rationale for Selection of Investigational Product or Intervention 
 
We have designed the primary endpoint based on preliminary mechanistic understandings of T cell modifications over 
time during immunotherapy. When first activated, T-cells initially start making Th2 products like IL4 and IL13, but over 
the course of therapy they start making more interferon gamma and start expressing less CD28 so that they appear 
more anergic (Ryan et al. PNAS 2016; Syed, et al. JACI 2014; Pellerin, et al. JACI 2018).  The hypothesis would be to 
expect a change of 20% in the T cell population to shift within 52 weeks toward this activated allergen-specific subset 
that makes interferon gamma and is more anergic. Exploratory endpoints will include the changes in the transcriptomes 
and phenotypes of tetramer+ T cells from baseline to 52 weeks, 58 weeks and to 64 weeks. 
Our and others’ community-based participatory research7-9 show that many patients and families would prefer to be 
desensitized to a low dose of FA protein (300m mg) to avoid worry about accidentally eating a contaminated food, while 
others would prefer to safely ingest a larger dose of FA protein (1,000 mg or more) to be able to try certain foods 
containing the FA; therefore, we have proposed using these two quantities in our clinical study as the treatment dose 
(1000 mg) and the desensitization threshold (2,043 mg).  There are several lines of evidence (Jones, et al. AAAAI, 2018, 
Phase 3 results of PALISADES study and Andorf, et al. AACI 2017 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738818/) demonstrating that 300 mg of maintenance of each food 
allergen protein will allow some protection in the majority of participants to at least 1000 mg of each food allergen 
protein during a standardized food challenge. However, recent data has shown that maintenance at higher levels (i.e. 
1000 mg) would afford protection to higher levels of accidental ingestion (for shrimp, since the average shrimp is 
approximately 8g, we prefer to propose 1000 mg maintenance in this study) and perhaps could improve SU outcomes. 
 
The data from previous and our current OIT Phase 1 and 2 studies indicate that a clinically meaningful level of 
desensitization can be achieved after updosing. Accordingly, our pilot phase 2 clinical trial proposes to achieve 
maintenance dosing by week 52 and to test desensitization with DBPCFCs at week 52 and sustained unresponsiveness 
with DBPCFCs at weeks 58 and 64.which should provide sufficient time to test efficacy and assess trends in safety.   
1.3. Preclinical Experience 

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Not Applicable 
1.4. Clinical Studies  
We and others have published using cashew or shrimp food allergen OIT (Andorf, et al. 2018, Begin et al. 2014, Muraro, 
et al. 2017, Wood, et al. 2017, Paviqua, et al. 2010).  Most of the studies are phase 1 and phase 2 studies to test safety 
and to optimize dosing.  
 
Under IND 
 we have dosed more than 50 participants (4-55 yrs) with cashew or shrimp allergies. The key goal of 
the IND was to develop a customized regimen for oral immunotherapy that reflected what the participant was allergic 
to in a clinically significant way (i.e., the offending food allergen is defined as a food allergen with a positive skin test or 
positive specific IgE and a positive DBPCFC).  We also followed participants long term (out to 8 yrs +).  
 
Few studies have been conducted to identify the immunological mechanism(s) underlying any long-lasting effects of 
OIT, currently termed “sustained unresponsiveness”, or to address the safety of ingesting a food allergen for a 
prolonged period of time. To address these questions in the field of food allergy research, we designed a phase 1 study 
to test the long-term safety of multi-food OIT. We enrolled children and adults (4-55 years of age) with proven severe 
multiple food allergies that include peanut, and/or milk, and/or egg, and/or tree nut, and/or seed and/or wheat. Entry 
criteria for the study included allergen-specific IgE > 7 kU/L or skin test reactivity to each food item ≥ 5 mm wheal 
diameter and a clinical history consistent with an allergic reaction to each of these foods within 1 hour of ingestion, as 
well as positive double-blinded, placebo-controlled food challenges (DBPCFC performed separately) for each food 
allergen (Andorf, et al. AACI 2017.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738818/).  
The active phase of the study was approximately 12 months, and the follow up phase was approximately 12 months. 
Clinical and laboratory-based assessments were performed for safety parameters in addition to blood sampling for 
translational/mechanistic studies. Careful monitoring occurred every two weeks and daily diaries were collected. Safety 
data were collected as per Good Clinical Practice guidelines and allergic reactions were defined as those adverse events 
related to study drug vs non-allergic adverse events were defined as those events not related to study drug.  
Of 50 participants enrolled, 12 withdrew (3 moved out of state, 6 switched to food equivalents, and 3 were non-
compliant with reaction medications—i.e. each of the 3 had substituted herbal medicines for antihistamine medicines). 
In total, there were 24,606 doses of study drug over approximately 24 months for each participant and 1227 adverse 
events related to study drug (about 3.3%).   
 
Overall, at the end of the study, participants were able to escalate to the top dose of each of their allergens (4g of 
protein). There were no SAEs. There were no cases of life threatening anaphylaxis. There were no cases of angioedema, 
respiratory, or cardiovascular compromise. The most frequent reaction involved skin/subcutaneous tissues and was mild 
(58%). Out of the 1227 adverse events related to study drug, 10 reactions were defined as severe or Grade 3 Bock’s 
criteria per protocol (Andorf, et al. 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738818/). Although this is a 
phase 1 study and neither blinded, nor controlled, the data seem to suggest a satisfactory safety profile (compared to 
historical literature). No reaction had any sequelae after treatment.  
 
There are several lines of evidence showing that the protection afforded by OIT wanes over time if withdrawal occurs, 
however, some participants have been able to discontinue therapy and yet remain able to tolerate doses of food 
allergen that would have provoked a reaction prior to therapy. Studying sustained unresponsiveness (SU) will help us 
define new targets (in food allergen specific T cell subsets and other cellular compartments) for longer lasting effects in 
OIT and will help us understand the mechanisms of OIT and possible sustained, long term successful clinical outcomes.  
Therefore, we have added a 6-week discontinuation period to our study. There does not seem to be any increased risk 
of severe allergic reactions due to the 6 weeks discontinuation (Andorf, et al. 2019 Burks et al. 2012); therefore, we have 
chosen this rather than a longer time period to monitor participants.  
2. Study Hypotheses/Objectives 

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We hypothesize that OIT to cashew or shrimp results in distinctive patterns of T cell responses throughout the course of 
treatment and that these patterns can be revealed by immunophenotyping of cells responding to specific epitopes. If 
proven correct, the results will aid in the development of tools for T cell reagents for cashew, and shrimp allergens, and 
provide a platform for developing a diagnostic program for FA OIT response. We also hypothesize that the results will 
advance our knowledge of FA prognosis. 
2.1. Primary Objective(s) 
To determine T cell, immune-based mechanisms of food allergy and to optimize T cell reagent discovery and validation 
by obtaining blood samples from FA participants undergoing OIT, and simultaneously, develop diagnostic, prognostic, 
and mechanistic tools based on the T cell reagents developed during the course of OIT.  
2.2.  Secondary Objective(s) 
• 
Identify, characterize, and validate new T cell epitopes for important food allergens (cashew, shrimp) 
• 
Track the numbers and functions of epitope-specific T cells during stages of FA OIT 
• 
Associate these parameters with phenotype and endotype characterizations in food-allergic individuals 
• 
Determine whether immune monitoring measurements reflecting these underlying mechanisms can be used to 
predict responses to OIT 
 
2.3. Exploratory Clinical objectives: 
• 
To evaluate desensitization protocols for cashew and shrimp in allergic individuals 
• 
Determine whether the achievement of sustained unresponsiveness is different between cashew or shrimp food 
allergy participants after a period of withdrawal from OIT 
• 
Exploring changes in the transcriptomes and phenotypes of tetramer+ T cells from baseline to 52 weeks, 58 weeks, 
and to 64 weeks. 
 
2.4.  Safety Objectives 
• 
The proportion of participants with only mild AEs during the course of the study. 
• 
The proportion of participants with respiratory or abdominal severe AEs during the course of the study. 
• 
The proportion of participants who successfully pass a DBPCFC with no or mild objective reactions to a 
cumulative 2043 mg of the FA allergen at the end of OIT (desensitization, week 52). 
• 
The proportion of participants who successfully pass a DBPCFC with no or mild objective reactions to a 
cumulative 2043 mg of the FA allergen after 6 weeks off OIT (sustained unresponsiveness, week 58) as 
completed (please see Appendix 2). 
3.  Study Design 
3.1. Description of Study Design  
This is a prospective Phase 2, single-center, single-allergen OIT in cashew or shrimp in participants with proven allergies 
to either cashew or shrimp, respectively. Our intent is to treat a total of 72 participants, ages 7 to 55 years, with an 
allergy to either cashew or shrimp determined by Double Blind-Placebo Controlled-Food Challenges (DBPCFC), allergy 
history, clinical symptoms, food-allergen (FA)-specific IgE levels, and skin prick test (SPT). Enrolled participants must be 
positive at or before the 300 mg (443 mg cumulative) dosing level of FA protein. OIT treatment groups will be cashew or 
shrimp, total number of participants (n=72).  
 

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Screening phase (Week -52 to Week 0): Under an existing protocol IRB-approved ‘Prescreening Protocol’ at Stanford, 
and this protocol, we propose to screen approximately 100 individuals ages 7-55 years, of both sexes. Participants will 
initially be screened for the FA using blood test and SPT. If participants show positive IgE and SPT to more than one of 
the studied FAs (cashew, shrimp), they will undergo multiple DBPCFCs that will be performed on different days. 
Participants must be positive at or before the 300 mg (443 mg cumulative) dosing level of FA protein in accordance with 
PRACTALL (Practical Issues in Allergology) consensus guidelines, regardless of how they were initially diagnosed as food-
allergic. No more than 52 weeks should elapse between the qualifying DBPCFC and the initial dosing day.
Figure 1. A Prospective Pilot Phase 2 Study in Cashew- or Shrimp-allergic Participants
Enrollment phase (Week 0/Day 1): After assuming a 50% screening success (based on our previous phase 2 studies and 
their screening- to- enrollment ratio), we plan to enroll 72 participants as the intent-to-treat population. Participants will 
be enrolled onto the OIT treatment groups. If a participant has 2 out of the 2 FA, then the allergen will be chosen based 
on research needs with respect to patient preference. .
Updosing phase (Week 1 to Week 28): All cohorts will undergo an updosing regimen starting at 5 mg allergen, with dose 
escalation every 2 weeks to reach a maximum maintenance dose of 1000 mg dose at Week 28. We expect active OIT 
treatment subjects to reach 1000 mg of allergen protein (cashew or shrimp) between 26 to 28 weeks.  Participants who 
have not reached 1000 mg by week 28 will continue to be updosed, if considered safe, until week 52. In case of 
unforeseen circumstances that make an in-person visit in clinic difficult, doses may need to be sent to the participant’s 
home.
Maintenance phase (Week 28 to Week 52): Once participants get to the 1000 mg dose at week 28, they will stay on that 
dosage until Week 52. At week 52, participants will undergo DBPCFC. Participants that pass their food challenge with no 
or mild objective reactions to up to a cumulative 2043 mg of the FA allergen in their OIT at the end of this phase 
(primary outcome) will be considered desensitized and have successfully met the primary endpoint. 
Withdrawal phase (Week 52 to Week 58 and Optional Week 64): Withdrawal from OIT will occur for 6 weeks, from 
week 52 to week 58 for all participants (Refer to Appendix 2 for participant disposition).  This withdrawal phase is 
designed to examine mechanisms underlying sustained unresponsiveness (SU).  SU will be defined as a participant’s 

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passing a DBPCFC with no or mild objective reaction to up to a cumulative 2043 mg of the FA allergen in their OIT at 
week 58. We chose a 6-week period of withdrawal based on prior studies (Andorf et al, 2018, Burks, et al. New England 
Journal of Medicine, 2012).  If the participant passes the Week 58 DBPCFC up to a cumulative of 2043 mg, he/she will be 
given the option to continue avoidance until Week 64 and perform another set of DBPCFCs to further assess SU.  
End of study (Week 58 or Week 64): Participants will be followed until week 58 or until Week 64 for those who choose 
to continue avoidance beyond Week 58). Participants will be given guidance on how to consume real food equivalents 
based on their current tolerated dose. (Appendix 2).  
Participant Disposition (see Appendix 2): 
Any participant that at least can tolerate 300 mg of FA protein will continue to dose at 300 mg and will be asked to come 
back at week 52, and 58 for blood and/or skin tests.  
Any participant that terminates early or who reaches week 58 or the optional Week 64 , will be referred to an allergy 
practitioner for further follow up and clinical care. 
Mechanistic controls: 
We will compare our results against non treated mechanistic controls with similar clinical characteristics. These 
mechanistic controls are historical controls that are allergen-matched and clinically matched as best as possible. These 
participants consent for blood sampling under a separate IRB-approved consent.  
Figure 2. Study Flow Chart 
Timepoint/Visit 
Screen 
Week 0 / 
Day 1 
Every 2 wks 
(Weeks 0-28 
or until 
maintenance 
reached) 
Week 52 
Week 
58 /End 
of 
Study 
Week 
64 
(Option
al) 
 
Informed Consent 
x 
 
 
 
 
 
Medical History 
X 
 
Physical Assessment 
X 
X 
X 
X 
X 
X 
 
Con Meds 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
Specific IgE/IgG4* 
X 
X 
X 
X 
 
Skin testing 
X 
X 
X 
X 
 
Blood for T cell studies* 
X 
X 
X 
X 
X 
 
Urine pregnancy test 
X 
 
Lung Function 
X 
X 
X 
X 
X 
X 
 
Diaries 
X 
X 
X 
X 
X 
 
Inject Epi training 
X 
X 
X 
 
 
Fecal samples 
X 
X 
X 
 
 
DBPCFC 
X 
X TEST 
DESENSIT
IZATION 
X TEST SU 
X TEST SU 
OIT (cashew or 
shrimp) 
X 
X 
 
 
QOL questionnaires* 
X 
X 
X 
X 
 
 

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*If unable to perform at both screening and Week 0, sample from either visit will suffice. 
 In case of unforeseen circumstances that make an in-person visit in clinic difficult, doses may need to be sent to the 
participant’s home. 
 
We plan to identify the basic immune mechanisms monitored by epitope-specific T cell methods which could potentially 
explain the differences in the effects of OIT in individuals who do or do not become clinically tolerant and to determine 
whether immune monitoring can predict the safety and efficacy outcomes in OIT protocols, and predictors of re-
emergent allergic reactivity.  After initial screening and enrollment, there are three phases of the study (Figure 1):  
• 
Dose escalation and Build up Phase  
• 
Maintenance phase 
• 
Withdrawal phase 
Treatment Failures: 
• 
Treatment failures will be defined as those participants who withdraw or who are withdrawn due to 
unacceptable side effects of OIT by week 52 
• 
If participants demonstrate moderate or severe clinical reactivity ( Appendix 3) in DBPCFC at week 58, they will 
be considered desensitized but SU failures.  
All participants who start home dosing of OIT will be considered in statistical analyses of the intent-to-treat population. 
 
Integration with mechanistic science program: This is a pilot, prospective, phase 2 clinical trial to study safety and 
dosing of OIT; in addition, the clinical trial’s mechanistic purpose is to provide blood samples to identify the basic 
immune mechanisms monitored by epitope-specific T cell methods which could explain the differences in the effects of 
OIT in individuals. Based on our results (Ryan, et al. PNAS 2016, Syed, et al. JACI 2014) (IND 
 and IND 
) we 
expect significant differences in food- allergen epitope-specific T cell immunophenotypes and clinical outcomes with the 
total sample size proposed here. 
 
Study Design Safety Considerations 
The design considers important safety issues: 
• 
All updosing visits will be supervised in a hospital setting where trained study physicians are available. 
• 
Standing orders from an MD are provided for all clinical study personnel (RN, NP, PA, etc.) to initiate treatment 
of reactions immediately (i.e., prior to MD notification), including IM administration of epinephrine, based on 
their own clinical judgment.  
• 
A crash cart with pediatric and adult equipment is available in close proximity of all patient hospital rooms. 
• 
A code team is available for pediatric and adult patients. 
• 
Dosing symptoms and adverse events will be captured throughout the study. 
• 
Subjects will be prescribed an epinephrine auto-injector (if not prescribed by a treating clinician previous to 
study entry) and all subjects will be trained in its use. 
Subjects will be cautioned against consuming any foods containing the FA allergen they are being treated for, other than 
study-supplied food allergen while on study. 
3.2. Primary Endpoint(s)/Outcome(s) 
Change in expression of CD28 in the CD4+ allergen specific (CD154+ ) T-cells at 52 weeks relative to baseline values 
between those who do and do not pass a cumulative of 2043 mg at the DBPCFC at week 52.  
3.3. Secondary Endpoint(s)/Outcome(s) 

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• 
Compare changes in expression of CD28+ allergen specific (CD154+ ) T-cells over multiple time points from 
baseline to week 58 and week 64 between those with sustained unresponsiveness (SU) vs those desensitized but 
SU failures vs those who do not pass the desensitization DBPCFC: 
• 
Compare changes in the following measures in CD4+CD28+ allergen specific (CD154+ ) T-cells at week 52 and 
week 58  between those who achieved sustained unresponsiveness (SU) vs those desensitized but SU failures vs 
those who did not pass desensitization DBPCFC at week 52 
o Levels of IFN-gamma 
o levels of IL-4  
o Receptor diversity in allergen specific T cell CDR3b as compared to non-specific T cells 
o levels of IL-10  
o levels of TGF-beta 
o levels of GPR15  
o Levels of CCR4+ 
o Levels of CRTh2 
3.4.  Exploratory Clinical Objectives  
• 
Comparing the proportion of participants who become desensitized vs all others (i.e. treatment failures) at week 
52 DBPCFC. 
• 
Comparing the proportion of participants who reach SU vs desensitized but SU failures at week 58 DBPCFC. 
• 
Comparing changes in the transcriptomes and phenotypes of tetramer+ T cells from baseline to 52 weeks, 58 
weeks, and to 64 weeks. 
 
3.5. Safety Endpoints 
• 
The proportion of participants with only mild AEs  (i.e. Grade 1) during the course of the study. 
 
• 
The proportion of participants with respiratory or abdominal severe AEs (i.e. Grade 3)  during the course of the 
study. 
 
• 
The proportion of participants who successfully pass a DBPCFC with no or mild objective reactions to a 
cumulative 2043 mg of the FA allergen at the end of OIT (desensitization, week 52). 
 
• 
The proportion of participants who successfully pass a DBPCFC with no or mild objective reactions to a 
cumulative 2043 mg of the FA allergen after 6 weeks off OIT (sustained unresponsiveness, week 58) and 
subsequent optional DBPCFC at week 64 (please see Appendix 2). 
3.6. Stratification, Randomization, and Blinding/Masking 
There will be no stratification, randomization or blinding in the arms of the study. 
4. Selection of Participants and Clinical Sites/Laboratories 
4.1. Rationale for Study Population 
This is a single site study to be conducted at the Sean N Parker Center for Allergy and Asthma Research at Stanford 
University. We will limit our age group to 7-55 years so that we may collect adequate blood volumes for mechanistic 
studies. The upper age limit of 55 years was selected to reduce the risk that the patients have undiagnosed, underlying 

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cardiovascular conditions that could entail significant risk with the use of epinephrine in subjects exposed to the risk of 
anaphylaxis. 
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. Age 7 through 55 years (inclusive) 
3. Clinical history of allergy to cashew or shrimp-containing foods 
4. Serum IgE to cashew or shrimp of ≥0.35 kUA/L [determined by UniCAPTM within the past 12 months] and/or a SPT 
to cashew, or shrimp ≥3 mm compared to control 
5. Experience dose limiting symptoms at or before the 300 mg challenge dose of FA protein on Screening DBPCFC 
conducted in accordance with PRACTALL guidelines 
6. Written informed consent from adult participants 
7. Written informed consent parent/guardian for minor participants 
8. Written assent from minor participants as appropriate (e.g., above the age of 7 years or the applicable age per 
local regulatory requirements) 
9. All female subjects of child-bearing potential will be required to provide a blood or urine sample for pregnancy 
testing that must be negative one week before being allowed to participate in the study. 
10. Use of effective birth control by female participants of child-bearing potential 
4.3. 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. History of uncontrolled cardiovascular disease, including uncontrolled or inadequately controlled hypertension 
3. History of other chronic disease (other than asthma, atopic dermatitis, or allergic rhinitis) requiring therapy (e.g., 
heart disease, diabetes) that is, or is at significant risk of becoming unstable or requiring a change in chronic 
therapeutic regimen and, in the opinion of the Principal Investigator, would represent a risk to the subject’s health 
or safety in this study or the subject’s ability to comply with the study protocol. 
4. History of eosinophilic esophagitis (EoE), other eosinophilic gastrointestinal disease, chronic, recurrent, or severe 
gastroesophageal reflux disease (GERD) grade 3 according to CTCAE version 5.0, symptoms of dysphagia (e.g., 
difficulty swallowing, food “getting stuck”), or recurrent gastrointestinal symptoms of undiagnosed etiology 
5. Current participation in any other interventional study 
6. Subject is currently in the build-up phase of  immunotherapy to another allergen and is on maintenance 
immunotherapy dose for an allergen related to cashew or shrimp. 
7. Severe asthma (NAEPP EPR-3Medication Criteria Steps 5 or 6)  
8. Mild or moderate asthma (NAEPP EPR-3Medication Criteria Steps 1-4), if not controlled as measured by an ACT<19, 
9. A hospitalization for asthma in the past 6 months 
10. ER visit for asthma within the past 6 months 
11. Burst or steroid course for asthma in the past 6 months  
12. Use of omalizumab or biologic therapy (e.g., infliximab, rituximab, etc.) within the past 6 months 
13. Use of complementary and alternative medicine (CAM) treatment modalities (e.g., herbal remedies) for atopic and 
/or non-atopic disease within 90 days preceding Initial Dose Escalation Day (IDED) or at any time after the IDED 

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14. Use of beta-blockers (oral) 
15. Pregnancy or lactation 
16. Allergy to oat  
17. History of severe anaphylaxis to cashew or shrimp with symptoms including hypotension requiring fluid resuscitation 
and/or the need for mechanical ventilation within the last year. 
18. Use of investigational drugs within 12 weeks of participation 
19. Past or current medical problems or findings from physical assessment or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks  
 
4.4. Selection of Clinical Sites/Labs  
Not applicable. This is a single site study 
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 
 
Daily food OIT dosing may cause normal allergic reactions, including anaphylaxis. Participants will be prescribed 
EpiPens® and trained in their use and they will have emergency plans in place with instructions to go to an emergency 
department in the event of an acute allergic reaction. The likelihood of a subject experiencing allergic symptoms will be 
lessened by the OIT protocol, starting at extremely small amounts of the shrimp protein for dosing under close 
medical supervision in the Stanford Food Allergy clinical research unit. Escalations are aborted at the first sign of an 
allergic reaction with equipment and medications (i.v. fluids, steroid, antihistamine, epinephrine) immediately 
available to treat allergic reactions. In the previous OIT studies milder reactions like oral pruritus or abdominal pain 
have successfully been managed by decreasing the rate of increase of OIT dosing and the use of antihistamines. 
 
Ingesting an offending food allergen on a regular basis may worsen food allergy and result in allergic reactions to the 
offending food allergy such as hives, stomach pain, vomiting, diarrhea, runny nose or cough. It may also worsen skin 
allergy (eczema) or cause decreased weight gain, which will be monitored. Ingesting shrimp may also delay or prevent 
outgrowing the offending food allergy. The long-term effects of daily offending food allergen ingestion on growth have 
not been reported. 
 
Complications of Oral Immunotherapy 
During the initial desensitization period subjects may experience generally mild allergic reactions to the multi-food OIT.  
Although rare, the risk of severe anaphylaxis to OIT exists. In a recent review of over 352 subject undergoing OIT to 
peanut, Wasserman et al (9) reported that 95 subjects required the use of epinephrine at some point in the treatment. 
However, all cases resolved with the use of epinephrine and none escalated and needed further treatment suggesting 
that severe reactions during OIT are recognized promptly and treated appropriately.  
5.2  Risks of Investigational Product or Intervention cited in Medical Literature 
 
During the initial desensitization period subjects may experience generally mild allergic reactions to the multi-food OIT.  
Although rare, the risk of severe anaphylaxis to OIT exists. In a recent review of over 352 subjects undergoing OIT to 
peanut, Wasserman et al (9) reported that 95 subjects required the use of epinephrine at some point in the treatment. 
However, all cases resolved with the use of epinephrine and none escalated and needed further treatment suggesting 
that severe reactions during OIT are recognized promptly and treated appropriately.  
 

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In patients with food allergy, there have been many oral immunotherapy trials performed using procedures and dosing 
similar to those proposed in this Phase 2 trial. In general, safety profile has been very good across the studies, and based 
on those studies approximately 80%, 15% and <1% of the subjects are expected to have a mild, moderate, or severe 
symptoms, respectively, during some point in their dosing with the oral immunotherapy. It is important to note that 
essentially all adverse events have been allergy-related, predictable, and reversible. The only major atypical adverse 
event has been several reported cases of eosinophilic esophagitis, reversible upon cessation of dosing. There was a 
recent report of a fatal reaction to rush OIT to milk in a facility in Japan (Gordon Research Conference, Ventura, CA2018) 
Specifically, the buildup and daily maintenance doses of food OIT may cause allergic symptoms including sneezing, 
rhinorrhea, urticaria, angioedema, flushing, flares of eczema, ocular, nasal, oral and/or throat pruritus, nausea, vomiting, 
abdominal discomfort, cough, wheezing and/or shortness of breath in addition to severe anaphylaxis.  Although no 
subject will be allowed to enroll who carries the diagnosis of eosinophilic disorder, the risk of eosinophilic esophagitis 
during OIT will be evaluated during the study. The likelihood of a subject experiencing any allergic symptoms is expected 
to be lessened by initiating dosing at extremely small amounts of characterized food allergen and by buildup dosing 
under observation in a clinical setting until the maintenance dose is achieved. 
 
Oral food challenges may induce an allergic response. Allergic reactions can be severe including life-threatening allergic 
reactions; however, the risk of an allergic reaction is reduced by initiating the challenge with a very small amount of the 
food, gradually increasing the dose, and stopping the challenge at the first sign of a reaction. If subjects have an allergic 
reaction during the challenges, they may need oral, intramuscular, or intravenous medications. Subjects could have an 
IV catheter placed per clinician advice before the OFCs if they have a history of anaphylaxis with hypotension requiring 
IV fluid resuscitation.   IV catheters may be placed, at physician discretion for any visit, based on factors such as previous 
reactions, recent clinical history, and clinical status observed during the visit. Trained personnel, including a study 
physician, as well as medications and equipment, will be immediately available to treat any reaction.  The anticipated 
rate of life-threatening anaphylactic reactions would be < 0.1%. 
 
There may be a risk that during participation in the trial the subjects may decrease their vigilance against accidental food 
allergen (cashew, or shrimp) ingestion because they believe they are protected from it. This phenomenon has been 
reported in previous trials, and subjects in the trial will be warned that they should continue to practice their usual 
vigilance against accidental ingestion of these foods. 
5.2. Risks of Other Protocol Specified Medications 
Epinephrine injection – Common side effects of epinephrine when used properly include anxiety; apprehensiveness; 
restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or 
respiratory difficulties. Heart problems and stroke, particularly in the elderly and people with health problems, have 
been seen. Rare cases of serious skin and soft tissue infections have been reported at the injection site following 
epinephrine injection in the thigh. 
It is very important to use proper techniques when giving epinephrine to avoid injury to the person administering the 
epinephrine or to the person receiving the injection. In addition to the common side effects above, accidental injection 
into the finger, hand or foot may result in loss of blood flow to the area causing paleness; coldness; numbness; bruising; 
bleeding; redness or damage to the bones.  Epinephrine should not be injected into the buttocks and has resulted in 
cases of gas gangrene. 
 
5.3. Risks of Study Procedures  
Food allergen dosing (Initial dose day; Updosing; Oral food challenges): 
A potential serious risk associated with the administration of food allergen is the risk of anaphylaxis.  Symptoms of 
anaphylaxis may include pruritus, urticaria, angioedema, wheezing, cough, dyspnea, emesis, diarrhea, and hypotension 
that may progress to hypotensive shock.      

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The potential discomforts with the Initial dose day procedure, updosing procedure, and oral food challenges are similar 
to the exposure to the suspected food in the past. Symptoms are usually transient lasting less than 2 hours and include 
pruritus, urticaria, nausea, abdominal discomfort, emesis and/or diarrhea, rhinitis, and sneezing and/or wheezing. The 
major risks involved include respiratory distress and rarely anaphylactic shock. Medication, personnel, and equipment 
are immediately available in the SNPRU to treat allergic reactions.  Subjects will be provided a prescription and training 
for an EpiPen® or EpiPen, Jr.® or equivalent to have with them at all times and to use in case of an allergic reaction. 
Phlebotomy:  
Risks associated with phlebotomy or insertion of an intravenous catheter include infection, syncope, and localized pain, 
stinging, bleeding, or contusions at the phlebotomy site where the needle is inserted into the vein. 
Skin prick test: 
The risk involved with skin testing includes discomfort from the needle prick, along with erythema, urticaria, pruritus, 
and swelling at the skin test site in positive responses. Rare side effects include severe allergic reactions. 
Spirometry: 
The risk of a lung function test is the discomfort of exhaling forcefully.  This may be associated with mild shortness of 
breath, slight dizziness, temporary cough and/or chest discomfort.  Most patients do not have any symptoms. 
 
5.4. Potential Benefits 
There are no certain benefits to participating in this study. The only direct benefit to the participants is, for those 
participants who develop desensitization as a result of OIT, an ability to decrease their reactions to the offending 
allergen. The likelihood of this is unknown. 
6. Investigational Agents  
6.1. Cashew Flour or Shrimp Powder for OIT 
The cashew flour and shrimp powder for OIT and food challenges, as well as placebo (oat) for food challenges, will be 
manufactured and provided by the Sean N Parker Manufacturing Facility. See ‘Chemistry, Manufacturing, and Controls – 
Food Allergen Powder for Oral Immunotherapy” cross-referenced under IND# 
 for additional information. 
 
6.1.1. Formulation, Packaging, and Labeling 
The active study products, cashew and shrimp protein (provided as separate products), are characterized 
cashew and shrimp allergen in the form of cashew flour or shrimp powder, respectively, with no added 
excipients. The placebo used for the purpose of scheduled DBPCFCs is oat flour with no cashew or shrimp 
protein and no other added excipients. Please see ‘Chemistry, Manufacturing, and Controls – Food Allergen 
Powder for Oral Immunotherapy’ cross-referenced under IND# 
 for full detail. 
 
6.1.2. Dosage, Preparation, Administration 
Cashew flour and shrimp powder (and placebo where appropriate during OFC) will be provided in unit dose cups 
and stored as per manufacturer’s recommendations at 36°F to 46°F (2°C to 8°C) to maximize stability. Research 
staff will administer doses to the participant orally in a non-offending, age-appropriate food vehicle. Dosage will 
be done per the protocol. 
 
The SNP Center Manufacturing Facility complies with relevant sections of the Food Drug and Cosmetic Act (21 U.S.C. 
351) for early phase products appropriate for a university-based clinical research program. Specifically, drug candidates 
are produced in compliance with current Good Manufacturing Practices (cGMP) as defined in 21 CFR 210 and 211. In 
addition, the cGMP unit adheres to pertinent sections of the July 2008 Guidance for Industry cGMP for Phase 1 
Investigational Drugs. This document is intended to assist innovators involved with the manufacture of investigational 
drugs in early stage clinical trials. In order to manage the documentation requirements, Standard Operating Procedures 

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(SOPs) and standards set forth in the aforementioned FDA Guidances and Regulations, the SNP Center Manufacturing 
Facility uses an electronic document control system and will be reviewed and supported from trained research and 
regulatory personnel. 
6.2. Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will maintain adequate records of the 
disposition of the investigational agent, including the date and quantity of the drug received, to whom the drug was 
dispensed (participant-by-participant accounting), and a detailed accounting of any drug accidentally or deliberately 
destroyed. 
Records for receipt, storage, use, and disposition will be maintained by the study site.  A drug-dispensing log will be kept 
current for each participant.  This log will contain the identification of each participant and the date and quantity of drug 
dispensed. 
All records regarding the disposition of the investigational product will be available for inspection. 
Following study drug administration, the site personnel will dispose of unused or partially used vials.  All drug material 
will be released and recorded by the personnel. 
6.3. Assessment of Participant Compliance with Investigational Agent 
Families will document daily dosing and any reaction from at-home dosing on diary logs. Monitoring of compliance will 
be performed by reviewing the participant’s diary and monitoring and counting their returned study medication. Unused 
study medication will be brought back to the SNP-CRU with each visit and collected by study staff for reconciliation of 
remaining IP product. In case of unforeseen circumstances that make an in-person visit in clinic difficult, doses may need 
to be sent to the participant’s home. 
6.4. Toxicity Prevention and  Management (CoFAR guidelines will be used at all times unless specified otherwise) 
6.4.1 Reactions to OIT During Initial Dose Day  
The investigator will determine if the 5 mg dose was tolerated and if the participant can be sent home on that dose 
based on Appendix 3.      
 6.4.2 Reactions to OIT During build-up or Maintenance Phase 
To be able to be eligible for an updosing or maintenance dose visit, subjects cannot have active wheezing, spirometry  
demonstrating FEV1 < 80% predicted and/or Peak Expiratory Flow (PEF) < 80% predicted or a current flare of atopic 
dermatitis that contraindicates updosing in the clinical judgment of the study physician.  As needed, subjects will be 
maintained on their current dose of study product until their flare of asthma or atopic dermatitis is resolved.   
If a subject has an updosing in the SNP-CRU without symptoms, the action should be to continue per protocol with daily 
home dosing of the tolerated dose with the next updosing visit 2 weeks later.   
 
If the subject only experiences oral/pharyngeal pruritus during the administration of the daily dose, then the same dose 
can be repeated the next day at home and continued throughout the interval unless other symptoms begin to develop. 
 
For other mild objective symptoms (Appendix 3), the action should be either to repeat the dose the next day (day 2) at 
home or to have the subject return to the SNP-CRU the next day (day 2) for a repeat of the previous day’s dose or the 
last tolerated dose (at the study physician’s discretion).  If the dose is tolerated, then the subject will continue on that 
dose and return at the normal interval.  If the dose causes mild symptoms again, then the subject may return to the 
SNP-CRU the next day (day 3) and be given the last tolerated dose or a 1-2 step dose reduction.  If tolerated, the 
subject will continue on this dose for the normal time interval.  If mild symptoms recur, a 1-2 step reduction 
should be administered the next day (day 4).  If tolerated, then that dose should be continued for 2 weeks.  If 
not tolerated, consultation with the PI is indicated.   
 
If moderate symptoms (Grade 2, Appendix 3) occur, the action should be to have the subject return to the SNP-CRU the 
next day (day 2) for dosing with the previous days dose or the last tolerated dose, at study physician discretion, under 

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observation.  If the dose is tolerated, the subject will continue on that daily home dose for the normal time interval per 
protocol.  If the subject does not tolerate this dose, the subject should receive the last tolerated dose or a 1-2 step dose 
reduction the next day (day 3) in the SNP-CRU or at home if the planned dose was previously tolerated.  If this dose is 
tolerated, it will be continued as the daily home dose for the normal time interval, then escalation attempted in the 
SNP-CRU as noted below.  If this dose is not tolerated, then the next dose will be a 1-2-step reduction in dosing, and the 
dose will be given at the SNP-CRU on the next day (day 4).  If this next dose is not tolerated, then a discussion with the PI 
will ensue to make a decision about whether to continue the subject on active treatment in the study. 
 
If severe symptoms (Grade 3, Appendix 3) occur the action should be to treat the subject, and at the study physician’s 
discretion either 1) have them return to the SNP-CRU the next day (day 2) for dosing with a 2-step reduction in dose 
under observation or 2) discontinue them from the active treatment.  If the subject tolerates the dose reduction, then 
they will remain on that dose for 2 weeks and then return to the SNP-CRU for the dose escalation. A discussion with the 
PI may ensue to make a decision about whether to continue the subject on active treatment in the study. 
 
If a subject fails dose escalation after three consecutive (with 2-4 weeks between) attempts, he/she will be considered a 
maintenance failure and the last tolerated dose will be accepted as the maintenance dose.  
For a completed dose escalation with no symptoms, participants should be observed for 30 minutes. For mild symptoms, 
participants should have a one to two-hour post-protocol observation period. For moderate to severe symptoms, the 
observation period should be at least four hours and up to 24 hours based on symptoms and treatment regimen needed 
to stabilize the participant.  Any subject deemed to have severe allergic reactions to OIT, including hypoxia, hypotension 
or change in mental status and receives aggressive therapy (e.g., IV fluid resuscitation, mechanical ventilation, more 
than 2 doses of epinephrine for a life-threatening reaction) at any time should be discussed with the PI and discontinued 
from active therapy. 
 
For specific questions related to dosing escalation or continuation of the same dose that are not answered in the above 
protocol, the PI will be available for questions and decision-making.   
 
If, at any point in the study, the subject complains of new onset vomiting, dysphagia, chronic abdominal pain, and/or 
difficulty swallowing for more than 2 weeks despite use of daily anti acids (https://www.webmd.com/heartburn-
gerd/qa/what-are-examples-of-antacids), the subject will be given daily proton pump inhibitors (dosed per age and 
weight) https://medlineplus.gov/ency/patientinstructions/000381.html and if no relief occurs in 2 weeks, they will be 
referred to a gastroenterologist for assessment of possible gastroenterological disorders associated with food allergy 
(i.e., eosinophilic esophagitis). If at any point, side effects develop from the use of antacids or PPIs, the subject will be 
discontinued for the concomitant medication and referred to a GI specialist. 
Any subject who discontinues build-up dosing due to repeated allergic reactions to the characterized food allergen will 
have his/her blood drawn for mechanistic studies within approximately 1 week of discontinuation of therapy. 
 6.4.3 Treatment for reactions during the Build-up and Maintenance Phase 
Generally, for mild and moderate symptoms, the subject should receive antihistamines, and for more severe symptoms, 
the subjects should receive epinephrine, antihistamines, and then the other medications as indicated. Epinephrine can 
be used to treat any reaction (mild to severe) at the discretion of the investigator 
If severe symptoms that do not meet the treatment stopping criteria occur at any time, decisions about participant 
continuation will be discussed with the NIAID Medical Officer. 
Antihistamines 
If a subject requires only antihistamines for treatment of allergic symptoms, the dose escalation can be continued. If 
symptoms during a build-up day require antihistamines in multiple doses or in combination with other medications 
(except epinephrine), there should be a dose reduction by 1-2 doses with the next dose given in SNP-CRU.  If dose 
escalation fails or requires treatment after two more escalation attempts each spaced 2 to 4 weeks apart, the dose 
should be reduced to the last tolerated dose and continued long term without further escalation.   

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Epinephrine 
Any reaction (in SNP-CTRU or at home) that requires two or more doses of epinephrine will require evaluation by study 
team before further OIT doses are administered.  OIT dose will be reduced and administered under observation in CTRU. 
In the event the patient is unable to return to clinic, the patient should contact study clinician for further guidance. 
SNP-CRU 
If a single administration of epinephrine is required during in SNP-CRU escalation, the dose should be reduced by two 
doses, and the subject continued on that dose for four weeks.  After 4 weeks at the reduced dose, an escalation attempt 
may be tried in SNP-CRU. 
If a single administration of epinephrine is required a second consecutive time during this escalation attempt, the dose 
should be reduced by two doses, and the subject continues on that dose for 6-8 weeks. After 6-8 weeks at the reduced 
dose, an escalation attempt may be tried in SNP-CRU. 
If a single administration of epinephrine is required a third consecutive time during this escalation attempt, the dose 
should be reduced by two doses and the subject continued on that dose as long-term maintenance without further 
escalation. 
Home 
If a single administration of epinephrine use occurs during dosing at home, this epinephrine use is not counted as one of 
the uses described above, unless severe anaphylaxis occurs at home. The subject should return to SNP-CRU for an 
observed dose prior to resuming any dosing at home. In the event the patient is unable to return to clinic, the patient 
should contact study clinician for further guidance. 
6.5. Premature Discontinuation of Investigational Agent 
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
• 
Poor control or persistent activation of secondary atopic disease (e.g., AD, asthma)  
• 
Started on beta-blockers, or other prohibited medications, with no alternative medications available per the 
prescribing physician 
• 
Non-adherence with home OIT dosing protocol (excessive missed days; i.e., > 20 consecutive days) without 
consulting with study staff would be a safety issue warranting discontinuation 
• 
The subject develops biopsy-documented eosinophilic esophagitis (EoE) with synchronous clinical symptoms or 
other eosinophilic gastrointestinal disease 
• 
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. 
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. 
 
Follow-up of Subjects Who Discontinue Treatment Only 
Subjects who prematurely discontinue treatment with OIT may remain in the study until the end of study visit at Week 
58.  
Subjects who initiate therapy (i.e., who do not fail the Initial dose day AND initiate home dosing) in this trial will not be 
replaced. 
7. Other Medications 
7.1. Concomitant Medications 
7.1.1. Protocol-mandated 
There are no protocol-mandated concomitant medications.  

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7.1.2.  Other permitted concomitant medications 
All subjects may continue their usual medications, including those taken for asthma, allergic rhinitis and atopic 
dermatitis, during the study. However, they must be able to discontinue antihistamines prior to the initial day of 
escalation, skin testing and all oral food challenges. Usual topical steroid use is permitted at the time of skin 
testing. Up-dosing will not occur within 3 days of systemic steroid use. 
7.2. Prophylactic Medications 
There will be no prophylactic medications required in this protocol. 
7.3. Prohibited Medications 
Participants will be removed from the trial if any of the following meds are started and cannot be safely stopped: 
• 
Omalizumab (Xolair) 
• 
Oral β-blockers 
7.4. Rescue Medications  
Treatment of individual allergic reactions during OIT therapy should be with either an antihistamine and/or epinephrine, 
along with IV fluids, albuterol and steroids as indicated. Subjects and parents are likely to already have EpiPens®, but for 
those who do not, a prescription for EpiPens® (or equivalent device) will be provided. Subjects and parents will be 
trained in proper use and will be able to demonstrate proper technique with the EpiPen® (or equivalent device). 
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. Participants will be considered enrolled into 
the study and assigned a unique study identification number after signing the informed consent/assent document(s). 
8.2. Screening/Baseline Visit 
The purpose of the screening period is to confirm eligibility to continue in the study. The Screening/Baseline 
assessments may take place over several visits. Baseline/screening visits following requirements below, conducted 
under a different protocol (Screening Protocol) can be used towards this study. 
All assessments must be completed no more than 40 weeks (Appendix 1) preceding initiation of FA treatment.  
The following procedures, assessments, and laboratory measures will be conducted to determine participant eligibility:  
• 
Consent and assent  
• 
Medical history, including review of all food allergies 
• 
Review of medications participants are currently taking 
• 
Physical assessment 
• 
Pregnancy test, if subject is a female who has undergone menarche and is of childbearing potential (i.e., not 
otherwise incapable of having children from a previous medical condition, surgery, or other circumstance 
• 
Blood draw for allergen-specific IgE and IgG4 measurement, lab tests and research samples 
• 
Skin prick test to FA extract (neat extract with no dilution, Greer Laboratories, Lenoir, NC) 
• 
Spirometry and/or Peak Expiratory Flow (PEF) 
• 
Stool sample collection 
• 
DBPCFC to a 443 mg cumulative total allergen protein 
Any of the above items may be repeated within the 40 weeks preceding initiation of study treatment if warranted, in the 
opinion of the investigator, by changes in the subject’s clinical status. 
 

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Double-Blind Placebo-Controlled Food Challenge (DBPCFC) at Screening 
Randomization and reparation of the challenge materials will be performed by trained study personnel in the GMP 
facility at Stanford. Prior to the food challenge, subjects will be asked to restrict the use of oral antihistamines (five 
half-lives), beta-agonists (12 hours), theophylline (12 hours), and cromolyn (12 hours).  
Subjects will not have active wheezing, spirometry demonstrating FEV1 <80% predicted, or a current flare of atopic 
dermatitis that contraindicates dosing in the clinical judgment of the study physician. If the participant is unable to 
perform spirometry, a peak expiratory flow ≥ 80% predicted and clear breath sounds on a lung examination will be used 
to determine if an oral food challenge can be performed. 
The screening DBPCFC will consist of doses given every 15-30 minutes in increasing amounts up to a cumulative total of 
443 mg of allergen protein. If the study team suspects a reaction may be developing, they may exercise their clinical 
judgment to separate doses by up to an additional 30 minutes (one hour maximum between doses). The other challenge 
will consist of placebo material given also in an equal number of doses. The doses will be 3 mg, 10 mg, 30 mg, 100 mg 
and 300 mg  modified PRACTALL dosing by Sampson et al, JACI 2012; https://www.jacionline.org/article/S0091-
6749(12)01663-6/pdf) Before each challenge, the subject will have a physical assessment administered by a trained 
physician’s assistant, registered nurse, nurse practitioner, and/or physician of the study team who is blinded to the 
testing material. The supervising investigator will also be blinded to testing material.   
The food challenge  will be stopped based on dose limiting symptoms defined in Appendix 3 If the subject begins to have 
any objective symptoms or subjective symptoms deemed clinically significant, the food challenge will be terminated, and 
the subject will be given appropriate treatment. The subject will be observed for a minimum of two hours after the final 
administered dose and discharged only when deemed clinically stable by a study physician. All food challenges will be 
performed under physician supervision. If the subject has no symptoms related to allergic reactions to the food allergen 
ingestion with the DBPCFC at or before 443 mg, they will not be enrolled in the study. 
8.3. Study Visits or Study Assessments  
Allergen-Specific OIT Treatment Overview 
Food allergen OIT administration will include an Initial dose day (IDD) with oral immunotherapy dosing beginning at 
5 mg occurring in the Stanford SNP-CRU.   
A targeted history and physical assessment will be performed at each in person visit. Physical assessments performed in 
this protocol will be allergy focused and include the following systems: head and neck, including thyroid; eyes, ears, 
nose, and throat; lungs; heart; abdomen; and skin. Subjects will be assessed for exacerbation of atopic dermatitis or 
asthma (as determined by active wheezing or report of an increased need for rescue medication in the prior week) prior 
to each in-SNP-CRU dosing. In the presence of an exacerbation of atopic dermatitis, the study physician will use their 
professional judgment in deciding whether the exacerbation should preclude an attempt at updosing. In the presence of 
wheezing in any child, regardless of asthma history, spirometry (per manual of procedures) will be performed to assess 
FEV1. If FEV1<80% predicted value, bronchodilators will be administered, and spirometry will be repeated. If FEV1 ≥80% 
predicted value (with or without bronchodilator administration) the updose may  be attempted in SNP-CRU. If FEV1 
<80% predicted value after bronchodilator administration, the participant will remain at their current dose for two 
additional weeks. That day’s dose should be administered either in SNP-CRU and monitored as an updose. 
In addition to dosing visits, subjects will return to the SNP-CRU at designated visits (see Appendix 1) for their OFC or 
other assessments/blood draws. A medical and diary review, and targeted physical assessment will also be performed at 
these visits. OFCs will occur at screening, end of maintenance phase (Week 52), end of withdrawal phase at Week 58 
and at Week 64 if opted for by the participant.  
After subjects have met the criteria outlined above (Section 3.1), medical history, diet history, spirometry, SPT, and a 
physical assessment will be performed.  

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Allergen-Specific OIT: 
Initial Dose Day (Day 1) – The Initial Dose Day will be done at the SNP-CRU and consist of either cashew or shrimp OIT 
dosing. Subjects will not have active wheezing, spirometry demonstrating FEV1 <80% predicted, or a current flare of 
atopic dermatitis that contraindicates dosing in the clinical judgment of the study physician. If the participant is unable 
to perform spirometry, a peak expiratory flow > 80% predicted and clear breath sounds on a lung examination will be 
used to determine if a dose escalation can be performed. A physician will be present at all times during any of the SNP-
CRU food allergen OIT dosing visits and will be available to respond within 60 seconds to any allergic reaction. Subjects 
tolerating the 5 mg single dose will remain on that daily dose for 2 weeks. They will then return every 2 weeks to the 
SNP-CRU for single updose.  
 
Updosing Phase (Build-up Phase) (Week 2-28):  Subjects will receive subsequent doses (Table 2) at home for the next 14 
days. Subjects* who do not tolerate the 5 mg dose will be given 3 mg daily and return in about 7 days for updosing to 5 
mg before proceeding to next dose.  Subjects will be instructed to continue dietary food allergen (cashew or shrimp) 
avoidance throughout the entire study. They will also be instructed not to introduce any new foods to the diet and to 
continue avoidance of the subject’s other known food allergens, if any. At 2-week intervals, the subjects will return for a 
possible increase in the daily oral dose until they reach 1000 mg FA protein build-up phase.   
During dose escalation, there should be increased hydration (i.e. about 16 oz or more given orally for an adult and an 
adjusted volume for children based on size) and restricted exercise for 2 hours after dosing. 
 
 
 
 
 
Table 2: Daily FA Protein Dosing and Increase Schedule for Build-Up Phase 
Dose # 
Dose 
Interval 
(Weeks) 
% of Increase 
1 
5 mg* 
2 
Initial dose day   
2 
7.5 mg 
2 
50% 
3 
15 mg 
2 
100% 
4 
30 mg 
2 
100% 
5 
50 mg 
2 
67% 
6 
75 mg 
2 
50% 
7 
100 mg 
2 
33% 
8 
150 mg 
2 
50% 
9 
200 mg 
2 
33% 
10 
300 mg 
2 
50% 
11 
400 mg 
2 
33% 
12 
550 mg 
2 
38% 
13 
700 mg 
2 
28% 
14 
1000 mg 
2 
36% 

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*: Note: Participants may return a second time within a period of a week to be given 5 mg. The criteria to be given it 
again will be if there is a moderate reaction (as per CoFAR criteria) on the first attempt. 
Subjects will begin the SNP-CRU dosing schedule as outlined above until 1000 mg of FA protein is reached. Any updosing 
attempts may be postponed for 1-2 extra visits based on clinical judgment. However, an updosing attempt must be 
made within a maximum of 3 consecutive scheduled clinic visits. Subjects should withhold their daily home dose and any 
prophylactic antihistamines on the in-SNP-CRU updosing day but should take all other prescribed medications. Note that 
the daily home dose should be taken as part of a meal at a consistent time (within 24±2 hours of the previous day’s 
dose), and it is critical to take the dose every day. Doses should be separated by at least 12 hours. Subjects who require 
dosing reduction by 50% during the 2-week period due to illness will undergo an attempted updosing only after 
resuming their full dose for a minimum 3 days.  
If participants miss a dose and remember less than 12 hours from when they were supposed to take that dose, 
participants may take the dose and resume the next dose on schedule. If they are within 12 hours of the next dose, they 
should not take the missed dose, but wait and take the next scheduled dose at the usual time (or if they miss a dose by 
more than 12 hours, they should contact study personnel to receive instructions on how to proceed). 
As stated above, an updosing attempt must be made within 3 clinic visits on a given dose, unless updosing is delayed 
due to administration of epinephrine as defined in Section 6.4.3 or illness.  If the subject fails to successfully increase 
updosing for three consecutive attempts, updosing will be halted at the last tolerated dose. Please refer to the 
Participant Disposition (Appendix 2) for follow up depending on the dose tolerated. 
Vigorous exercise is not permitted for at least 2 hours after the dose of oral allergen immunotherapy. Also, there must 
be at least 1 hour between vigorous exercise and taking a dose of oral allergen immunotherapy. Allergic reactions are 
still possible when exercise takes place more than 2 hours after the dose. 
 
Should significant systemic symptoms, which may include mild symptoms based on physician discretion or moderate or 
greater symptoms, be reported during the daily home dosing, the symptom/dosing algorithm will be followed to 
determine the best course of action. The appropriate treatment will depend on the type and number of symptoms.  
Subjects will be allowed to take their other daily medications during the build-up and maintenance phases of the study 
(i.e., antihistamines, albuterol) except where prohibited in this protocol. 
 In the event of an epidemic/pandemic or other unforeseen circumstances during which the patient cannot come into 
clinic, we will plan on sending doses to their homes/residences, and/or perform home visits or telehealth visits. Subjects 
may be maintained on the previously tolerated dose until a dose-escalation can be performed safely. 
 
Maintenance Phase (Week 28-52):  Subjects will undergo updosing until reaching a daily maintenance dose of 1000 mg 
and they will remain at that dose and return for follow-up visit at Week 52. Based on our previous data using a similar 
dosing method (Table 2), we expect all subjects on active treatment to reach 1000 mg between the Week 28 and Week 
52 visits. 
On Study DBPCFC (Week 52): At Week 52 all subjects will have a DBPCFC to up to 4043 mg to assess desensitization. 
The visit will also include a physical assessment, spirometry and/or PEF, stool sample collection and blood draw for 
allergy tests and mechanistic studies.  
The subject’s sensitivity to food allergen is defined as the dose at which the subject experiences allergic reactions. All 
symptoms and signs will be evaluated and rated based on a standardized oral food challenge scoring system (CoFAR 
guidelines, Appendix 3). During the oral food challenge, there should be increased hydration (i.e. about 16 oz or more 
orally). 
Updosing during the DBPCFC will be stopped when the Principal Investigator (or designee) finds symptoms and/or signs 
that indicate a definite allergic reaction (CoFAR guidelines) has occurred based on clinically significant changes in 
reported symptoms, physical findings, or vital signs that the subject is experiencing to the challenge material. The 
challenge will consist of doses based on modified PRACTALL guidelines and will include 3mg, 10mg, 30mg, 100mg, 

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300mg, 600mg, 1000mg and 2000mg. . Both food allergens (cashew or shrimp) and oat protein will be concealed in a 
food that masks the taste. After the last dose of the DBPCFC, the subject will be monitored for 2 hours and then 
discharged home. Subjects will be considered to have tolerated the OFC if they do not experience any objective 
reactions by Appendix aa. 
If the subject experiences reactions, they will be treated with the necessary rescue medications. They will be observed 
for a minimum two hours after the final administered dose and discharged home only when deemed clinically stable by 
a study physician. 
After the Week 52 DBPCFC, subjects who meet the following criteria will discontinue FA protein daily dosing entirely: 
• 
On OIT treatment for 52 weeks,  
• 
Taking daily maintenance dose of 1000 mg protein for approximately 3 weeks, 
• 
No severe reactions (CoFAR criteria) to home dosing, and/or 
Subjects who do not pass a cumulative of 2043 mg at Week 52 will be considered desensitization failures. They will be 
considered in statistical analyses of the intent-to-treat population. They will be followed until the end of study (week 
58). 
After Week 52, all subjects will begin their withdrawal phase for 6 weeks.  
On Study DBPCFC (Week 58, Week 64): At Week 58 subjects will have a DBPCFC to up to 4043 mg to assess sustained 
unresponsiveness (tolerance). The visit will also include a physical assessment, spirometry, fecal matter collection, skin 
prick test, and blood draw for  mechanistic studies. 
 
During the oral food challenge, there should be increased hydration (i.e. about 16 oz or more given orally). 
There are no published data indicating whether repeating food challenges every 6 weeks will or will not maintain 
desensitization or otherwise affect the outcomes in this study. Our preliminary studies in which we have performed 
DBPCFCs every 3 months in a separate phase 1 study cohort (n=87 subjects) have demonstrated no increased risk of 
sensitization (as per repeat cumulative doses on repeat DBPCFC and as per severity of reaction). 
End of study (Week 58 or Week 64): Participants will be followed until week 58 or until Week 64 if they opt to 
continue avoidance of OIT for 8 more weeks after Week 58.  
8.4. Unscheduled Visits  
If disease activity increases or other concerns arise between regularly scheduled visits, participants should be instructed 
to contact study personnel and may be asked to return to the study site for an “unscheduled” visit.  
Unscheduled visits may be performed for significant food allergy episodes which may be reported by the subject 
between regularly scheduled visits. Significant food allergy episodes are defined as those for which epinephrine is 
administered based on criteria in the subject’s Food Allergy Action Plan. Unscheduled visits may include physical 
assessment, blood draw and/or skin prick test. Review of the circumstances around the episode and appropriate 
documentation of the adverse event will be recorded in the study chart. 
8.5. Visit Windows 
Study visits should take place within the time limits specified below: the designated visit windows (i.e. +/- n days) for 
each scheduled visit are also indicated on the Table of Events. 
 
 
Table 3: Visit Windows* 
Visit Type 
Target Date 
Visit Window 

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Screening/Baseline/Randomization Day -364 to 1 
Day -364 to Day 1 
Initial dose day 
Day 1 
Within 364 days from 
screening  
Dose Escalation Phase 
Weeks 2, 4, 6, 8, etc. until 
maintenance dose is reached 
±7 days 
Maintenance Phase 
Weeks 28 to 52 
Tolerance Phase 
Weeks 52 to 58 and up to optional 
Week 64 
* in the time of an epidemic, doses might need to be sent to the participant’s home at the same dose.  
9. Mechanistic Assays 
 Comparisons for each of the parameters discussed below could occur between: 
• 
On Treatment vs. Baseline for each participant, and  
• 
SU vs. Desensitized but SU Failures clinical outcomes at week 58 DBPCFC.  
• 
Desensitized vs all others at week 52 DBPCFC 
I) 
Serum Assays  
Serum Assays 
Panel 
Volume needed for each sample 
collection 
Specific IgE, IgG4, IgA anti-food allergen and the 
component-resolved testing where applicable 
1 ml 
Epitope Arrays 
350 microliters 
 
Expected Results for Serum Parameters 
 
Parameter 
Desensitization 
SU 
Specific IgE 
And Specific IgG4 
Progressive 
decrease in 
specific IgE to 
food allergen 
(FA) and increase 
in specific IgG4 
Low specific IgE 
and increased 
IgG4  
Epitope Array for 
IgE for FA 
peptides—
predictive 
marker for 
outcome 
Progressive 
Inhibitory 
antibodies 
present in 
epitope array 
Intermediate 
epitope 
spreading at 
baseline  
Specific IgA 
Progressive 
increases in 
specific IgA over 
time 
Intermediate 
levels of specific 
IgA  
Note: Compared to placebo, in which we assume no changes will occur. 
 
II)           Cell components for CyTOF  

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Expected Results for Cell Parameters 
Parameter 
Desensitization 
SU 
Th2 
Progressive 
decrease in Th2 
absolute numbers 
and ICS 
transcription 
factors and Th2 
cytokines 
Low Th2 cells 
and low ability to 
proliferate in 
response to FA  
Anergy 
Decreased CD28 
and CD38 
Lack of CD28 and 
CD38 
Th1 
Progressive 
increase in Th1 
absolute numbers 
and ICS 
transcription 
factors and Th1 
cytokines 
High Th1 cell 
numbers and 
ability to 
proliferate in 
response to FA  
Th17 
Do not expect 
change 
Do not expect 
change 
Treg 
Progressive 
increase in 
absolute counts of 
Treg but then 
decline by 12 mo. 
Intermediate 
Treg cell 
numbers and 
decreased ability 
to proliferate in 
response to FA  
NKT 
Progressive 
increase in 
absolute counts of 
NKT cells 
Intermediate 
NKT cell 
numbers 
associated with 
desensitization 
DC 
Progressive 
decrease of TSLP 
receptor in mDCs, 
progressive 
increase in CD103 
and CCR9 in DCs 
Intermediate 
TSLP receptor 
expression in 
mDCs and 
intermediate DC 
expression of 
CD103 and CCR9 
Cell death 
markers 
Progressive 
increase in cell 
death of allergen-
specific Th2 
memory cells 
Intermediate cell 
death of 
allergen-specific 
Th2 memory 
cells 
Chemokine 
receptors 
Progressive 
increase in CCR4 
and CCR8 in Treg 
Intermediate 
expression of 
CCR4 and CCR8 
in Treg 
Allergen 
specific cells 
Switch from mostly 
Th2 to Th1 or Treg 
Intermediate 
decrease in Th2 

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subset over course 
of therapy 
cytokines and 
transc. factors  
Note: Compared to placebo, in which we assume no changes will occur. 
 
III)          Sample Basophil Assay: 
Expected Results for Basophil Activation Parameters 
Parameter 
Desensitization 
SU 
CD203c/CD63 
During course of 
therapy, will see 
decrease in 
basophil 
reactivity sooner 
than lowering of 
specific IgE in 
participants 
Basophil 
reactivity 
decreases. 
Logistics: We will collect up to 30 mL on any one blood draw not to exceed 5ml/kg over a 12 week period These volumes 
are more conservative than Stanford IRB limitations (3ml/kg over a 12-week period) and NIH guidelines (for children: 5 
ml/kg at any single draw, no more than 9.5 ml/kg over an 8-week period; for adults: the smaller of 10.5 ml/kg or 550 ml 
total at any single draw)... 
10. Biospecimen Storage 
Biospecimen storage will occur in the Nadeau laboratory using a previously validated and published storage procedure 
for samples (available upon request).  
11. Criteria for Participant and Study Completion and Premature Study Termination 
11.1. 
Participant Completion 
Completion of the study will be defined as reaching the Week 58 visit. 
11.2. 
Participant Stopping Rules and Withdrawal Criteria 
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. 
5. Individual safety stopping rules: 
The participant experiences an allergic reaction to any IP (CoFAR Grade 4; see Table in section 12.3.1).  
Table in section 12.3.1 (page 49)  
i. 
CoFAR Grading Scale for Systemic Allergic Reactions Modified Version 2.0 Any subject deemed to have 
severe allergic reactions and who receives aggressive therapy (e.g., IV fluid resuscitation, mechanical 
ventilation, repeated doses of epinephrine for a life-threatening reaction) at any time should be 
discontinued from further therapy   
ii. 
Other circumstances including, but not limited to, the following: 

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- 
Severe adverse event, other than anaphylaxis, related to investigational product  
- 
Pregnancy 
11.3. 
Participant Replacement 
Participants who withdraw or are withdrawn after initiation of home dosing will not be replaced. 
11.4. 
Follow-up after Early Study Withdrawal 
Subjects who prematurely discontinue treatment with OIT may remain in the study until end of study visit at week  58 to 
monitor safety and efficacy parameters.  These visits will include skin testing and/or a blood draw for mechanistic 
studies at the study time points. 
If the subject refuses this follow-up, or begins and then elects to discontinue the follow-up, they will be asked to come in 
for a final study visit consisting of a physical assessment, skin test, blood draw, review of their Food Allergy Action Plan, 
and instructions to discontinue any OIT dosing and continue food allergen avoidance. 
 
11.5.  Study Stopping Rules 
During the course of this study, if the investigator or the NIAID Medical Officer discovers conditions that indicate that 
the study should be discontinued, an appropriate procedure for stopping the study pending DSMB review will be 
instituted, including notification of the FDA and IRB.  See section 12.8.2.2 
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, DAIT/NIAID.  Appropriate notifications will also be made to site 
principal investigators, Institutional Review Boards (IRBs), [replace with “Institutional Ethics Committees (IECs)”, if 
applicable] 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, a related adverse event will include any untoward or unfavorable medical occurrence associated 
with:   
• 
Study therapy regimen:  
Home OIT Dosing 

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 
Food allergy episodes in response to home dosing that are objective Grade 1 or 2 by Appendix 3 will 
be recorded on the paper AE CRFs and graded by CoFAR criteria. 
 
Food allergy episodes in response to home dosing that are Grade 3 by Appendix 3 or that are 
classified as SAEs defined in Section 12.2.3 below will be recorded on the AE/SAE CRF as appropriate 
and graded by CoFAR criteria. 
• 
Study mandated procedures:  
For the procedures below, clinical situations are listed that are considered to be outside the normal 
range of outcomes and will be recorded as Adverse Events.  These situations do not limit an investigator 
from recording and reporting any other events, associated or not with these procedures as AEs.    
Allergen Skin Testing 
 
Prolonged (>24 hours) itching at test site 
 
Swelling (> 10 cm) at site of test lasting more than 24 hours 
 
Nasal allergic symptoms within 30 minutes from the procedure 
 
Fainting /Vasovagal event within 30 minutes from the procedure 
Phlebotomy 
 
Bruising at phlebotomy site >5 cm with onset within 24 hours of procedure 
 
Erythema at phlebotomy site >5 cm with onset within 24 hours of procedure 
 
Infection at phlebotomy site 
 
Fainting /Vasovagal event within 30 minutes from the procedure 
 
Spirometry or Peak Flow 
 
Feeling breathless 
 
Fainting/Vasovagal event within 30 minutes from the procedure 
 
Double-Blind Placebo Controlled Food Challenges 
During DBPCFCs, reactions will be recorded.  DBPCFC material is not considered study drug, and as 
such, reactions will be recorded and reported separately. 
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 Investigator 
Brochure or protocol, or is not listed at the specificity, severity or rate of occurrence that has been observed. 
The Principal Investigator will review all adverse events related to skin prick testing, spirometry, 
DBPCFC, or other study procedures to determine if they are unexpected.  
12.2.3 Serious Adverse Event (SAE) 

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An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator 
or Sponsor DAIT/NIAID, it results in any of the following outcomes (21 CFR 312.32(a)): 
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 DAIT/NIAID, its occurrence places the subject at immediate risk of death. It does not 
include an AE or SAR that, had it occurred in a more severe form, might have caused death.  
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. 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol mandated 
procedures are not to be reported as an SAE unless hospitalization is prolonged due to complications. 
 
12.3 Grading and Attribution of Adverse Events 
12.3.1 Grading Criteria 
The study site will grade the severity of non-allergic 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 
(CTCAE) version 5.0. 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 Principal Investigator 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. 
Events grade 1 or higher will be recorded on the appropriate AE paper case report form (CRF) 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 therapy or monitoring are 
implemented as a consequence of the event/result. 
 
Clinical criteria for diagnosing anaphylaxis will be as follows (Sampson, HA, et. Al, 200679): 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 

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1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced Peak expiratory flow 
(PEF), hypoxemia) 
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to 
several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP* (age specific) or greater than 30% decrease in systolic BP 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline 
*Low Systolic BP is defined as less than (70 + [2 x age]) mm Hg 
 
Anaphylaxis severity will be graded according to the following CoFAR specific grading system scale: 
 
 
 
 
 
 
 
Anaphylaxis Staging System 
 
Staging System of Severity of Anaphylaxis 
Stage 
Defined By 
1. Mild (skin & subcutaneous tissues, GI, 
&/or mild respiratory) 
Flushing, urticaria, periorbital or facial angioedema; 
mild dyspnea, wheeze or upper respiratory 
symptoms; mild abdominal pain and/or emesis 
2. Moderate (mild symptoms + 
features suggesting moderate 
respiratory, cardiovascular or GI 
symptoms) 
Marked dysphagia, hoarseness and/or stridor; 
shortness of breath, wheezing & retractions; crampy 
abdominal pain, recurrent vomiting and/or diarrhea; 
and/or mild dizziness 
3. Severe (hypoxia, hypotension*, 
or neurological compromise) 
Cyanosis or SpO2 < 92% at any stage, hypotension, 
confusion, collapse, loss of consciousness; or 
incontinence 
* https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf 
     Other allergic reactions will be graded according to the following CoFAR specific grading system: 
 
 
 
 

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Table 4 COFAR Grading Scale for Systemic Allergic Reactions 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 

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Reaction involving 
one of the following 
organ systems in 
which the 
symptoms are mild: 
Cutaneous 
Generalized 
pruritus, 
generalized 
urticaria, flushing, 
angioedema 
Upper respiratory 
Rhinitis, cough 
unrelated to 
laryngeal edema or 
bronchospasm 
Conjunctival 
Injection/rednes
s, itching, 
tearing 
 
GI 
Nausea, 
abdominal pain 
(no change in 
activity level), 
single episode 
of vomiting 
and/or single 
episode of 
diarrhea 
 
Reaction involving 
two or more of the 
following organ 
systems in which the 
symptoms are mild: 
Cutaneous 
Generalized 
pruritus, 
generalized 
urticaria, flushing, 
angioedema 
Upper respiratory 
Rhinitis, cough 
unrelated to 
laryngeal edema or 
bronchospasm 
Conjunctival 
Injection/redness, 
itching, tearing 
 
GI 
Nausea, abdominal 
pain (no change in 
activity level), single 
episode of vomiting, 
and/or single episode 
of diarrhea 
 
 
Reaction involving: 
Lower respiratory 
Throat tightness 
without 
hoarseness, 
wheezing, chest 
tightness, 
dyspnea, cough 
that responds to 
short- acting 
bronchodilator 
treatment (including 
IM epinephrine) 
AND/OR 
GI 
Severe abdominal 
pain, more than two 
episodes of vomiting 
and/or diarrhea 
Reaction involving 
ANY of the 
following with or 
without other 
symptoms listed in 
Grades 1 to 3: 
Laryngeal edema 
AND/OR 
Severe lower 
respiratory (throat 
tightness with 
hoarseness, 
wheezing, chest 
tightness, dyspnea, 
cough) including: 
a) Refractoriness2 to 
short-acting 
bronchodilator 
treatment 
(including IM 
epinephrine) 
AND/OR 
b) Hypoxia (O2 
saturation 
≤92%) 
 
Death 
 
 
 
 

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OR 
Reaction involving one 
of the following organ 
systems in which the 
symptoms are 
moderate: 
Cutaneous 
Generalized pruritus, 
generalized urticarial, 
flushing, angioedema 
Upper respiratory 
Rhinitis, cough 
unrelated to laryngeal 
edema or 
bronchospasm 
Conjunctival 
Injection/redness, 
itching, tearing 
 
GI 
Nausea, abdominal pain 
(with change in activity 
level), two episodes of 
vomiting and/or 
diarrhea 
 
AND/OR 
c) Respiratory 
compromise 
requiring 
mechanical support 
AND/OR 
Cardiovascular 
Reduced BP with 
associated symptoms 
of end-organ 
dysfunction (e.g., 
hypotonia [collapse], 
syncope) defined as: 
• Children: low 
systolic BP (age 
specific1) or >30% 
decrease in 
systolic BP 
• Adults: systolic BP 
of less than 90 
mmHg or >30% 
decrease from 
baseline 
 
1.  Low systolic BP for children is defined as: less than 70 mmHg from 1 month to 1 year of age, less than (70 mmHg + [2 x age]) from 1 to 10 years 
of age, and less than 90 mmHg from 11 to 17 years of age. 
2- For instance, this would include continuous nebulizer or epinephrine iv infusion or more than 3 epinephrine intramuscular injections 
 
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 and recorded on the appropriate AE paper case report form 
(AE/SAE paper CRF).  Final determination of attribution for safety reporting will be determined by DAIT/NIAID.  
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.  
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. 
 
       
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. 

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 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 time of consent until a subject completes study participation 
or until 30 days after he/she prematurely withdraws (without withdrawing consent) or is withdrawn from the 
study. 
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 appropriate AE/SAE paper CRF regardless of the relationship to 
study therapy regimen or study procedure. 
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 
12.5.1 Reporting of Serious Adverse Events to DAIT/NIAID 
Site investigators will report all serious adverse events (see Section 12.2.3, Serious Adverse Event), regardless of 
relationship or expectedness within 24 hours of discovering the event. 
For serious adverse events, all requested information on the AE/SAE paper 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 pager CRF will be updated and submitted. 
The site investigator will report to the NIAID Medical Officer and the Independent Medical Monitor all serious 
adverse events within 24 hours of becoming aware of the event, regardless of relationship or expectedness.  
CONTACT INFORMATION FOR NIAID MEDICAL OFFICER:  
, MD MPH 
 
NIAID/ DAIT/ AAABB 
5601 Fishers Lane 
 

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Bethesda, MD 20892  
 
P: 
  M: 
 
Email:
 
 
12.5.2 Reporting to Health Authority 
Dr. Sindher will be the sponsor of the IND and has the responsibility of reporting all AEs and SAEs to the FDA 
within the reporting time limits set forth by the FDA. It is Dr. Sindher’s ultimate responsibility to report any 
serious adverse event to the Independent Medical Monitor at her 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 submitted by the site investigator and assessed by DAIT/NIAID, there are two options for Dr. Sindher 
to report the adverse event to the appropriate health authorities: 
12.5.2.1 Annual Reporting 
Dr. Sindher will include in the annual study report to health authorities 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 12.2.2, 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 and unexpected suspected adverse reaction [SUSAR] (see Section 12.2.1.1, 
Suspected Adverse Reaction and Section 12.2, Unexpected Adverse Event and 21 CFR 312.32I(1)i).  
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); 
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. 
 
Certain SAEs occur commonly in this study population.  Anaphylaxis to study food ingestion will 
be reported in the annual report, unless it is life-threatening or results in death, in which cases 
an expedited report will be filed.    
 
 

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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, Dr. Sindher, shall notify the appropriate health authorities and all participating sub 
investigators of safety reporting 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 Safety Reports to the FDA 
shall be distributed by Dr. Sindher or designee for site IRB/IEC submission. 
   12.6  Pregnancy Reporting 
 
The investigator shall be informed immediately of any pregnancy in a study subject. A pregnant subject shall be 
instructed to stop taking study medication. 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.    
The investigator shall report to the DAIT/NIAID all pregnancies within 1 business day of becoming aware of the 
event using the Pregnancy paper CRF.  All pregnancies identified during the study shall be followed to conclusion 
and the outcome of each must be reported.  The Pregnancy paper CRF shall be updated and submitted to the 
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 
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 DAIT/NIAID using the SAE reporting procedures described 
above.  
12.7 Reporting of Other Safety Information 
An investigator shall promptly notify the site IRB as well as the DAIT/NIAID 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 DAIT/NIAID Medical Monitor shall receive annual reports from the protocol investigator compiling new and 
accumulating information on AEs, SAEs, and pregnancies recorded by the study site(s) on appropriate paper 
CRFs. 

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In addition, the Medical Monitor shall review and make decisions on the disposition of the SAE and pregnancy 
reports received by the protocol 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:  
• 
Any death related to food allergen OIT dosing 
• 
One case of severe and prolonged anaphylaxis that does not respond to 3 doses of epinephrine, or 
that includes intubation and that is related to food allergen dosing or to oral food challenge. 
• 
More than 2 cases of hypotension related to food allergen dosing or to oral food challenge. 
• 
More than 3 of either of the following events: 
o Severe adverse event, other than anaphylaxis, related to investigational product or 
o Eosinophilic esophagitis with synchronous clinical symptoms and confirmatory biopsy 
findings 
 
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/drug dosing or both for ad hoc DSMB Safety Review    
A temporary halt in enrollment, initial dose days and drug updosing will be implemented if an ad hoc 
DSMB safety review is required per the criteria outlined in section 12.8.2.2. above.   
In the event of a study halt for DSMB review, subjects in the screening phase will continue to undergo 
screening procedures unless the review was triggered by events related to screening. Subjects already 
receiving therapy will remain on study treatment at their current tolerated dose. 
Based on the outcome of the DSMB review, the consent and/or assent forms may be revised. Upon 
approval of these revisions by the IRB, all subjects who have previously provided informed consent for 
the study and are affected by the new information will be re-consented. 
13. Statistical Considerations and Analytical Plan 
13.1 
Overview  
This phase 2 single site study in cashew or shrimp-allergic children and adults intends to identify basic immune 
mechanisms that explain the effects of OIT in individuals who do or do not become clinically tolerant and to 
determine whether immune monitoring can predict safety and outcomes in OIT protocols. We will rely on 
analysis of covariance (ANCOVA) methods to model the change of CD28 expression measured at week 52 from 
baseline as a continuous variable as a function of: the change of CD28 measurement from the baseline and an 
indicator for whether the subject passed the DBPCFC at week 52, where the parameter for the latter is of main 

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interest and represents whether changes in expression of CD28 differ for those who achieve desensitization 
versus those who do not. In addition, methods appropriate for right-censored data (time to achieving 
desensitization) such as the Cox proportional hazards model also will be considered. We also will use methods 
such as the Least Absolute Selective Shrinkage Operator (LASSO) to identify immunophenotypes that correlate 
with clinical outcomes, and to Identify epitopes and/or clonotypes associated with clinical phenotypes. Such 
methods are appropriate when jointly considering a large number of correlated features, as we anticipate with 
data generated from the CyTOF platform. Finally, we will consider hierarchical clustering techniques to explore 
the clustering of both mechanistic features and patients, to provide insight into whether mechanistic features 
can be used to describe clinical phenotypes of interest. 
13.2 
Endpoints and anticipated results 
13.2.1 Primary Endpoint(s)/Outcome(s) 
Change in expression of CD28 in the CD4+ allergen specific (CD154+ ) T-cells at 52 weeks relative to baseline 
values between those who do and do not pass the DBPCFC at week 52 at a cumulative tolerated dose of 2043 
mg. 
i.e. Comparing those who pass the desensitization challenge vs all others there will be at least a 20% increase in 
the allergen specific (CD154+ ) T-cell activation towards a Th1/ anergic state at week 52 DBPCFC.  
13.2.2 Secondary Endpoint(s)/Outcome(s) 
 
• 
Compare changes in expression of CD28+ allergen specific (CD154+ ) T-cells over multiple time points from 
baseline to week 58 and week 64 between those with sustained unresponsiveness (SU) vs those desensitized but 
SU failures vs those who did not pass the desensitization DBPCFC. 
• 
Compare changes in the following measures in CD4+CD28+ allergen specific (CD154+ ) T-cells at week 52 and 
over multiple time points through week 58 between those who achieved sustained unresponsiveness (SU) vs 
those desensitized but SU failures vs those who did not pass the week 52 (desensitization) DBPCFC 
o Levels of IFN-gamma 
o levels of IL-4  
o Receptor diversity in allergen specific T cell CDR3b as compared to non-specific T cells 
o levels of IL-10  
o levels of TGF-beta 
o levels of GPR15 
o levels of CCR4+ 
o levels of CRTh2 
 
• 
Changes in distribution of immune cells representing difference in regulatory T cells vs eosinophils and mast 
cells over multiple time points obtained with GI biopsy tissues across those who achieved sustained 
unresponsiveness (SU) vs those desensitized but SU failures vs those who did not pass the week 52 DBPCFC. 
 
Expectations: 
• 
Comparing sustained unresponsiveness (SU) vs desensitized but SU failures, there will be at least a 50% 
increase in the absolute allergen tetramer + T-cell numbers at week 58. 
• 
Comparing SU vs desensitized but SU failures. There will be at least a 20% change in the allergen specific 
(CD154+ ) T-cell activation towards a Th1/ anergic state at week 58 DBPCFC. 
• 
 Comparing desensitized vs all other failures, there will be increased IFN, decreased IL-4, and increased T 
cell receptor diversity in allergen specific T cells as compared to non-specific T cells at week 52. 

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• 
Comparing SU vs desensitized but SU failures, there will be increased IFN, decreased IL-4, and increased T 
cell receptor diversity in allergen specific T cells as compared to non-specific T cells at week 58. 
• 
Comparing SU vs desensitized but SU failures, allergen specific T cells from participants with mild to no 
allergic reactions on DBPCFC at week 58 will demonstrate increased IL-10, TGF-, GPR15, and less T cell 
receptor diversity.   
Other Endpoints: 
• 
Comparing the proportion of participants who become desensitized vs all others (i.e. treatment failures) at week 
52 DBPCFC. 
• 
Comparing the proportion of participants who reach SU vs desensitized but SU failures at week 58 DBPCFC. 
• 
Comparing the proportion of participants who reach SU vs desensitized but SU failures at week 64 DBPCFC. 
Safety Endpoints 
• 
The proportion of participants with only mild AEs during the course of the study. 
• 
The proportion of participants with respiratory or abdominal severe AEs during the course of the study. 
• 
The proportion of participants who successfully pass a DBPCFC with no or mild objective reactions to a 
cumulative 2043 mg of the FA allergen at the end of OIT (week 52). 
• 
The proportion of participants who successfully pass a DBPCFC with no or mild objective reactions to a 
cumulative 2043 mg of the FA allergen after 6 weeks off OIT (week 58). 
 
Measurement: A DBPCFC is considered a “pass” if the subject has no dose limiting symptoms (appendix 3) 
during the challenge (from administration of first dose through observation period lasting 2 hours after 
administration of the final dose). 
• 
Frequency of anaphylaxis. 
• 
Frequency of use of epinephrine as a rescue medication. 
• 
Frequency of AEs leading to premature withdrawal. 
• 
Frequency of AEs in each treatment regimen leading to discontinuation of extended interval dosing. 
 
13.3 
Measures to Minimize Bias  
We will use centralized laboratories and /or masking of laboratory staff to minimize bias.  Because we 
are interested in the marginal association between CD28 expression and clinical phenotype 
(desensitization at 52 weeks), we will not adjust for additional covariates in the primary analysis that 
addresses the primary objective. Associations adjusted for sex, age and allergy type will be provided in 
secondary analyses. 
13.4 
Analysis Plan 
13.4.1 Analysis Populations. 
• 
Intent-to-treat (ITT) sample: All subjects who are enrolled will comprise the ITT sample. 
• 
The Safety Sample (SS) is defined as all enrolled participants who receive at least one dose of OIT. 
Participants in the SS will be analyzed according to the treatment that they actually received. This 
sample will be utilized to assess differences in safety endpoints. 
• 
We will also compare against results found in treated, mechanistic controls (n=estimate 25) with 
similar clinical characteristics. These historical controls  will be allergen-matched and clinically 

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matched as best as possible to determine if they can be used to add to the mechanistic knowledge 
provided by the use of tetramers and CD154 testing.  
13.4.2 Primary Analysis of Primary Endpoint(s)/Outcome(s)   
We will rely on analysis of covariance (ANCOVA) methods to model the change of CD28 expression 
measured at week 52 from baseline as a continuous variable as a function of: the baseline CD28 
measurement and an indicator for whether the subject passed the DBPCFC at week 52, where the 
parameter for the latter is of main interest and represents whether changes in expression of CD28 differ 
for those who achieve desensitization versus those who do not. We will test whether the parameter of 
interest differs significantly from zero using a two-sided F-test at the 0.05 level of significance. 
13.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s)  
Sensitivity analyses will be performed in secondary analyses where associations between change in 
CD28 expression at week 52 and desensitization are adjusted for age, sex, and allergy type (shrimp, 
cashew).  
13.4.4 Analyses of Secondary and Other Endpoint(s)/Outcome(s) 
Similar methods will be used to address secondary objectives. For example, we will regress CD28 
expression on a categorical variable for time (baseline, week 52, or week 58), a categorical variable for 
clinical phenotype (did not achieve desensitization, achieved desensitization but not SU, achieved SU), 
and their interaction to assess whether trajectories of CD28 over time are differential by response to 
therapy. Additionally, we will assess whether changes over time in other markers (IFN, IL-4, IL-10, 
TGF-, GPR15) vary by response to therapy. We will also examine whether diversity in T cell receptor 
status at baseline or whether changes in diversity vary by responder status.  
All statistical tests will be two-sided and conducted at the 0.05 level of significance. We acknowledge, 
however, that we are proposing numerous secondary hypotheses and that such an approach can result 
in false discoveries. We will therefore be fully transparent when reporting any such findings as 
secondary and hypothesis generating in contrast to how the primary analysis will be reported. 
13.4.5 Analyses of Exploratory Endpoint(s)/Outcome(s) 
There are numerous questions of interest that involve the utility of data generated on a variety of 
platforms for predicting clinical response, or for describing other relevant clinical phenotypes that could 
provide insight into OIT. An important goal is to identify those with potential ability to discriminate 
across phenotypes relevant for characterizing and treating patients with significant FA. Thus, for each 
platform of interest, we will evaluate the roles of mechanistic features in predicting SU and control the 
false discovery rate (FDR) to be no more than 5%. In addition to statistical testing, analyses (e.g., those 
that employ LASSO) will jointly evaluate features and identify those with relatively more importance 
with respect to the clinical phenotype of interest. Additionally, other analyses (such as hierarchical 
clustering) will provide graphical depictions of clustering of features and of subjects, providing insight 
into features within and across platforms and potentially meaningful clinical phenotypes. Similar to our 
approach for secondary analyses, we will be fully transparent in reporting any findings as exploratory 
and hypothesis generating in contrast to how the primary analysis will be reported. 
13.4.6 Descriptive Analyses  
Means, medians, standard deviations, and interquartile ranges will be presented for continuous 
variables. Frequency tables will be provided for categorical and discrete terms, such as family history 
and ethnicity. Graphical tools such as boxplots and histograms will be used to assess distributional 
properties of continuous variables. Transformations for primary and secondary endpoints may be 
necessary to better adhere to modeling assumptions. For example, expression of CD28 may be log- or 
arcsin-transformed prior to analysis.  

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Covariates and Confounders  
For all statistical analyses that yield estimates of associations, we will provide unadjusted associations of 
relevant quantities as well as associations that adjust for pre-specified confounders. Comparisons 
between unadjusted and adjusted associations will provide insight into how estimates vary through 
associations. 
Effect Modification  
To evaluate effect modification of an exposure-outcome association by risk for FA, we will rely on 
interaction terms in the model to assess the statistical significance of any observed difference in 
association among levels of the potential effect modifier. These analyses are not specified in our primary 
analysis but may be included in exploratory analyses. 
 
13.5 
Interim Analyses  
Interim analysis to investigate the change of CD28 from baseline is planned when 30 participants (either cashew 
or shrimp) are enrolled and complete the CD28 measurement at week 52.  
13.5.1 Interim Analysis of Efficacy Data  
The interim analysis for an early evaluation of the change in CD28 from the baseline will be conducted after 30 
participants are enrolled and complete the CD28 measurement at week 52. We designed the interim analysis for 
early stopping when we rejected the null hypothesis with a significant difference of changes on CD28 expression 
compared to baseline.  The O'Brien-Fleming decision boundary is used to control the overall type I error 
probability at the conventional 0.05 level. The Lan-DeMets error-spending approach that approximates O’Brien-
Fleming is used to determine the alpha with the information fraction of 41.7% The interim analysis stage, the 
null hypothesis will be rejected if the test is significant at the alpha level of 0.001 with an associated absolute Z 
statistic of 3.28. Thus the trial will be stopped if the test statistic is less than or equal to -3.28 or greater than or 
equal to 3.28 with p value ≤ 0.001; otherwise the null hypothesis will be accepted and the trial will be continued.   
Considering the possibly slow pace of participant enrollment, we will conduct our interim analysis based on data 
accumulated by January 31, 2021, if the pre-planned information fraction of 41.7% is not reached by that time. 
We will use the Lan-DeMets O’Brien-Fleming error-spending approach to determine the corresponding alpha 
and boundary based on the true information fraction. 
13.5.2 Interim Analysis of Safety Data 
Not applicable. 
13.5.3 Futility Analysis 
Not applicable. 
 
13.6 
Statistical Hypotheses  
Our hypothesis is that CD28 expression in the allergen specific (CD154+ or tetramer+) T-cell activation towards 
a Th1/ anergic state at week 52 DBPCFC relative to baseline will be significantly decreased among those who 
achieve desensitization versus those who do not.  
13.7 
Sample Size Considerations  
We have excellent power to address our primary objective using the ANCOVA methods. For example, assuming 
that 81% of subjects achieve desensitization at week 52, we will have approximately 58 responders and 14 non-
responders. Given this sample size and group distribution, assuming 2 repeated measurements having a 
compound symmetry covariance structure, that the correlation between observations on the same subject is 
0.5, and assuming a standard deviation for change in CD28 expression on the arc-sin scale at week 52 of 0.90, 
we have 87% power to detect a difference in change in CD28 expression between responders versus non-

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responders of 0.75 on the arcsin scale. If we assume 85% are desensitized, corresponding to 61 responders with 
assumptions similar to those made above, we have 82% power to detect the same difference. If we consider a 
15% missing data on CD28 expression on week 52, we would have 80% power to detect the same change in 
CD28 expression, assuming 81% are desensitized. If the standard deviation is assumed to be higher – for 
example due to missing data --  and is as high as 1.1 on the arcsin scale for example, we have 77% power to 
detect a difference in change between responders and non-responders of 0.85 on the arcsin scale, assuming 
81% are desensitized. If we consider a 20% missing data, we would have 78% power to detect the change of 0.85 
on the arcsin scale. The treatment effect is assumed to be the same between two foods, however, to ensure 
that we have enough shrimp allergic participants to detect the SU, we will try to enroll at least 14 participants 
with shrimp allergies.  
 
Our phase 2 clinical study is designed to provide preliminary data on the feasibility of correlating mechanistic 
features with a number of clinical phenotypes of interest. We propose consistent, rigorous entry criteria as well 
as standardized, reproducible methods for OIT. This level of participant characterization should enhance the 
ability to determine the important epitopes and interpret any change in responses following OIT. For 
comparison, we will include naturally tolerant individuals and allergic individuals who are not treated. Naturally 
tolerant individuals are defined as individuals who had clinically diagnosed food allergies (by OFC) who then lost 
those food allergies over time and have a verified negative OFC upon repeat OFC for that food allergen. The 
sample size calculations are based on our prior work and successful outcomes of clinical trials. The sample size 
has been selected in consideration of the needs to acquire a sufficiently large set of immunophenotypes via 
targeted RNA-Seq, CyTOF, and TCR sequencing measurements to significantly differentiate desensitization vs SU 
vs clinical failure.  
 
Our sample size provides adequate information to explore whether mechanistic features or changes in 
mechanistic features can discriminate participants into clusters of clinical interest including response to OIT 
(desensitization vs SU), type of allergy (cashew or shrimp), severity of allergic reaction at baseline, and natural 
tolerance vs persistence of FA. For example, in a prior study of n=5, in which we tested CD154+ T cells and 
tetramer + T cells over time during peanut immunotherapy, we found that there was a change of a 30% increase 
in Th1/anergy and Treg parameters (Ryan, et. al. PNAS 2016; Syed, et al. 2014) so this provides rationalization 
for choosing at least a 20% change compared to baseline in our primary endpoint.   
 
All participants will be HLA-typed. Given the HLA types that we have sequenced and found in our patient 
populations, we expect that we will be able to perform tetramer sorting of single cells in at least 60% of the 
participants. We plan to perform bulk sorting on activation-positive T cells (after epitope stimulation) for all 
participants. 
 
Finally, we believe it is important to test similarities and differences in T cell responses among food allergens, 
particularly those in common foods associated with near-fatal anaphylaxis, such as cashew and shrimp. We 
believe it will not be difficult to recruit patients or obtain data on these distinct allergens, since the tools are 
developed for epitope-specific use based on distinct peptides derived from the different food allergens. 
However, we will approach these studies in a stepwise manner, starting with one food. If either the recruitment 
of suitable participants or laboratory analysis are more arduous than anticipated, we will have complete data on 
at least one or two of the three foods. 
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. In 

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this protocol, source data will be recorded onto paper CRFs at the time of collection. Skin test results will be recorded via 
adhesive tape transfer of the outline of any wheal(s) and/or erythema. Spirometry results will be recorded as printouts 
from the software package used to perform the testing.  
14.2. 
Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID, 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 study staff will a) notify the site Principal Investigator, b) 
notify the NIAID Project Manager, and c) will complete a Protocol Deviation form. The DAIT/NIAID Medical Monitor will 
make the decision as to whether the Deviation is major or not and what the impact of the Deviation on the study 
participant or the entire study may be.  The study staff will submit the Protocol Deviation reports to the appropriate 
review bodies (IRB, DSMB, FDA etc.) and the principle investigator will review and approve the action plan that will be 
implemented as a result of the Protocol Deviation.   
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 

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initiation, the protocol and the informed consent documents will be reviewed and approved by the IRB.  Any 
amendments to the protocol or to the consent materials will also be approved by the IRB, 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 FDA 1572 will 
review the consent and answer questions.  The prospective participant 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. 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 
Publications will be reviewed with the Stanford and NIAID teams. 
18. References 
1. Cabrera CM & Urra JM. Food allergy and the oral immunotherapy approach. Arch Immunol Ther Exp (Warsz). 2015. 
63(1):31-39.   
2. Berin MC & Shreffler WG. Mechanisms Underlying Induction of Tolerance to Foods. Immunol Allergy Clin North Am. 
2016. 36(1):87-102.   
3. Begin P, Winterroth LC, Dominguez T, Wilson SP, Bacal L, Mehrotra A, Kausch B, Trela A, Hoyte E, O'Riordan G, Seki S, 
Blakemore A, Woch M, Hamilton RG & Nadeau KC. Safety and feasibility of oral immunotherapy to multiple allergens 
for food allergy. Allergy Asthma Clin Immunol. 2014. 10(1):1. PMCID: PMC3913318.   
4. Anagnostou K, Islam S, King Y, Foley L, Pasea L, Bond S, Palmer C, Deighton J, Ewan P & Clark A. Assessing the 
efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised 
controlled trial. Lancet. 2014. 383(9925):1297-1304. PMCID: PMC4255069.   
5. Schoos AM, Chawes BL, Rasmussen MA, Bloch J, Bonnelykke K & Bisgaard H. Atopic endotype in childhood. J Allergy 
Clin Immunol. 2016. 137(3):844-851 e844.   
6. Kucuksezer UC, Ozdemir C, Akdis M & Akdis CA. Mechanisms of immune tolerance to allergens in children. Korean J 
Pediatr. 2013. 56(12):505-513. PMCID: PMC3885784.   
7. Otani IM, Begin P, Kearney C, Dominguez TL, Mehrotra A, Bacal LR, Wilson S & Nadeau K. Multiple- allergen oral 
immunotherapy improves quality of life in caregivers of food-allergic pediatric subjects. Allergy Asthma Clin 
Immunol. 2014. 10(1):25. PMCID: PMC4032627.   
8. Arasi S, Otani IM, Klingbeil E, Begin P, Kearney C, Dominguez TL, Block WM, O'Riordan G & Nadeau KC. Two year 
effects of food allergen immunotherapy on quality of life in caregivers of children with food allergies. Allergy Asthma 
Clin Immunol. 2014. 10(1):57. PMCID: PMC4363059.   
9. Gupta RS, Kim JS, Barnathan JA, Amsden LB, Tummala LS & Holl JL. Food allergy knowledge, attitudes and beliefs: 
focus groups of parents, physicians and the general public. BMC Pediatr. 2008. 8:36. PMCID: PMC2564918.   
10. Ryan JF, Hovde R, Glanville J, Lyu SC, Ji X, Gupta S, Tibshirani RJ, Jay DC, Boyd SD3, Chinthrajah RS, Davis MM, Galli SJ, 
Maecker HT, Nadeau KC. Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell 

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subsets. Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1286-95. 
11. Syed A, Garcia MA, Lyu SC, Bucayu R, Kohli A, Ishida S, Berglund JP, Tsai M, Maecker H, O'Riordan G, Galli SJ, Nadeau 
KC. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation 
of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol. 2014 Feb;133(2):500-10. 
12. Begin P and Nadeau KC. Changes in peanut-specific T-cell clonotype with oral immunotherapy. J Allergy and Clin 
Immunol. 2015 Apr 27. (15) 408-410.  
13. Pellerin L, Jenks JA, Chinthrajah S, Dominguez T, Block W, Zhou X, Noshirvan A, Gregori S, Roncarolo MG, Bacchetta 
R, Nadeau KC. Peanut-specific Tr1 cells induced in vitro from allergic individuals are functionally impaired. J Allergy 
Clin Immunol. 2018 Jan;141(1):202-213.e8. 
14. Andorf S, Purington N, Kumar D, Long A, O'Laughlin K, Sicherer S, Sampson H, Cianferoni A, Whitehorn TB, Petroni D, 
Makhija M, Robison RG, Lierl M, Logsdon S, Desai M, Galli SJ, Rael E, Assa’ad A, Chinthrajah S, Pongracic J, Spergel 
JM, Tam J, Tilles S, Wang J,  Nadeau K. A Phase 2 randomized controlled multisite study using omalizumab-facilitated 
rapid desensitization to test continued vs discontinued dosing in multifood allergic individuals. Lancet EClinical 
Medicine 7 2019 (7):27-38 
 
 
 

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Appendix 1. Schedule of Events 
 
 
Timepoint/Visit 
Screen 
Week 0 / 
Day 1 
Every 2 wks 
(Weeks 0-28 
or until 
maintenance 
reached) 
Week 52 
Week 
58 /End 
of 
Study 
Week 
64 
(Option
al) 
 
Medical History 
X 
 
Physical Assessment 
X 
X 
X 
X 
X 
X 
 
Con Meds 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
Specific IgE/IgG4* 
X 
X 
X 
X 
 
Skin testing 
X 
X 
X 
X 
 
Blood for T cell studies* 
X 
X 
X 
X 
X 
 
Urine pregnancy test 
X 
 
Lung Function 
X 
X 
X 
X 
X 
X 
 
Diaries 
X 
X 
X 
X 
X 
 
Inject Epi training 
X 
X 
X 
 
 
Fecal samples 
X 
X 
X 
 
 
DBPCFC 
X 
X TEST 
DESENSIT
IZATION 
X TEST SU 
X TEST SU 
OIT (cashew or 
shrimp) 
X 
X 
 
 
QOL questionnaires* 
X 
X 
X 
X 
 
 
 
 

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Appendix 2: Participant Disposition
If pregnancy or if hypotensive event related to study drug occurs, participants will be terminated from the 
study  
Appendix 3: Dose Limiting Symptoms (CoFAR guidelines)
Challenges will be considered positive with the occurrence of any dose-limiting symptoms, which in the view of the PI 
indicate a true allergic reaction which should preclude the administration of any further doses. 
During a dose escalation in clinic, the clinician will use the following criteria to determine if the dose was well tolerated 
and if the participant may go home on that dose.
As defined below, mild symptoms are not usually considered dose-limiting, although a combination of mild symptoms 
might lead to the cessation of a challenge or reduction in the dose that the participant is allowed to go home on at the 
discretion of the PI 
All moderate and severe symptoms as defined below are considered dose-limiting.
Mild:
•
Skin – limited (few) or localized hives, swelling (e.g., mild lip edema), skin flushing (e.g., few areas of faint 
erythema) or mild pruritus (e.g., occasional scratching)
•
Respiratory – rhinorrhea (e.g., occasional sniffling or sneezing), nasal congestion, occasional cough, throat 
discomfort
•
GI – mild abdominal discomfort (including mild nausea with or without decreased activity), isolated emesis 
thought to be secondary to gag
Moderate:
•
Skin – systemic hives (e.g., numerous or widespread hives), swelling (e.g., significant lip or face edema), pruritus 
causing protracted scratching, more than a few areas of erythema or pronounced erythema
•
Respiratory – throat tightness without hoarseness, persistent cough, wheezing without dyspnea

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• 
GI – persistent moderate abdominal pain/cramping/nausea with decreased activity, vomiting 
Severe: 
• 
Skin – severe generalized urticaria/angioedema/erythema 
• 
Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea, stridor 
• 
GI – severe abdominal pain/cramping/repetitive vomiting 
• 
Neurological – change in mental status 
• 
Circulatory – clinically significant hypotension 
Appendix 4 Sample Serious Adverse Event Form 
Serious Adverse Event Form 
Date of Report:  ____________                                 
                                MM/DD/YYYY             
□ Initial Report    
□ Follow-up Report  (if follow-up complete participant identification and then only enter new/revised 
information)   Initial Report Date:  ____________ 
                      
 
 
MM/DD/YYYY                                                                                          
 
 
 
 
Reason for SAE designation (check all that apply): 
 
□ Death  _________________ 
 
 
MM/DD/YYYY 
□  Congenital anomaly or birth defect  
□ Hospitalization or prolonged hospitalization  
     Date of admission/prolongation :   
_________ 
 
□ Persistent or significant disability/incapacity or 
substantial disruption of the ability to conduct normal 
life functions 
□ Important medical event 
 
□ Life Threatening event  
 
□ Form used for other than SAE 
_____________________ (e.g. unexpected, related > 
Grade 2 AE or pregnancy  
  
 
Event Description 
Date of SAE:  _________________ 
                                MM/DD/YYYY 
Date site became aware of the SAE:  _________________ 
                                 
 
 
 
           
MM/DD/YYYY  
SAE Event Term (Diagnosis) and/or Symptoms  
 
 
Describe clinical course of events (include subject’s status in the study, how you became aware of the 
event, and relevant chronology): 
 
 
 
 
 
 
 
 
 

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Other relevant information: including:  
Pre-existing medical conditions (or attach Medical History CRF) 
 
(attach additional pages if necessary) 
Concomitant medications: (or attach Concomitant Medication Log) 
 
attach additional pages if necessary) 
Tests, and laboratory data relevant to the event: 
 
(attach additional pages sheet if necessary) 
 
 
Relation to the Study:   
Study 
Medication:_____________
_ 
□ Unrelated 
□ Possible 
 
□ Definite 
 
 
 
Study  
Medication:________________ 
□ Unrelated 
□ Possible 
 
□ Definite 
 
□  
 
  
If Unrelated to Study Medications 
Complete the following: 
Possible Alternative Etiology: 
□ Concomitant medication:  
_____________________ 
□ Concurrent  illness:  
________________________ 
□ Study Procedure/Rescue medication: 
_____________________ 
□ Other possible cause: 
_________________________ 
 
Date and time of last dose  
_____________ _________ 
MM/DD/YYYY     Time (or 
est) 
Date and time of last dose  
_____________ _________ 
MM/DD/YYYY       Time (or est) 
Expectedness  (An adverse event is considered “unexpected” when its nature, severity or it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information described in 
the general investigational plan or elsewhere in the IND (if applicable). 
□ Yes      
□ No  
Please provide additional discussion:   
 
 
 
 
 
 
Action taken:  Describe action taken in regard to Investigational Product (s) and the management of the 
event) 

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attach additional pages, if needed) 
 
Outcome of Event 
□ Resolved, no residual effects; date 
□ Resolved with sequelae; date:   
 
List Sequelae : ____________________________________________________________________ 
□ On-going  
□ Death  
Was a death certificate obtained?   □ No    □ Yes     
Was autopsy obtained: □ No      □ Yes, findings relevant to the relationship of the  
event________________________________________  
 
 
 
 
 
 
 
________________________________________________  
_____________________ 
Name and Signature of Principal Investigator 
 
 
Date 
 
Appendix 5: Sample Deviation Report Form 
 
PROTOCOL DEVIATION REPORTING FORM 
Instructions: Any noncompliance with the study protocol, Good Clinical Practice (GCP), or protocol specific Manual of 
Procedures (MOP) is considered a protocol deviation.   Each protocol deviation of any nature or severity should be 
documented.  Generally, one form should be used for each deviation.  However, if one deviation impacted more than 
one subject and the effect was the same for each subject, then list all subjects on one form.  Once completed and 
signed, the form is sent to the NIAID Project Manager  
 
 
 
 
 
                    
 
 
 
 
                                                                
 
Subject ID:  
 
Report Date        
 
Deviation date:          
 
      
 
 Date Site Staff became aware of Deviation:        
 
1.Description of Deviation (attach continuation form, if needed) : 
      

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2. Circumstances explaining /contributing to the deviation (attach continuation form, if needed):  
           
       
3.   Effect of Deviation on SAFETY or RISK from study participation: 
 No effect 
 
 
 
 Safety concern or increased risk     
      
Explain why the deviation has (or has not) an effect on subject’s safety or risk from study participation. In case 
that deviation has an effect please provide extent of potential safety impact.  Note: if the deviation resulted 
in an AE/SAE; major deviation (attach continuation form, if needed) : 
 
      
4. 
Effect of Deviation on the study endpoints or quality of study data:   
 
 No effect 
 
  
 Potential effect on data quality  
            
Explain why deviation has/has not had an effect on the quality of study data. In case that deviation has an 
effect please provide extent of potential effect on data quality major deviation (attach continuation form, if 
needed  : 
      
 
 
5. Corrective action(s) to resolve this Deviation (attach continuation form, if needed): 
      
 
6. 
Corrective action(s) to prevent similar occurrences (attach continuation form, if needed)  : 
      
7. 
Participant(s) will continue as a study subject(s):  (attach continuation form, if needed)  
       YES  
    NO  
     Justification:   
      
 
8. 
Notifications 
 
 
 
 
 
 
 
 
 
Date Notified 
NIAID Project Manager 
      

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9. Was continuation form used? 
YES  
   NO  
 
 
_______________________    _______           ___________________________   _______ 
Principal Investigator 
 
          Date  
 
Independent Medical Monitor      Date 
 
 
 
 
 
 
 
 
 
   (if applicable) 
 
For NIAID Use 
 
Major Deviation (as determined by the NIAID Project Manager)      YES 
 
NO 
____________________       
_______ 
Project Manager 
 
 
 
Date 
Subject ID:      
                         Report Date       
 
 
PROTOCOL DEVIATION REPORTING FORM CONTINUATION PAGE (do not submit if not used) 
 
      
 
 
Appendix 6: Epinephrine device Training Form 
 
Epinephrine device Training Form 
By signing the Epinephrine device training form, I acknowledge being appropriately trained and demonstrate 
understanding in the use and proper storage of EpiPens and have read the accompanying directions for use 
(instructions). 
 
 
____________________________________________        
___________________ 
Signature of Adult Participant 
 
 
 
 
 
     Date 
 
 
____________________________________________ ___________________ 
Signature of LAR (Parent, Guardian or Conservator) 
 
 
     Date 
 
 
____________________________________________ 
Authority to act for participant 
 
 
____________________________________________ ___________________ 
Signature of Trainer 
 
 
 
 
 
 
 
     Date 
 
Independent Medical Monitor (if 
applicable) 
      
IRB (if applicable) 
 
      

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____________________________________________ 
Printed Name of Trainer 
 
 
Current Wt: ________kg     q  EpiPen                  q  EpiPen Junior 
 
 
 
ANAPHYLAXIS INFORMATION (All boxes must be checked) 
 Reviewed epinephrine pictogram with subject and/or family  
 Subject and/or family given an Food Allergy Action Plan with a verbal review to ensure understanding 
 Subject and/or family given information on how to purchase medical identification jewelry tag (e.g. 
MedicAlert bracelet) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 7: Evaluation of Asthma 
The evaluation of asthma severity will be assessed using the NAEPP EPR-3 Medication Criteria as described below.  
 
 
 
 
 

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