Single Center, Placebo Controlled Clinical Study in Desensitization vs Tolerance Induction in Peanut Allergy Subjects
Phase: PHASE2
Conditions: Peanut Allergy
Sponsor: Stanford University

Single Center, Placebo Controlled Clinical Study in Desensitization vs 
Tolerance Induction in Peanut Allergy Subjects 
Study Protocol 
NCT02103270 
January 24, 2018 
 

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PROTOCOL NUMBER 
AADCRC-STAN-001 
LONG TITLE: Single Center, Placebo Controlled Clinical Study in Desensitization vs. Tolerance Induction in 
Peanut Allergy Subjects 
SHORT TITLE: Tolerance vs. Desensitization in Peanut-Allergic Individuals 
VERSION NUMBER / VERSION DATE: 7 / January 24, 2018 
IND# 
 
Amendment 14 
Study Sponsor(s): 
 
The National Institute of Allergy and Infectious Diseases (NIAID) 
 
NIAID Funding Mechanism: AADCRC (PI, Galli) IND Sponsor: Kari C. Nadeau, MD, PhD 
Study Drug Manufacturer/Provider: Stanford CFRU (Clinical Food Research Unit, 4th Floor and cGMP 
facility, 1st Floor, Stanford Packard El Camino Hospital, 2500 Grant Rd, Mountain View, CA. 
PROTOCOL STATISTICIAN 
, PhD 
Stanford University 
Department of Medicine 
 
Palo Alto, CA 94304 
Phone: 
 
Fax: 
 
E-mail: 
 
  PROTOCOL CHAIR-                                               CO-CHAIR                   
 Kari C. Nadeau, MD, PhD                           R. Sharon Chinthrajah, MD     
 Stanford University                                      (same) 
 
                                  (same) 
 Stanford, CA 94305                                      (same) 
 Phone: 650-723-5227                                  (same) 
 Fax: 650-498-5560                                       (same) 
 E-mail: knadeau@stanford.edu                schinths@stanford.edu 
NIAID MEDICAL MONITOR- 
, MD 
Division of Allergy, Immunology, 
and Transplantation – NIAID/NIH 
 
Rockville, MD 20852
, USA 
Phone: 
  
E-mail: 
  
NIAID PROJECT MANAGER- 
, RN, BSN 
Division of Allergy, Immunology, and 
Transplantation – NIAID/NIH 
 
Rockville, MD 20852, USA 
Phone: 
  
E-mail: 
  
REGULATORY OFFICER – 
 
Division of Allergy, Immunology, and 
Transplantation – NIAID/NIH 
 
Rockville, MD 20852, USA 
Phone: 
 
Fax: 
 
E-mail: 
 
 
 
 
 

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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INVESTIGATOR SIGNATURE PAGE 
Protocol:   AADCRC-STAN-001 
Version/Date: 7/January 24, 2018 
  
Site Principal Investigator: R. Sharon Chinthrajah, MD  
Title:   Single Center, Placebo Controlled Clinical Study in Desensitization vs. Tolerance 
Induction in Peanut Allergy Subjects 
Study Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID) 
INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated location 
below.  A copy should be kept for your records and the original signature page sent. After signature, 
please return the original of this form by surface mail to:  
, RN  
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will work 
according to the principles of Good Clinical Practice (GCP) as described in the United States Code of 
Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the International 
Conference on Harmonization (ICH) document Guidance for Industry: E6 Good clinical Practice: 
Consolidated Guidance dated April 1996.  Further, I will conduct the study in keeping with local legal 
and regulatory requirements. 
As the site Principal Investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without the written permission of the 
IRB and NIAID. 
____________________________________     
Site Principal Investigator  (Print) 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                          Date 

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Protocol Synopsis 
Title 
Single Center, Placebo Controlled Clinical Study in 
Desensitization vs. Tolerance Induction in Peanut Allergy 
Subjects 
Short Title 
Tolerance vs. Desensitization in Peanut-Allergic Individuals 
Clinical Phase 
Phase II 
Number of Sites 
1 
IND Sponsor/Number   
Kari C. Nadeau, MD, PhD/
 
Investigational 
Product(s)/Intervention(s) 
Investigational Product: Peanut Flour 
Interventions:  
• 
Medical and allergy history (including dietary history) 
• 
Physical assessment 
• 
Spirometry  
• 
Serum or urine pregnancy tests 
• 
Plasma analysis for IgE and IgG4 to peanut (UniCAPTM) 
• 
Oral food challenge to peanut 
• 
Skin prick test  
• 
Study product administration 
• 
Initial Dose Escalation Day Oral Immunotherapy (OIT) 
• 
Build up and maintenance OIT 
Study Objectives 
Primary Objective: 
Determine whether peanut oral immunotherapy induces clinical 
tolerance as assessed after the initial 3 month avoidance period  
 
Secondary Objectives: 
• 
Identify the basic immune mechanisms which can explain the 
differences in the effects of OIT in desensitized vs. tolerant 
individuals. 
• 
Determine whether immune monitoring measurements 
reflecting underlying mechanisms during OIT can be used to 
predict responses to OIT in individual subjects and, ultimately, to 
improve the safety and efficacy outcomes in peanut OIT 
protocols. 
Study Design 
A Phase 2, single-center, randomized, double blind, placebo controlled 
study of the induction of peanut tolerance by oral immunotherapy (OIT). 
Our intent to treat population will be 120 subjects, ages 7-55 years, with 
an allergy to peanut, as determined by DBPCFC, history, clinical 

4 
 
symptoms, and positive skin prick test (SPT). The 120 enrolled subjects 
will be randomized 2.4:1.4:1. Thus, there will be three arms: (1) Arm A on 
peanut OIT until week 104 and once meeting criteria [i.e.  1) assigned to 
OIT treatment for minimum 104 weeks, 2) reaching maintenance 13 
weeks prior to DBPCFC at week 104, 3) no severe reactions (Grade 3, 
APPENDIX 4) to home dosing from Week 92-Week 104, and/or 4) no 
objective reactions, (Appendix 4) at the Week 104 DBPCFC]  has been 
assigned to avoid peanut (i.e. 600 mg oat flour). (2) Arm B on peanut OIT 
until week 104 and once meeting criteria, has been assigned to be 
maintained on 300 mg peanut protein (i.e. 600 mg peanut flour). (3) Arm 
C that is maintained on placebo (oat flour) and once meeting criteria, will 
receive 600 mg oat flour beginning on week 104. This will be true even if 
a subject in the placebo group meets criteria at week 104. This way all 
participants will receive approximately the same volume of flour so that 
the subject blinding will be easier to maintain. The decision to maintain 
subjects on only 300 mg peanut protein after week 104 is for ease of 
eating peanut and to test if a lower amount of protein can still maintain 
desensitization.   
After week 104, subjects will then be rechallenged every 3 months for a 
year. Individuals will be defined as “clinically tolerant” if there is no 
clinical reactivity upon rechallenge. Clinical reactivity is defined as any 
objective reaction based on the Bock’s Criteria (Appendix 4).  
We plan to identify the basic immune mechanisms which can explain the 
differences in the effects of OIT in individuals who do or do not become 
tolerant and to determine whether immune monitoring can predict the 
safety and efficacy outcomes in peanut OIT protocols. 
 
Subjects will also be asked via a separate sub-study and consent which 
will look at biopsies from the gastrointestinal tract to show different 
markers at week 52, 104 and week 117 (or equivalent, with "or 
equivalent" meaning in this context that the visit may not be scheduled 
exactly in week 117, given such factors as the subject's schedule, etc…) 
compared to baseline. In addition, we will determine whether there are 
trends for differences in the markers detected in GI tissues in placebo vs 
avoidance vs treatment arms. 
 
Primary Endpoint(s) 
Proportion of peanut allergic subjects who pass a DBPCFC after the 
3 month avoidance period (Week 117 or equivalent) following the 
end of active treatment phase 
 
Secondary Endpoint(s)  
1. Proportion of PA subjects who pass a DBPCFC after a 6 month 
avoidance period. 
2. Proportion of PA subjects who pass a DBPCFC after a 9 month 
avoidance period. 
3. Proportion of PA subjects who pass a DBPCFC after a 12 month 
avoidance period. 

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4.Proportion of PA subjects who can successfully complete the 
build-up phase of peanut OIT to the highest dose (4,000 mg of 
peanut protein) with only mild (objective, APPENDIX 4) symptoms 
related to dosing. 
5. Proportion of PA subjects who can successfully undergo the 
build-up and maintenance phases of peanut OIT with only mild 
symptoms. 
6. Comparison of the proportion of subjects in placebo, avoidance, 
and 300 mg peanut protein groups who are able to undergo OFCs 
with no clinical reactivity after initiating OIT. 
 
Sub Study GI Endpoint 
Proportion of PA subjects who show increased immune cells consistent 
with immune tolerance (i.e. regulatory T cells) vs. inflammatory allergy 
(i.e. eosinophils, mast cells) over time points obtained with GI biopsy 
tissues. 
 
Accrual Objective 
120 
Study Duration 
This is a 5 year study. Participants will be in an active phase of the 
protocol for 3 years (see Appendix 1 for individual subject 
timeline); long term follow-up will be conducted but not beyond 
the 5 years of the grant. 
Treatment Description  
Subjects will undergo an Initial Dose Escalation Day to 
consumption of maximum single dose of 6 mg peanut/placebo 
protein.  They will consume this dose at home for two weeks and 
document reactions.  Upon returning to the CFRU (Clinical Food 
Research Unit) two weeks later, a dose escalation will be 
attempted.  This cycle will continue until the subject reaches a 
maximum dose of 4,000 mg peanut/placebo protein daily.   There 
will be three arms: (1) Arm A on peanut OIT until week 104 and once 
meeting criteria [i.e.  1) assigned to OIT treatment for minimum 104 
weeks, 2) reaching maintenance 13 weeks prior to DBPCFC at week 104 3) 
no severe reactions (Grade 3, APPENDIX 4) to home dosing from Week 92-
Week 104, and/or 4) no objective reactions, (Appendix 4) at the Week 104 
DBPCFC]   has been assigned to avoid peanut (i.e. 600 mg oat flour). (2) 
Arm B on peanut OIT until week 104 and once meeting criteria, has been 
assigned to be maintained on 300 mg peanut protein (i.e. 600 mg peanut 
flour). (3) Arm C that is maintained on placebo (oat flour) and once 
meeting criteria, will receive 600 mg oat flour beginning on week 104. 
This will be true even if a subject in the placebo group meets criteria at 
week 104.This way all participants will receive approximately the same 
volume of flour so that the subject blinding will be easier to maintain. The 
decision to maintain subjects on only 300 mg peanut protein after week 
104 is for ease of eating peanut and to test if a lower amount of protein 
can still maintain desensitization.   
 
Inclusion Criteria 
• 
Subject and/or parent guardian must be able to 
understand and provide informed consent and/or assent 
as applicable. 

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• 
Peanut-allergic subjects between the ages of 7-55 years 
old.  
• 
Weight equal or greater than 17 kg. 
• 
Sensitivity to peanut allergen as documented by a positive 
skin prick test result (5 mm or greater diameter wheal 
relative to negative control) within 10 months preceding 
enrollment.  
•    Allergy to peanut based on a double-blind placebo-
controlled oral food challenge (DBPCFC) (see Appendix 4 
for scoring details) failed at a cumulative dose ≤500 mg 
with peanut protein within 10 months preceding 
enrollment.   
• 
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.  
• 
Subjects must plan to remain in the study area during the 
trial. 
• 
Subjects must be trained on the proper use of the EpiPen 
(see Appendix 5) to be allowed to enroll in the study. 
• 
Subjects with other food allergies must agree to eliminate 
these other food items from their diet so as not to 
confound the safety and efficacy data from the study. 
• 
Use of birth control by female subjects 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 
• 
History of other chronic disease (other than asthma, atopic 
dermatitis, or rhinitis) requiring therapy (e.g., heart 
disease, diabetes) that, 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 gastrointestinal disease 
• 
Current participation in any other interventional study 
• 
Subject is on ‘build-up phase” of immunotherapy to 
another allergen (i.e., has not reached maintenance 
dosing) 
• 
Severe asthma (2007 NHLBI Criteria Steps 5 or 6) at time of 
enrollment 
• 
Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma 
at time of enrollment with any of the following criteria 
met: 
- 
FEV1 < 80% of predicted, or FEV1/FVC < 75%, with 
or without controller medications (only for age 6 
or greater and able to do spirometry) or 
- 
ICS dosing of >  220 mcg daily fluticasone (or 
equivalent inhaled corticosteroids based on NHLBI 
dosing chart) or 

7 
 
- 
1 hospitalization in the past year for asthma or 
- 
ER visit for asthma within the past six months  
• 
Use of steroid medications (IV, IM or oral) in the following 
manners  for asthma 
- 
history of daily oral steroid dosing for >1 month 
during the past year or 
- 
steroid burst (5 days or more of 1 mg/kg 
prednisone)  course in the past 3 months or 
- 
>2 steroid burst courses in the past year  
• 
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 
• 
Inability to discontinue antihistamines for the initial day of 
escalation, skin testing or OFCs 
• 
Use of omalizumab within the past six months, or 
immunomodulator therapy (not including corticosteroids) 
• 
Use of β-blockers (oral)  
• 
Pregnancy or lactation 
• 
History of sensitivity to oat 
• 
History of severe anaphylaxis to peanut with symptoms 
including hypotension requiring fluid resuscitation and/or 
the need for mechanical ventilation 
• 
Use of investigational drugs within 24 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 course of 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 Escalation days will be 
suspended, dose escalation during Build-up will be stopped, and all 
enrolled participants will remain on their current dose pending 
expedited review of all pertinent data by the Data Safety 
Monitoring Board: 
 
• 
Any death related to peanut OIT dosing 
• 
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 peanut 
dosing or to oral food challenge. 

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• 
More than 2 cases of hypotension related to peanut 
dosing or to oral food challenge. 
• 
More than 3 participants require more than 2 injections of 
epinephrine for anaphylaxis during a single dosing event of 
the peanut product due to study dosing 
• 
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 clinical symptoms 
and confirmatory biopsy findings 
 

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Table of Contents 
1. 
Background and Rationale ............................................................................................................................................ 14 
1.1. 
Background and Scientific Rationale .................................................................................................................... 14 
1.2. 
Rationale for Selection of Investigational Product or Intervention ...................................................................... 15 
1.3. 
Preclinical Experience ........................................................................................................................................... 15 
1.4. 
Clinical Studies ...................................................................................................................................................... 15 
2. 
Study Hypotheses/Objectives ....................................................................................................................................... 15 
2.1. 
Hypotheses ........................................................................................................................................................... 15 
2.2. 
Primary Objective(s) of the overall research program ......................................................................................... 15 
2.3.  Secondary Objective(s) of the overall research program ......................................................................................... 15 
3.1. 
Description of Study Design .................................................................................................................................. 17 
3.2. 
Primary Endpoint .................................................................................................................................................. 19 
3.4. 
Stratification, Randomization, and Blinding/Masking .......................................................................................... 20 
3.4.1. 
Procedure for Unblinding/Unmasking .............................................................................................................. 20 
3.5.2 
Securing Blinding and Randomization Information ...................................................................................... 20 
4. 
Selection of Participants and Clinical Sites/Laboratories ............................................................................................. 20 
4.1. 
Rationale for Study Population ............................................................................................................................. 20 
4.2. 
Inclusion Criteria ................................................................................................................................................... 21 
4.3. 
Exclusion Criteria................................................................................................................................................... 21 
5. 
Known and Potential Risks and Benefits to Participants .............................................................................................. 22 
5.1. 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert ................ 22 
5.2. 
Risks of Investigational Product or Intervention cited in Medical Literature and/or those based on the 
Investigators’ experience .................................................................................................................................................. 22 
5.3. 
Risks of Other Protocol Specified Medications ..................................................................................................... 23 
5.4. 
Risks of Study Procedures ..................................................................................................................................... 23 
5.5. 
Potential Benefits .................................................................................................................................................. 23 
6. 
Investigational Agent .................................................................................................................................................... 23 
6.1. 
Investigational Agent ............................................................................................................................................ 24 
6.1.1. 
Study Drug (Peanut Flour) ............................................................................................................................. 24 
6.1.1.1. 
Formulation, Packaging, and Labeling ...................................................................................................... 24 
6.1.1.2. 
Dosage, Preparation, and Administration ................................................................................................ 24 
6.1.2. 
Placebo (Oat Flour) ........................................................................................................................................... 26 
6.1.2.1. 
Formulation, Packaging, and Labeling ...................................................................................................... 26 
6.1.2.2. 
Dosage, Preparation, and Administration ................................................................................................ 26 
6.2. 
Drug Accountability............................................................................................................................................... 27 
6.3. 
Assessment of Participant Compliance with Investigational Agent ..................................................................... 27 

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6.4. 
Toxicity Prevention and Management .................................................................................................................. 27 
6.5. 
Premature Discontinuation of Investigational Agent ........................................................................................... 29 
7. 
Other Medications ........................................................................................................................................................ 30 
7.1. 
Concomitant Medications ..................................................................................................................................... 30 
7.2. 
Prophylactic Medications ...................................................................................................................................... 30 
7.3. 
Prohibited Medications ......................................................................................................................................... 30 
7.4. 
Rescue Medications .............................................................................................................................................. 31 
8. 
Study Procedures .......................................................................................................................................................... 31 
8.1. 
Enrollment ............................................................................................................................................................ 31 
8.2. 
Screening/Baseline Visit(s) .................................................................................................................................... 32 
8.3. 
Study Visits ............................................................................................................................................................ 33 
8.4. 
Unscheduled Visits ................................................................................................................................................ 36 
8.5. 
Visit Windows ....................................................................................................................................................... 37 
9. 
Mechanistic Assays ....................................................................................................................................................... 37 
10. 
Biospecimen Storage ................................................................................................................................................ 41 
11. 
Criteria for Participant and Study Completion and Premature Study Termination ................................................. 41 
11.1. 
Participant Completion ..................................................................................................................................... 42 
11.2. 
Participant Stopping Rules and Withdrawal Criteria ........................................................................................ 42 
11.3. 
Participant Replacement ................................................................................................................................... 42 
11.4. 
Follow-up after Early Study Withdrawal ........................................................................................................... 42 
12. 
Safety Monitoring and Reporting ............................................................................................................................. 43 
12.1.  Overview ................................................................................................................................................................. 43 
12.2.  Definitions ............................................................................................................................................................... 43 
12.2.1.  Adverse Event (AE) ........................................................................................................................................... 43 
12.2.2.  Unexpected Adverse Event .............................................................................................................................. 44 
12.2.3.  Serious Adverse Event (SAE) ............................................................................................................................ 44 
12.3.  Grading and Attribution of Adverse Events ............................................................................................................ 44 
12.3.1.  Grading Criteria ................................................................................................................................................ 44 
12.3.2.  Attribution Definitions ..................................................................................................................................... 45 
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 ...................................................................................... 46 
12.5.1.  Reporting of Serious Adverse Events to Sponsor............................................................................................. 46 
12.5.2.  Reporting to Health Authority ......................................................................................................................... 46 

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12.5.3.  Reporting of Adverse Events to IRBs/IECs ....................................................................................................... 47 
12.6.   
Pregnancy Reporting ......................................................................................................................................... 47 
12.7.  Reporting of Other Safety Information ................................................................................................................... 48 
12.8.  Review of Safety Information ................................................................................................................................. 48 
12.8.1. Medical Monitor Review ................................................................................................................................... 48 
12.8.2.  DSMB Review ................................................................................................................................................... 48 
13. 
Statistical Considerations and Analytical Plan .......................................................................................................... 49 
13.1 
Overview ............................................................................................................................................................... 49 
13.2. 
Endpoints .......................................................................................................................................................... 49 
13.4. 
Analysis Plan...................................................................................................................................................... 50 
13.4.1 
Analysis Populations ..................................................................................................................................... 50 
13.4.2 
Primary Analysis of Primary Endpoint(s)/Outcome(s) .................................................................................. 50 
13.4.3 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s) ...................................................................... 50 
13.4.4 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) ......................................................................... 50 
13.4.5 
Analyses of Exploratory Endpoint(s)/Outcome(s) ........................................................................................ 51 
13.4.6 
Descriptive Analyses ..................................................................................................................................... 51 
13.5. 
Interim Analyses................................................................................................................................................ 51 
13.6. 
Statistical Hypotheses ....................................................................................................................................... 51 
13.7. 
Sample Size Considerations .............................................................................................................................. 51 
14. 
Identification and Access to Source Data ................................................................................................................. 52 
14.1. 
Source Data ....................................................................................................................................................... 52 
14.2. 
Access to Source Data ....................................................................................................................................... 52 
15. 
Protocol Deviations ................................................................................................................................................... 52 
15.1. 
Protocol Deviation Definitions .......................................................................................................................... 52 
15.2. 
Reporting and Managing Protocol Deviations .................................................................................................. 53 
16. 
Ethical Considerations and Compliance with Good clinical Practice ........................................................................ 53 
16.1. 
Statement of Compliance ................................................................................................................................. 53 
16.2. 
Informed Consent Process ................................................................................................................................ 53 
16.3. 
Privacy and Confidentiality ............................................................................................................................... 53 
17. 
Publication Policy ...................................................................................................................................................... 53 
18. 
References ................................................................................................................................................................ 54 
Appendix 1: Schedule of Events ........................................................................................................................................ 57 
Appendix  2: Sample Serious Adverse Event Form ........................................................................................................... 59 
Appendix  3: Sample Deviation Report Form .................................................................................................................... 62 
Appendix 4: Scoring of Clinical Food Allergic Reactions ....................................................................................................... 64 
Appendix 5: EpiPen Training Form ........................................................................................................................................ 68 

12 
 
Appendix 6: Evaluation of Asthma ........................................................................................................................................ 69 
Appendix 7: Sample Certificate of Analysis for Peanut Flour ............................................................................................... 70 
Appendix 8: Open Label Follow-Up ...................................................................................................................................... 70 
List of Tables ......................................................................................................................................................................... 71 
List of Figures ........................................................................................................................................................................ 71 
List of Appendices ................................................................................................................................................................. 71 

13 
 
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 
CFRU 
Clinical Food Research Unit 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IDED 
Initial Dose Escalation 
IEC 
Institutional Ethics Committee 
IMM 
Independent Medical Monitor 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases 
PC 
Protocol Chair 
PI 
[Site] Principal Investigator 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
 
 
 
 
 
 

14 
 
1. Background and Rationale  
1.1. Background and Scientific Rationale  
Few studies have been conducted to optimize safety and to identify the immunological mechanism(s) underlying any 
long-lasting effects of oral immunotherapy (OIT). Specifically, it is not yet clear what factors will determine, in an 
individual subject, whether OIT has induced tolerance (in which he or she can safely ingest peanut ad lib without the 
need for daily consumption of peanut).1, 2 To address these challenges in the field of food allergy research, the Stanford 
Alliance for Food Allergy Research (SAFAR) proposes to link the findings of this current clinical study to mechanistic 
studies (proposed as distinct projects under the same  AADCRC study). This current clinical study (n=95 OIT and 
n=25 placebo conducted over 5 years in subjects 7-55 years of age with peanut allergies), together with the three 
mechanistic-based research projects (Section 9), presents a unique opportunity to create a comprehensive dataset 
combining the clinical outcomes of the OIT protocol with the results of innovative studies of tolerance in order to better 
understand mechanisms of OIT and to improve the safety and efficacy of oral immunotherapy of peanut allergy (PA). 
There have been reports of success in a small number of mostly pediatric (under 18 years) patients in which oral food 
allergen immunotherapy has achieved desensitization (i.e. clinical non-reactivity to ingestion of a known allergen that 
must be maintained by daily consumption of that allergen) for milk1,4,5, egg6,7, and peanut8-25. The protocols for such 
trials are varied, involving rush therapy phases, weekly increases in doses, or both. In our first Phase 1 peanut oral 
immunotherapy (OIT) study conducted at Stanford from July 2009 to present, we focused on the safety parameters of 
peanut OIT in children and adults. Since the incidence and prevalence of food allergies in adults and children are rising 
(http://www.foodallergy.org/files/FoodAllergyFactsandStatistics.pdf) it is important to be able to understand the 
therapeutic and mechanistic effects of food allergy oral immunotherapy in both populations. We recently published our 
safety findings on some subjects in the Phase 1 peanut OIT study3.  All subjects are tolerating peanut at increasing doses. 
Twenty (20) subjects were given placebo OIT in our study, which is important to evaluate the rate of spontaneous 
remission of peanut allergy and to compare safety profiles between the OIT and placebo groups. In addition, 16 of the 
current peanut OIT subjects have been tested for tolerance; 6 have become “immune tolerant” (referred to herein as 
“tolerant”) (i.e., they can eat peanut with no clinical reaction after a period of avoidance from peanut OIT—in the case 
of our subjects to date, 3 months); by contrast, 10 have not become tolerant to peanut (i.e., they developed a clinical 
reaction to peanut challenge after a period of avoidance from peanut OIT).  
Our proposal, representing a new clinical study of OIT in adult and pediatric subjects with PA, is designed to provide data 
that can help identify mechanisms in the development of immune tolerance and improve the safety of future OIT 
studies. The new protocol proposed here will enroll different patients from those already studied at Stanford and will 
differ from our Phase 1 study (Syed, American Academy of Asthma, Allergy and Immunology Conference, San Antonio, 
TX, 2013) and from that of others since:  1) the patients will include both adults and children; 2) subjects will have the 
opportunity to be tested for immune tolerance during longer intervals of peanut avoidance; 3) we will perform 
sophisticated tests to discriminate clinically between tolerance and lack of tolerance; and 4) we will perform basic 
science studies on immune indicators in an attempt to identify those tests that are useful for allowing the safe and 
efficacious dosing of individual PA subjects during OIT and/or for discriminating between those patients who do or do 
not develop tolerance as a result of OIT.  
In a separate substudy of 20 subjects, we will look at biopsy samples from the gastrointestinal tract of participants who 
have enrolled in the main study.  Allergic disorders of the gastrointestinal tract are characterized by infiltration of the 
mucosal lining with inflammatory cells, such as eosinophils. These disorders include eosinophilic gastroenteritis, 
esophagitis and colitis. Patients with these disorders often have a history of allergy, including a high IgE level, peripheral 
eosinophils and allergic disease (such as food allergies or allergic rhinitis).  This will help with our understanding of 
possible associations with eosinophilic disease and oral immunotherapy, with tolerance markers in the local organ vs 
peripheral blood and how it affects the local tissue in the GI tract over time. We will explore whether the 20 participants 
with GI biopsies show different markers at week 52 vs. week 104 vs. week 117 (or equivalent) vs. baseline. In addition, we 
will determine whether there are trends for differences in the markers detected in GI tissues in placebo vs avoidance vs 
treatment arms. The procedures to find these markers include immunohistochemistry to identify cells-inflammatory and 
regulatory (mast cells, basophils, eosinophils, T cells, B cells, dendritic cells, and epithelial cells and associated markers –

15 
 
for example  TSLP, IL-33, IL-18, IL-10 ,  CD103, IL-4, IL-13, histamine, STAT6, GATA3, T-bet, IFN-g, TGF-b), single cell 
sorting with RNA Seq, and cryopreservation for future analysis outside the scope of the proposal. 
At the biopsy level, we anticipate that subjects will have increased IL-4/IL-13/IL-5 in T cells, and increased mast cells and 
eosinophils at baseline, and that, over time, they will have decreases in IL-4/IL-13/IL-5 in T cells, mast cells, eosinophils 
and increases in Treg and interferon gamma secreting T effector cells at the local tissue level over time at week 52, week 
104 and week 117 (or equivalent).  Samples will be read by a trained Pathologist and results will be available within one 
week. If changes indicate EoE, participants will be referred to our gastroenterology clinics and will discontinue the study. 
 We also expect increases in tolerogenic DCs overtime (i.e. increases in CD103).  Overall, we think that this study will be 
the first of its kind to examine the local tissue of the GI tract during immunotherapy in food allergy and this is an 
exploratory study to be able to move forward with further hypothesis testing on future trials. 
 
 
1.2. Rationale for Selection of Investigational Product or Intervention 
The rationale for dosing builds on the work of the Consortium of Food Allergy Research (CoFAR), a Stanford Phase 1 
study, and other studies by Dr. Burks (University of North Carolina) and Dr. Jones (University of Arkansas). The dosing 
consists of a single-day initial escalation at very low doses, followed by a build-up phase of increasing doses, occurring 
every 2 weeks. This has been demonstrated to be well tolerated and efficacious in previous studies and will be used in 
this current trial.  
1.3. Preclinical Experience 
n/a 
1.4. Clinical Studies 
Recently, Dr. Wesley Burks presented work showing that 10 children with PA completed an OIT protocol and underwent 
an oral food challenge (OFC) 4 weeks after cessation of oral intake of peanut to evaluate for the possibility of clinical 
tolerance (Vickery, et al., American Academy of Allergy, Asthma, and Immunology National Conference. Orlando, 
Florida, March 6, 2012). Three (3) out of 10 subjects passed the OFC; the authors considered these subjects clinically 
tolerant. Over the course of treatment, peanut IgE levels lower than 85 kU/L at a time point of 3 months into OIT was 
predictive of subjects who became immune tolerant. These initial findings, along with our preliminary data, are 
provocative and require further studies to be conducted to evaluate the reproducibility of the results obtained in this 
small group of children, to extend the work to adults with PA, and also to document the duration of the clinical lack of 
reactivity to peanut achieved in such subjects. A recent review by Byrne, et al. succinctly asks a key question: “How do 
we know when peanut and tree nut allergy have resolved, and how do we keep it resolved?”26 
2. Study Hypotheses/Objectives 
2.1. Hypotheses 
Our hypothesis is that peanut immunotherapy will induce changes in subject’s cellular and humoral immune system and 
thus make them less allergic to peanut allergens.  
2.2. Primary Objective(s) of the overall research program 
Determine whether peanut oral immunotherapy induces clinical tolerance as assessed after the initial 3 month 
peanut avoidance period  
2.3.  Secondary Objective(s) of the overall research program 
• 
Identify the basic immune mechanisms which can explain the differences in the effects of OIT in desensitized vs. 
tolerant individuals.  

16 
 
• 
Determine whether immune monitoring measurements reflecting underlying mechanisms during OIT can be 
used to predict responses to OIT in individual subjects and, ultimately, to improve the safety and efficacy 
outcomes in peanut OIT protocols. 
 
 
 
 

17 
Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appen 
 
 
 
 
 
 
 
 
 
* The 120 enrolled subjects will be randomized 2.4:1.4:1 (please see section 13). Thus, there will be three arms: 
(1) Arm A on peanut OIT until week 104 and once meeting criteria [i.e.  1) on OIT treatment for minimum 104 weeks, 
2) taking daily maintenance dose of 4,000 mg protein for at least 13 weeks, 3) no severe reactions (Grade 3, APPENDIX 4) to 
home dosing from Week 92-Week 104, and/or 4) no objective reactions, (Appendix 4) at the Week 104 DBPCFC]   has been 
assigned to avoid peanut (i.e. 600 mg oat flour). (2) Arm B on peanut OIT until week 104 and once meeting 
criteria, has been assigned to be maintained on 300 mg peanut protein (i.e. 600 mg peanut flour). (3) Arm C that 
is maintained on placebo (oat flour) and once meeting criteria, this arm will receive 600 mg oat flour beginning 
on week 104. This will be true even if a subject in the placebo group meets criteria at week 104. This way all 
participants will receive approximately the same volume of flour so that the subject blinding will be easier to 
maintain. The decision to maintain subjects on only 300 mg peanut protein after week 104 is for ease of eating 
peanut and to test if a lower amount of protein can still maintain desensitization.   
3. Study Design 
3.1. Description of Study Design  
A Phase 2, single-center, randomized double blind, placebo controlled study of the induction of peanut tolerance by oral 
immunotherapy (OIT). Our intent to treat population will be 120 subjects, ages 7-55 years, with an allergy to peanut, as 
determined by DBPCFC, history, clinical symptoms, and positive skin prick test (SPT). Please see Figure 1. 
Part I: Screening Period and Enrollment 
J3HULR
Part II: Randomization for Arm A,B,C* 
Peanut OIT (arms A and B)* 
(N=95)
Placebo (arm C)* 
(N=25)
3ODFHER D
PV$DQG%
1 

Part III: Build up phase with every 2 Week Visits 
 Dosing to 4g peanut protein maximum daily 
KDVH Z
DQXWSU
Part IV: Maintenance Every 13wk Visits (approximately Wks52—104) Dosing at 4g peanut protein daily. First on-study 
DBPCFC at 104wks.  
 
Then at week 104, do subjects meet criteria: 1) on OIT treatment for minimum 104 weeks, 2) taking daily maintenance 
dose of 4,000 mg protein for at least 13 weeks, 3) no severe reactions (Grade 3, Appendix 4 to home dosing from Week 92-
Week 104, and/or 4) no reactions, (objective, Appendix 4) at the Week 104 DBPCFC?  
YES 
NO 
DWWKH:
<(6
QGRU 
12
Part V:  Tolerance and Desensitization testing phase every 13wk 
Visits (Wks117-156) 
 
At DBPCFC every 13wk visit, is there clinical reactivity on DBPCFC? 
Part III: Initial Dose Escalation Day 
UHDFWLY
NO, then continue part V  
YES
Desensitization Failure 
OXUH
&)&HYH
<(6
randomized 2 4:
If Arm B, Desensitization Failure 
If Arm A, Tolerance Failure 
Sub-study GI Endoscopy -Baseline 
Sub-study GI Endoscopy 
Week 104
Sub Study GI Endoscopy Week 117 
Sub-study GI Endoscopy 
Week 52

18 
 
First, subjects will be screened (Part I, Figure 1). The 120 enrolled subjects will be randomized 2.4:1.4:1 (please see 
section 13). Thus, there will be three arms: (1) Arm A on peanut OIT until week 104 and once meeting criteria [i.e.  1) on 
OIT treatment for minimum 104 weeks, 2) taking daily maintenance dose of 4,000 mg protein for at least 13 weeks, 3) no severe 
reactions (Grade 3, APPENDIX 4) to home dosing from Week 92-Week 104, and/or 4) no objective reactions, (Appendix 4) at the 
Week 104 DBPCFC] has been assigned to avoid peanut (i.e. 600 mg oat flour). (2) Arm B on peanut OIT until week 104 and 
once meeting criteria, has been assigned to be maintained on 300 mg peanut protein (i.e. 600 mg peanut flour). (3) Arm 
C that is maintained on placebo (oat flour) and once meeting criteria, will receive 600 mg oat flour beginning on week 
104. This will be true even if a subject in the placebo group meets criteria at week 104. This way all participants will 
receive approximately the same volume of flour so that the subject blinding will be easier to maintain. The decision to 
maintain subjects on only 300 mg peanut protein after week 104 is for ease of eating peanut and to test if a lower amount 
of protein can still maintain desensitization.  This upfront randomization is performed because our statistical analysis plan is 
focused on an intent to treat analysis.     
All arms will undergo an Initial Dose Escalation (IDE) Day and updosing regimen with a maintenance phase of OIT or 
placebo to a maximum of 4,000 mg protein daily, as peanut flour, in the OIT groups, and to a maximum of an equivalent 
amount of oat flour for the placebo group). (Part III, Figure 1).  After maintenance is achieved, all subjects will begin 
performing DBPCFCs (staged so as to ensure safety) at Week 104 and every 13 weeks thereafter (Part IV, Figure 1).  At 
Week 104, individuals that reach criteria (Part IV, Figure 1) will, based on the randomization that was done at the start of 
the study, either stop therapy with peanut and be switched to oat flour, or will be maintained on 300 mg peanut protein 
per day (Parts V, Figure 1). If subjects fail the week 104 DBPCFC they will not be given home doses. Those that fail the 
week 104 FC will remain in the study and return for a study completion visit at week 117 to meet the primary endpoint 
(will be analyzed in the intent to treat comparisons). All subjects will be evaluated every 13 weeks thereafter until the 
end of study.   
Individuals in Arm A will be defined as “clinically tolerant” if there is no clinical reactivity at the Week 104 and Week 117 
(or equivalent) DBPCFC. Clinical reactivity is defined as any objective reaction based on the Bock’s Criteria (Appendix 4).  
Individuals in Arm A who meet the definition of “clinically tolerant” will continue to avoid peanut protein (i.e. continue 
on 600 mg per day of oat flour) as long as each subsequent DBPCFC (performed every 13 weeks until end of study) 
shows no clinical reactivity. 
Individuals in Arm B will be defined as “desensitized” to a minimum of 300 mg per day of peanut protein if they show no 
clinical reactivity at DBPCFCs (week 117 (or equivalent) to end of study). 
Individuals in Arm C will be defined as “natural loss of responsiveness” if they show no clinical reactivity at DBPCFCs 
(week 117 (or equivalent) to end of study). 
We plan to identify the basic immune mechanisms which can 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 peanut OIT protocols.  After initial screening and enrollment, there are three phases of the study:  
• 
Dose escalation and Build up Phase (Part III, Figure 1)  
• 
Maintenance phase  (Part IV, Figure 1) 
• 
Tolerance and Desensitization Testing phase (Part V, Figure 1) 
Overall, 120 subjects who are eligible will undergo the Initial Dose Escalation Day.  Subsequent updosing visits will occur 
every 2 weeks as a part of the build-up phase. They will continue to updose until they reach 4,000 mg protein daily, 
which is the maximum maintenance amount of protein. We expect active OIT treatment subjects to reach 4,000 mg of 
peanut protein between 44-78 weeks. 
GI Sub Study. 

19 
 
Subjects will also have the opportunity to participate in this study via a separate consent after they have enrolled in the 
study and prior to starting IDED at week 0.  
Treatment and Desensitization Failures: 
A treatment failure will be defined as a) failure to reach 1.5 mg peanut protein (single dose) during the Initial Dose 
Escalation Day or b) failure to reach 1,000 mg peanut protein by week 104.  
Subjects who do not meet the criteria (Part IV, Figure 1) at Week 104 and who demonstrate clinical reactivity (objective, 
Appendix 4) will be considered desensitization failures.  
If Arm B subjects demonstrate clinical reactivity (objective, Appendix 4) in any DBPCFC from Week 117 (or equivalent) to 
end of study, they will be considered desensitization failures.  
If Arm A subjects demonstrate clinical reactivity (objective, Appendix 4) in any DBPCFC from Week 117 (or equivalent) to 
end of study, they will be considered tolerance failures.  
Research staff may be unblinded when the primary endpoint (at the completion of the week 117 visit) is reached for the 
study. Treatment failures, desensitization failures, and tolerance failures may be unblinded (both participant and 
research staff) at week 117 and/or may be followed until the end of the study at the specified study visits (Appendix 1, 
Schedule of Events, early completion visit).  They will be considered in statistical analyses of the intent-to-treat 
population. 
 
Integration with mechanistic science program: We will use blood samples and clinical outcome measurements from this 
study to identify specific features of the immune response that are associated with ”clinical tolerance” at week 104, 117 
(or equivalent), 130, 143, and 156. . We will also determine special immune features associated with subjects who are 
desensitized at week 104, 117 (or equivalent), 130, 143, and 156. It will be important to compare any of the immune 
features to those of the placebo arm, treatment failures, and desensitization failures.  Treatment groups A, B, and C are 
key cohorts to be able to identify possible quantitative and/or qualitative differences in immune phenotypic features 
among subjects in the tolerance, desensitization, and placebo groups, since such information is critical to our efforts to 
identify possible differences in the mechanisms that underlie immune tolerance vs. desensitization. 
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 within 60 
seconds 
• 
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 (within 50 feet) of all patient 
hospital rooms 
• 
A code team is available for pediatric and adult patients 
• 
The peanut OIT will only escalate to a maximum 6 mg single dose during the initial dose escalation Day  
• 
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 peanuts or peanut-containing foods other than study-supplied food 
allergen while on study. 
3.2. Primary Endpoint 
Proportion of peanut allergic subjects who pass a DBPCFC after the 3-month avoidance period (Week 117 or 
equivalent) following the end of active treatment phase 
3.3. Secondary Endpoints 

20 
 
• 
Proportion of PA subjects who pass a DBPCFC after a 6-month avoidance period. 
• 
Proportion of PA subjects who pass a DBPCFC after a 9-month avoidance period. 
• 
Proportion of PA subjects who pass a DBPCFC after a 12-month avoidance period. 
• 
Proportion of PA subjects who can successfully complete the build-up phase of peanut OIT to the highest dose 
(4,000 mg of peanut protein) with only mild Objective APPENDIX 4symptoms  
• 
Proportion of PA subjects who can successfully undergo the build-up and maintenance phases of peanut OIT 
with only mild symptoms. 
• 
Comparison of the proportion of subjects in placebo, avoidance, and 300 mg peanut protein/day groups who are 
able to undergo OFCs with no clinical reactivity after initiating OIT. 
 
Sub Study GI Endpoint 
• 
Proportion of PA subjects who show increased immune cells consistent with immune tolerance (i.e. regulatory T 
cells) vs inflammatory allergy (i.e. eosinophils, mast cells) over time points obtained with GI biopsy tissues. 
 
3.4. Stratification, Randomization, and Blinding/Masking 
Randomization will occur in a 2 by 2 block design performed by Dr. Turnbull using a computerized system. 
3.4.1. Procedure for Unblinding/Unmasking 
Unblinding must be approved by the study NIAID Medical Monitor unless an immediate life-threatening 
condition has developed and the NIAID Medical Monitor is not accessible.  In all cases of unblinding, the site 
investigator will notify the NIAID Medical Monitor within 24 hours.  The emergency unblinding will also be 
reported to the Data and Safety Monitoring Board (DSMB). 
A full account of the event will be recorded, including the date and time of the unblinding, the reason for the 
decision to unblind, and the name of the individual who made the decision and the names of the Medical 
Monitor and others who were notified.  
Unblinding the study due to an approved interim analysis, final analysis, or study termination will require written 
approval from NIAID. 
3.5.2 
Securing Blinding and Randomization Information 
Randomization lists are maintained in a secured area, the pharmacy, by the individuals responsible for maintaining 
the blind, the unblinded pharmacists. The PPD site monitor (Clinical Research Associate) inspects the lists at each 
site visit to ensure they remain in the secured pharmacy, only accessible by the unblinded pharmacists. In the case 
of unscheduled unblinding or the removal of the randomization lists from the secured pharmacy binder, the 
Clinical Research Associate will verify that the site Principal Investigator and the NIAID Medical Monitor have been 
notified and that a written account has been completed and forwarded to these individuals. 
4. Selection of Participants and Clinical Sites/Laboratories 
4.1. Rationale for Study Population 
The lower cutoff of 7 years of age was selected to include only subjects with sufficient blood volumes (to perform the 
mechanistic studies we need blood every 3 months or per schedule of events (+ or - 1 clinic visit).  We have included a 
weight cut off of 17 kg so that we are compliant with IRB and NIH guideline—i.e. (for children: 5 ml/kg at any single 
draw, no more than 9.5 ml/kg over an 8-week period; adults: the smaller of 10.5 ml/kg or 550 ml total at any single draw  
). The upper age limit of 55 years was selected to ensure that the patients do not have underlying cardiovascular 
conditions that could preclude the use of epinephrine in subjects exposed to the risk of anaphylaxis. 

21 
 
Cross-reactivity between peanut and grass pollen may affect the SPTs performed to peanut.  All subjects will be 
screened for appropriate environmental allergen sensitivity by SPT. 
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 and/or assent as 
applicable. 
2. Peanut-allergic subjects between the ages of 7-55 years old.  
3. Weight equal or greater than 17 kg. 
 
4. Sensitivity to peanut allergen as documented by a positive skin prick test result (5 mm or greater diameter wheal 
relative to negative control) within 6 months preceding enrollment.  
5. Allergy to peanut based on a double-blind placebo-controlled oral food challenge (DBPCFC) (see Appendix 4 for 
scoring details) failed at  a cumulative dose ≤500 mg peanut protein within 6 months preceding enrollment.   
6. All female subjects of child-bearing potential will be required to provide a blood sample for pregnancy testing that 
must be negative one week before being allowed to participate in the study.  
7. Subjects must agree to remain in the study area during the trial. 
8. Subjects must be trained on the proper use of the EpiPen and patient comprehension should be confirmed (see 
Appendix 5) to be allowed to enroll in the study. 
9. Subjects with other food allergies must agree to eliminate these other food items from their diet so as not to 
confound the safety and efficacy data from the study. 
10. Female subjects of child bearing potential must agree to use birth control for the duration of the study. 
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 
3. History of other chronic disease (other than asthma, atopic dermatitis, or rhinitis) requiring therapy (e.g., heart 
disease, diabetes) that, 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 gastrointestinal disease 
5. Current participation or participation within the last 6 months in any other interventional study. 
6. Subject is on ‘build-up phase” of immunotherapy to another allergen (i.e., has not reached maintenance dosing) 
7. Severe asthma (2007 NHLBI Criteria Steps 5 or 6) at time of enrollment 
8. Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma at time of enrollment with any of the following criteria 
met: 
a. FEV1 < 80% of predicted, or FEV1/FVC < 75%, with or without controller medications (only for age 6 or greater 
and able to do spirometry) or 
b. ICS dosing of > 220 mcg daily fluticasone (or equivalent inhaled corticosteroids based on NHLBI dosing chart) or 
c. 1 hospitalization in the past year for asthma or 
d. ER visit for asthma within the past six months  
9. Use of steroid medications (IV, IM or oral) in the following manners  for asthma 
a. history of daily oral steroid dosing for >1 month during the past year or 

22 
 
b. burst or steroid course in the past 3 months  or 
c. >2 burst steroid courses in the past year  
10. 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 
11. Inability to discontinue antihistamines for the Initial Dose Escalation Day, skin testing or OFCs 
12. Use of omalizumab within the past six months, or immunomodulator therapy (not including corticosteroids) 
13. Use of β-blockers (oral)  
14. Pregnancy or lactation 
15. History of sensitivity to oat 
16. 
History of severe anaphylaxis to peanut with symptoms including hypotension requiring fluid resuscitation and/or 
the need for mechanical ventilation 
17. Use of investigational drugs within 24 weeks of participation 
18. 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.  
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 
There is no IB or Package Insert for the peanut flour.  
5.2. Risks of Investigational Product or Intervention cited in Medical Literature and/or those based 
on the Investigators’ experience 
In patients with peanut allergy, there have been many oral immunotherapy studies performed using procedures and 
dosing similar to those proposed in this Phase 2 study. 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 peanut 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. 
Specifically, the buildup and daily maintenance doses of peanut 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 study37-38. The likelihood of a subject experiencing any allergic symptoms is 
expected to be lessened by initiating dosing at extremely small amounts of characterized peanut 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 will have an IV 
catheter placed before the OFCs if they have a history of anaphylaxis with hypotension requiring IV fluid resuscitation.  
Additionally, 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 at the visit.   Trained personnel, including a study physician, 

23 
 
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 
peanut 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 peanuts or peanut-containing foods.   
5.3. Risks of Other Protocol Specified Medications 
Anti H-1 blockers (e.g., cetirizine, loratadine, fexofenadine) will be used orally according to manufacturer’s instructions 
approximately one hour prior to each food allergen dose at home.  The risks of these medications include:  
 
• 
Central nervous system: Headache, fatigue, somnolence, drowsiness, insomnia, sleep disorders, dizziness, 
muscle pain 
• 
Gastrointestinal: Diarrhea, nausea, vomiting, dyspepsia, abdominal pain, dry mouth 
• 
Neuromuscular & skeletal: Myalgia, back pain, pain in extremities 
• 
Hypersensitivity reactions (anaphylaxis, angioedema, chest tightness, dyspnea, flushing, pruritus, rash, urticaria) 
5.4. Risks of Study Procedures  
A potential risk associated with the Initial Dose Escalation Day procedure, updosing procedure, and oral food challenges 
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.      
The potential discomforts with the Initial Dose Escalation Day procedure, updosing procedure, and oral food challenges 
are no more than when eating 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 CFRU to treat allergic reactions.  Subjects will be provided a prescription 
for an EpiPen® or EpiPen, Jr.® or equivalent to have with them at all times and to use in case of an allergic reaction. 
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. 
The risk involved with skin testing includes discomfort from the needle prick, along with pruritus and swelling at the skin 
test site in positive responses. Less common side effects include severe allergic reactions. 
There may be an increased risk of developing Eosinophilic esophagitis (EoE), which is an immune-mediated disease as a 
result of inflammation of the esophagus. Symptoms range by age, with children potentially presenting with feeding 
difficulties, abdominal pain, and/or vomiting and adults may experience chest pain, food getting “stuck”, and/or 
abdominal pain. If these symptoms are present, an endoscopy will be needed to confirm diagnosis, which may be 
performed by a gastroenterologist.   
The risks involved with the GI Sub-study endoscopy are rare and include bleeding, perforation of the esophagus, 
stomach or duodenum, sepsis and pneumonia.  The risks associated with the biopsy procedure include bleeding and 
perforation of the esophagus, stomach and duodenum.  The risks associated with the use of the FDA approved 
medications routinely used for standard of care endoscopies (fentanyl, midazolam and Benadryl) include respiratory 
depression, constipation, dry mouth, dizziness, blurred vision, sleepiness and agitation. 
5.5. Potential Benefits 
There are no benefits to participating in this study.  A potential benefit for the subjects randomized to the active 
(peanut) oral immunotherapy is the potential decrease in the subject’s reactivity to peanuts after an accidental 
exposure/ ingestion of peanut.  The likelihood of this is unknown. 
6. Investigational Agent  

24 
 
6.1. Investigational Agent 
6.1.1. Study Drug (Peanut Flour) 
The investigational product in this trial is partially defatted peanut flour, 12% fat, light roast.  This material is 
purchased from:  
Byrd Mill Company  
P.O. Box 1775  
Ashland, VA 23005  
Byrd Mill has stated that the peanut flour is manufactured under GMP for food products, no other nuts are 
processed at this peanut processing facility, and the peanut flour is not stored with material derived from other 
nuts. Analysis conducted to determine the peanut protein content in the bulk peanut flour has been done and a 
sample copy of the result is presented in the Appendix 8. 
6.1.1.1. Formulation, Packaging, and Labeling 
The raw material used in the manufacture of investigational product is peanut protein, manufactured by 
Byrd Mill Company.  Raw material is accepted based upon review of the Certificate of Analysis, 
reproduced below. 
The labels on Soufflé portion cups of investigational product and placebo are white, with dimensions 
1 x 2.625 inches and the text is Arial font. The text that will appear on the labels is provided below: 
Peanut Powder or Placebo 
SUMC (Stanford University Medical Center)  
Kari Nadeau, MD, PhD, IND #: ______ 
Lot #: _______________        Protocol #: 0001   
Dose: ________   
Keep refrigerated (2-8°C)  
Caution:  New Drug – Limited by Federal Law to Investigational Use 
6.1.1.2. Dosage, Preparation, and Administration 
The drug product consists of 27 different amounts of peanut protein, which are listed in Table 1 and 
Table 2 below. Each dosage of investigational product will be supplied in a 1oz (or other appropriately 
sized) Soufflé Portion Cup manufactured by Solo Cup Company (Highland Park, IL).  The Soufflé Portions 
Cups are closed with plastic lids obtained from the same manufacturer.  No other excipients are added 
to the peanut flour.  The investigational product is supplied as a dry, tan powder, which should be stored 
in a cool, dry place at 2 - 8 °C. 
Measuring, packaging and labeling will be done by: 
Stanford University Medical Center  
Clinical Food Research Unit (CFRU) cGMP 
Stanford Packard El Camino Hospital, PEC, 1st Floor 
2500 Grant Road 
Mountain View, CA 
Distinct peanut protein products will be measured and packaged using batch records for each dose.  
Each dose is filled at a ±5% tolerance by weight. Copies of completed batch records are available upon 
request.  Each Soufflé portion cup containing the dose will be labeled and identified by a unique random 

25 
 
assignment number and the dose number.  A flow diagram describing the filling of Soufflé portion cups 
for each dose is presented below.   
The CFRU cGMP unit 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 (SOPs) and standards set forth in the 
aforementioned FDA Guidances and Regulations, the CFRU cGMP unit uses an electronic document 
control system and will be reviewed and supported from trained research and regulatory personnel. 

26 
 
Figure 2: Manufacturing Flow Diagram 
 
The balance is calibrated at the beginning of each shift 
 
 
 
Tare the soufflé cup and weigh the appropriate amount of peanut/oat powder 
 
 
 
 
Document the weight of every measurement 
 
 
 
Repeat all the steps until all Soufflé cups have been filled for that kit 
 
 
 
Once all Soufflé cups in the kit are filled, they are labeled 
 
 
 
A separate batch record is generated for each kit 
 
6.1.2. Placebo (Oat Flour) 
The placebo, oat flour, will be purchased commercially from the following manufacturer:  
Arrowhead Mills, Inc. 
A Division of the Hain Celestial Group. Inc. 
Melville, NY 11747 
Toasted oat flour, prepared as described in IND 
 is acceptable based upon being approved and used 
previously for IND 
.  
6.1.2.1. Formulation, Packaging, and Labeling 
Packaging and labeling will be identical to that used for peanut flour as described under Section 6.1.1.1. 
6.1.2.2. Dosage, Preparation, and Administration 
Dosage, preparation, and administration will be identical to that used for peanut flour as described 
under Section 6.1.1.2. 

27 
 
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. 
Original records for receipt, storage, use, and disposition will be maintained by the study site.  An original 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/placebo administration, the site personnel will retain all empty or partially used vials.  All drug 
material will be released and recorded by the nutrition 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 CFRU with each visit and collected by study staff for reconciliation of 
remaining peanut/oat flour. 
6.4. Toxicity Prevention and Management 
Reactions to Peanut OIT During Initial Dose Escalation Day 
Participants may develop symptoms during the initial escalation. The investigator’s judgment will be required to 
determine the best course of action with possible actions being: 
1. Extend time interval between dosing (up to an additional 30 minutes). 
2. Return to previously tolerated dose (i.e., repeat of last tolerated dose) then advance forward. 
3. Discontinue protocol. 
For oral or pharyngeal pruritus, the action should be to continue the normal dosing in 30 minutes. 
For mild symptoms, defined as: 
• 
skin — limited or localized hives or swelling, skin flushing or pruritus 
• 
respiratory — rhinorrhea or sneezing, nasal congestion, occasional cough, throat discomfort 
• 
GI — mild abdominal discomfort or minor episode of vomiting 
 
the action should be either to repeat the last dose in 30-60 minutes or to advance in 30-60 minutes depending on the 
physician’s discretion. 
For moderate symptoms, defined as: 
• 
skin — systemic hives or swelling 
• 
respiratory — throat tightness without hoarseness, persistent cough, wheezing without 
• 
dyspnea 
• 
GI — persistent moderate abdominal pain/cramping/nausea, increased vomiting 
the action should be to implement a 30-60 minute observation period and if symptoms resolve, reduce the dose by one 
step, repeat the same dose, or increase the dose by one step; if symptoms continue or worsen, the participant can be 
treated with antihistamines: if symptoms resolve, reduce the dose by one step, repeat the same dose, or increase the 
dose by one step; if symptoms require additional treatment, then consultation with the Principal Investigator is 
warranted to determine the next course of action. 
For severe symptoms, defined as: 
• 
respiratory — laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea 

28 
 
• 
GI — significant severe abdominal pain/cramping/repetitive vomiting 
• 
neurological — change in mental status 
• 
circulatory — hypotension 
The initial escalation dose should be discontinued and the appropriate rescue medications administered. 
If the subject requires treatment for symptoms with antihistamines on one occasion during the initial escalation 
protocol, then the rest of the protocol may be followed. If the subject requires more than one medication (e.g., 
albuterol, diphenhydramine, epinephrine, or others) or multiple doses of antihistamines, the initial escalation protocol 
should be terminated. 
The PI will be available for questions and decision making for any questions related to the study protocol at all times. 
All subjects will be observed for a minimum of 2 hours following administration of the final dose and will be discharged 
only when deemed clinically stable by a study physician. 
Figure 3: Management of Symptoms During Initial Dose Escalation Day 
 
 
 
Reactions to Peanut 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 (as 
per manual of procedures) demonstrating FEV1 <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.   

29 
 
If a subject has an updosing in the CFRU 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 symptoms (Objective, APPENDIX 4), the action should be either to repeat the dose the next day (day 2) at 
home or to have the subject return to the CFRU 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 CFRU 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 4) occur, the action should be to have the subject return to the CFRU the 
next day (day 2) for dosing with the previous days dose or the last tolerated dose, at study physician discretion, under 
observation.  If the dose is tolerated, the subject will continue on that daily home dose for the normal time interval per 
protocol.  If the subject does not tolerate this dose, the subject should receive the last tolerated dose or a 1-2 step dose 
reduction the next day (day 3) in the CFRU 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 
CFRU as noted below.  If this dose is not tolerated, then the next dose will be a 1-2-step reduction in dosing, and the 
dose will be given on the CFRU 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 4) occur the action should be to treat the subject, and at the study physician’s 
discretion either 1) have them return to the CFRU 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 CFRU 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 
dose escalation failure and the last tolerated dose will be accepted as the maintenance dose.  
For a completed dose escalation with no symptoms, subjects should be observed for 30 minutes.  For mild symptoms, 
subjects should have a 1-2 hours post-protocol observation period.  For moderate to severe symptoms, the observation 
period should be at least 4 hours and up to 24 hours based on symptoms and treatment regimen needed to stabilize the 
subject. 
Any subject deemed to have severe allergic reactions to OIT, including hypoxia, hypotension or change in mental status 
and receives aggressive therapy (e.g., IV fluid resuscitation, mechanical ventilation, repeated 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.   
Any subject who discontinues build-up dosing due to repeated allergic reactions to the characterized peanut allergen 
will have his/her blood drawn for mechanistic studies within approximately 1 week of discontinuation of therapy. 
 
6.5. Premature Discontinuation of Investigational Agent 
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
• 
Anaphylaxis resulting in hypotension, neurological compromise or mechanical ventilation secondary to peanut 
OIT dosing or any peanut food challenge 

30 
 
Any subject deemed to have severe allergic reactions to OIT 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.  The circumstances include, but may not be limited to, the following: 
• 
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 
• 
Pregnancy  
• 
Circumstances (e.g., concurrent illness, such as gastroenteritis) requiring missed peanut OIT maintenance dosing 
of > 7 consecutive days  
• 
Non-adherence with home peanut OIT dosing protocol (excessive missed days; i.e., > 3 consecutive days missed 
on 3 or more occasions) without consulting with study staff would be a safety issue warranting discontinuation 
Any  subject may be prematurely terminated from the study if: 
• 
The subject elects to avoid consent from all future study activities, including follow-up 
• 
The subject is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish contact 
with the subject have failed)  
• 
The subject develops biopsy-documented eosinophilic esophagitis (EoE) with clinical symptoms or other 
eosinophilic gastrointestinal disease 
• 
The subject dies  
• 
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 peanut OIT may remain in the study until the end of study visit at 
Week 156.  All willing subjects will be followed every 13 weeks for the duration of the study to monitor safety and 
efficacy parameters.  
Subjects who initiate therapy (i.e., who do not fail the Initial Dose Escalation Day AND also 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. 
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.  Systemic (oral, IV, IM) steroid use longer than 5 days at one time or longer than 3 weeks (21 days) 
duration each year is not allowed.  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 

31 
 
• 
Omalizumab (Xolair) 
• 
Systemic (oral, IV, IM) corticosteroids used for any greater than 5 days at one time or longer than a total of 
3 weeks (21 days) duration each year for asthma.  If used, subjects must not be up-dosed until at least 3 days 
after ceasing the administration of oral steroids 
• 
Oral β-blockers 
7.4. Rescue Medications  
Treatment of individual allergic reactions during peanut 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). 
Generally, for mild and moderate symptoms, the subject should receive antihistamines, and for more severe symptoms, 
the subjects should receive epinephrine, antihistamines, and then the other medications as indicated. If severe 
anaphylaxis occurs at any time, dose escalation will stop and the dose will be reduced to the last tolerated dose and the 
subject continued on that dose as long-term maintenance without further escalation. 
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 CFRU.  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.   
Epinephrine 
Any reaction (in CFRU or at home) that requires two or more doses of epinephrine will halt further dose escalation for 
this individual. Maintenance on the last tolerated dose would be continued. 
CFRU 
If a single administration of epinephrine is required during in CFRU 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 CFRU. 
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 CFRU. 
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 CFRU for an observed 
dose prior to resuming any dosing at home. 
8. Study Procedures 
8.1. Enrollment 

32 
 
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(s) 
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.  All assessments must be completed no more than 10 months (Appendix 
1) preceding initiation of peanut/placebo treatment.  Baseline/screening visits following requirements below, conducted 
under a different protocol within the past 10 months prior to IDED, can be used towards this study. 
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 
• 
Physical assessment 
• 
Blood draw for peanut-specific IgE and IgG4 measurement 
• 
Skin prick test to peanut extract (neat extract with no dilution, Greer Laboratories, Lenoir, NC) 
• 
Spirometry 
• 
DBPCFC to a 500 mg cumulative total peanut protein 
• 
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) 
Any of the above items may be repeated within the 10 months preceding initiation of study treatment if warranted, in 
the opinion of the investigator, by changes in the subject’s clinical status. 
Double-Blind Placebo-Controlled Food Challenge (DBPCFC) at Screening 
Randomization and preparation 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).  
The screening DBPCFC will consist of 7 doses of peanut given every 15-30 minutes in increasing amounts up to a 
cumulative total of 500 mg of peanut 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 7 doses. The doses will be 5 mg, 20 mg, 50 mg, 
100 mg, 100 mg, 100 mg, and 125 mg. 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.   
Reactions will be scored using a Food Challenge Symptom Score sheet (see criteria in Appendix 4). 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 peanut ingestion with the DBPCFC, they will not be enrolled in the study. 
Separate GI Substudy. 
After enrollment into the study, participants who are 18 y.o. or over will be asked, via a separate consent,  if they are 
interested in participating in a study in which biopsies are obtained of the gastrointestinal track to test for safety and 
efficacy markers. There will be an upper GI endoscopy scheduled at baseline and then again at week 52, 104, and week 
117 (or equivalent) of the protocol. We expect to enroll approximately 20 adult subjects in this subset. 
Subjects will undergo an endoscopy prior to their IDED. This will be performed by a board certified gastroenterologist at 
Stanford Endoscopy suite. This will be performed under mild anesthesia using fentanyl, versed and midazolam and 

33 
 
subjects will be observed in the endoscopy recovery room per standard of care. Biopsies will be taken from the 
esophagus, stomach and duodenum. 
8.3. Study Visits  
 
Peanut OIT Treatment Overview 
Peanut OIT administration will include an Initial Dose Escalation Day (IDED) with peanut oral immunotherapy dosing 
beginning at 0.5 mg with graduated doses up to 6 mg (if tolerated) occurring in the Stanford CFRU. Subjects tolerating 
less than 1.5 mg single dose will be considered an Initial Dose Escalation Day failure and will be discontinued from the 
study.  
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) prior to each in-CFRU 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 will be attempted in CFRU.  If FEV1 <80% predicted value after bronchodilator 
administration, the participant will remain at their current dose for two additional weeks.  That day’s dose may be 
administered either in CFRU and monitored as an updose. 
In addition to dosing visits, subjects will return to the CFRU 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 every 3 months (approximately every 13 weeks) beginning with week 104.  
After subjects have met the criteria outlined above (Section 3.1), medical history, diet history, spirometry, SPT, and a 
physical assessment will be performed.  These subjects will be randomized 1:1 either to avoid OIT therapy (see Figure 1), 
and begin the avoidance phase, or they will be randomized to decrease their daily dose to 300 mg of peanut protein.  
After 3 months both arms will be re-challenged with 4,000 mg peanut protein, and then every 13 weeks for up to 4 
additional OFCs.  The placebo group may be unblinded to the research staff at week 117. 
 
Peanut OIT: 
Initial Dose Escalation Day (Day 0) – The Initial Dose Escalation (IDE) Day will be done at the CFRU  and consist of peanut 
OIT dosing, beginning at 0.5 mg of peanut protein with graduated doses every 30 minutes up to 6 mg (see schedule for 
initial day dose escalation, Table 1).  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.  A physician will be present at all times during any of the CFRU peanut OIT dosing visits and will be available to 
respond within 60 seconds to any allergic reaction.  Subjects tolerating the 6 mg single dose will remain on that daily 
dose for 2 weeks.  They will then return every 2 weeks to the CFRU for single updose.  Subjects who do not tolerate the 
1.5 mg dose will be considered treatment failures and will not initiate home dosing.  
Table 1: Peanut Protein or Placebo (oat protein)  
Dosage Escalation Schedule on the Initial Dose Escalation Day 
Dose # 
Peanut Dose 
Cumulative 
Peanut Dose 
1 
0.5 mg 
0.5 mg 
2 
0.8 mg 
1.3 mg 
3 
1.5 mg 
2.8 mg 
4 
3.0 mg 
5.8 mg 

34 
 
5 
6.0 mg 
11.8 mg 
Up-dosing phase (build-up phase) (Week 1-44):  Subjects will receive subsequent doses (Table 2) at home for the next 14 
days. Subjects who tolerate only 1.5 mg on the IDED will return in 7 days for updosing to 3 mg and then return 7 days 
later for updosing to 6 mg before proceeding to dose #6. Subjects who tolerate only 3 mg on the IDED will return in 7 
days for updosing to 6 mg before proceeding to dose #6.  Subjects will be instructed to continue dietary peanut 
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 4,000 mg peanut protein build-up phase).   
During dose escalation, there should be increased hydration (i.e. about 16 oz or more given orally) and restricted 
exercise for 2 hours after dosing. 
Table 2: Daily Peanut Protein Dosing and Increase Schedule for Build-Up Phase 
Dose # 
Dose 
Interval 
(Weeks) 
% of Increase 
5 
6 mg 
2 
Initial Dose Escalation 
Day   
6 
12 mg 
2 
100% 
7 
25 mg 
2 
108% 
8 
50 mg 
2 
100% 
9 
75 mg 
2 
50% 
10 
100 mg 
2 
33% 
11 
125 mg 
2 
25% 
12 
156 mg 
2 
25% 
13 
195 mg 
2 
25% 
14 
245 mg 
2 
25% 
15 
306 mg 
2 
25% 
16 
383 mg 
2 
25% 
17 
479 mg 
2 
25% 
18 
599 mg 
2 
25% 
19 
749 mg 
2 
25% 
20 
936 mg 
2 
25% 
21 
1,170 mg 
2 
25% 
22 
1,463 mg 
2 
25% 
23 
1,829 mg 
2 
25% 
24 
2,286 mg 
2 
25% 
25 
2,858 mg 
2 
25% 
26 
3,573 mg 
2 
25% 
27 
4,000 mg 
2 
12% 

35 
 
Subjects will begin the CFRU dosing schedule as outlined above until 4,000 mg of peanut 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-CFRU 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 during the 2-week period due to illness will undergo an attempted updosing only after 
resuming their full dose for a minimum 3 days.  
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 7.4 or illness.  If the subject fails to successfully increase 
updosing for three consecutive attempts, updosing will be halted at the last tolerated dose and the subject will continue 
on that dose as their maintenance dose for the remainder of the study.  The subject will be followed for the remainder 
of the study for safety and immunologic monitoring.   
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.  
Every 13 weeks during the build-up phase, subjects will have blood drawn for mechanistic labs, including basophil 
activation studies and pregnancy testing, if applicable.  Blood will be collected prior to attempted dose escalations, but 
the decision to updose will be made based on clinical parameters, not the results of the assays. 
Weeks 52, 65, 78, and 91– Maintenance Phase 
Subjects will undergo updosing until reaching a daily maintenance dose of 4,000 mg and they will remain at that dose 
and return for follow-up visits at Weeks 52, 65, 78, and 91.  Each of these visits will include a physical assessment, 
spirometry, skin test, and blood draw for mechanistic studies.  Based on our previous data using a similar dosing method 
(Table 2), we expect all subjects on active treatment to reach 4,000 mg between the Week 44 and Week 78 visits. 
 
Week 104 – On Study DBPCFC (to 4,000 mg) 
At Week 104 all subjects will have a DBPCFC to 4,000 mg (as per staged challenge above) to assess desensitization. The 
visit will also include a physical assessment, spirometry, skin prick test and blood draw for mechanistic studies.  
The subject’s sensitivity to peanut 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 
(Appendix 4).  
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 (Bock scoring system (objective, Appendix 4) 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 7 doses (peanut or placebo), given about every 15-30 minutes for lower 
doses and about every 45 minutes or longer for higher doses (in bold): 5 mg, 50 mg, 220 mg, 625 mg, 1,000 mg, and 
1,050 mg and 1,050 mg (4,000 mg protein total).  The doses for DBPCFCs conducted on or after Week 104 in this 

36 
 
protocol were selected with the rationale that some study subjects will be receiving placebo and would be expected to 
maintain the same level of sensitivity displayed at the screening DBPCFC to a cumulative dose of 500 mg of peanut 
protein.  Both peanut 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 Bock’s Criteria (Appendix 4). 
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 104 DBPCFC, subjects who meet the following criteria will reduce their daily maintenance dose to 300 
mg  peanut protein daily or to discontinue peanut protein daily dosing entirely (i.e., switch to 600mg oat flour): 
• 
On OIT treatment for minimum 104 weeks,  
• 
Taking daily maintenance dose of 4,000 mg protein for at least 3 months, 
• 
No severe reactions (Bock’s Criteria Grade 3, APPENDIX 4) to home dosing from Week 92-Week 104, and/or 
• 
No objective reactions by Bock’s Criteria, Appendix 4 at the DBPCFC at Week 104 
Subjects who do not meet these criteria at Week 104 will be considered desensitization failures and will be offered a 
follow-up protocol that is separate from this protocol once they reach the primary endpoint.  They will be considered in 
statistical analyses of the intent-to-treat population. 
After Week 104, double blinding will continue by using the same quantity of  flour for all groups (600 mg total of oat 
flour daily for placebo group and 600 mg total of oat flour daily for avoidance group; approximately 600 mg total of 
peanut flour --to provide exactly 300 mg peanut protein—for the 300 mg peanut protein  group). 
Separate GI Sub Study. 
Subjects will undergo the second endoscopy at week 52, and a third endoscopy at week 104 and a fourth endoscopy at 
week 117 (or equivalent). These will be performed by a board certified gastroenterologist at Stanford Endoscopy suite. 
This will be performed under mild anesthesia using fentanyl, versed and midazolam and subjects will be observed in the 
endoscopy recovery room per standard of care. Biopsies will be taken from the esophagus, stomach and duodenum. 
 
Weeks 117 (or equivalent), 130, 143, and 156 – On Study DBPCFC (to 4,000 mg) 
At Weeks 117 (or equivalent), 130, 143, and 156, subjects will have a DBPCFC to 4,000 mg (as per staged challenge 
above) to assess tolerance.  Subjects who fail these challenges (i.e., who exhibit objective reactions by Bock’s Criteria, 
Appendix 4) will be offered a follow-up protocol that is separate from this protocol. 
Subjects who are randomized either to 300 mg peanut protein or peanut avoidance or the placebo subjects who pass 
the week 104 criteria will return to CFRU at Weeks 117 (or equivalent), 130, 143, and 156.  Each of these visits will 
include a physical assessment, spirometry, skin test, blood draw for mechanistic studies, and a DBPCFC to 4,000 mg as 
outlined above to assess clinical reactivity.   
During the oral food challenge, there should be increased hydration (i.e. about 16 oz or more given orally). 
There are no data indicating that repeating food challenges every 3 months will or will not induce 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. 
8.4. 1. Unscheduled Visits  

37 
 
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. 
Visit Windows 
Table 3: Visit Windows 
Visit Type 
Target Date 
Visit Window 
Screening/Baseline/Randomization Day -300 to 0 
Day -300 to 0 
Initial Dose Escalation Day 
Day 0 
Day 0 (by definition) 
Dose Escalation Phase 
Weeks 2, 4, 6, 8 until maintenance 
dose is reached] 
±14 days 
Maintenance Phase 
Weeks 52, 65, 78, 91, and 104 
Tolerance Phase 
Weeks 117 (or equivalent), 130, 143, 
and 156 
 
9. Mechanistic Assays 
Comparisons for each of the parameters discussed below could occur between: 
• 
Treatment vs. Placebo group, and 
• 
On Treatment vs. Baseline for each subject, and  
• 
Tolerant vs. Desensitized vs. Refractory (those that terminate early due to not being able to be 
desensitized) clinical outcomes 
I) 
Serum Assays  
Table 4: Serum Assays 
Panel 
Volume needed for each sample 
collection 
Specific IgE, IgG4, IgA anti-peanut and the 
component-resolved (presume IgE and IgG4 anti-
Ara h 1,2,3,6,8) 
1 ml 
Epitope Array Peanut 
350 microliters 
Table 5: Expected Results for Serum Parameters 
Parameter 
On Therapy 
Tolerance 
Desensitization 
Refractory 
Specific IgE 
And Specific IgG4 
Progressive 
decrease in 
specific IgE to 
peanut and 
increase in 
specific IgG4 
Low specific IgE 
and increased 
IgG4 which 
persists despite 
the 3 month 
period of 
abstinence 
Low specific IgE 
and increased 
IgG4 which 
reverses in the 3 
month period of 
abstinence 
No change in 
specific IgG4 to 
peanut 
Epitope Array  
for IgE for 
peanut 
Progressive 
Inhibitory 
antibodies 
Lowest epitope 
spreading at 
Intermediate 
epitope 
spreading at 
Highest epitope 
spreading at 
baseline predicts 

38 
 
peptides—
predictive 
marker for 
outcome 
present in 
epitope array 
baseline predicts 
tolerance 
baseline predicts 
tolerance 
refractory 
outcome 
Specific IgA 
Progressive 
increases in 
specific IgA over 
time 
Increased 
specific IgA 
which persists 
despite the 3 
month period of 
abstinence 
Intermediate 
levels of specific 
IgA which 
persists despite 
the 3 month 
period of 
abstinence 
No change 
Note: Compared to placebo, in which we assume no changes will occur. 
II)           Cell components for CyTOF Parameters 
Table 6: Possible Cell Components for CyTOF Parameters 
Panel A  
“T” Marker 
Rationale  
Panel B  
“Non T” Marker 
Rationale  
CD4 
T cell panel for immunoprofiling 
CD19 
B cell panel for immunoprofiling 
CD8 
T cell panel for immunoprofiling 
CD20 
B cell panel for immunoprofiling 
CD3 
T cell panel for immunoprofiling 
CD3 
B cell panel for immunoprofiling 
LAG3 
Marker for Tr1 
CD24 
Mature B cell marker 
CD45RA 
Naïve phenotype 
CD27 
Memory B cell 
Ki-67 
Proliferation marker 
CD38 
B 
CD40L 
Activation marker 
CD16 
NK marker 
CD69 
Activation marker 
CD56 
NK marker 
HLA-DR 
MHC Class II 
CD94 
NK marker 
PD-1 
Programmed-death (Treg subset) 
CD314 
iNKT 
Helios 
Ikaros Family Transcription Factor, 
preferentially expressed on induced 
Treg 
Lin 
DC marker 
Foxp3 
Transcription Factor involved in Treg 
development and function 
CD123 
DC and basophil marker 
CD127 
Marker for native Treg 
CD11c 
DC marker 
CD49b 
Marker for Tr1 
CD103 
Pro-tolerance DC cell (GI tract?) 
CCR4 
Chemokine receptor for T cell 
trafficking into local tissues 
CCR9 
Pro-tolerance DC cell 
CCR8 
Chemokine receptor for T cell 
trafficking into local tissues 
HLA DR 
MHC Class II 
CCR6 
Chemokine receptor for T cell 
trafficking into local tissues 
CD63 
Basophil activation marker 
IL-17 
Th17 cell ICS 
CD203c 
Basophil activation marker 
IL-5 
Th2 cell ICS 
Psyk 
Basophil activation phosphoepitope 
pSTAT1 
Th1 ICS 
mTOR 
Basophil activation phosphoepitope 

39 
 
pSTAT3 
Th17 ICS 
pS6 
Basophil activation phosphoepitope 
pSTAT5 
Treg ICS 
TLR9 
Innate immune pathway associated with 
allergy treatment 
pSTAT6 
Th2 ICS 
CD8 
T cell, NKT 
GATA-3 
Directs Th2 development 
Ki67 
proliferation 
T-bet 
Directs Th1 development 
TSLP 
Pro-allergy ICS 
IL-10 
Treg ICS 
OX40L 
Allergy modifier 
TGF-b 
Treg ICS 
TSLP receptor 
DC marker pro allergy 
IFN-g 
Th1 ICS 
 
 
IL-13 
Th2 ICS 
 
 
IL-4 
Th2 ICS 
Live/Dead 
 
Tetramer Positive 
Antigen-specific 
 
 
Live/Dead 
 
 
 
Subset Definitions: 
 
T cells: CD3, CD4, CD8, CD27, CD45RA, CD28, CCR4, CCR8 
 
Activated T cells: CD3, CD4, CD8, CD38, HLA-DR, PD-1  
 
NK/NKT cells: CD3, CD8, CD16, CD56, CD94, CD314 (NKG2D), HLA-DR  
 
B cells: CD3, CD19, CD20, CD24, CD27, CD38,  
 
Regulatory T cells: CD3, CD4, CD8, CD25, CD127, CD45RA, GITR, Helios, PD-1, Foxp3, CD49b/LAG3 
 
DC: Lin-, HLA DR+, CCR9, CD103 
 
Plasmacytoid DC: Lin-, HLA DR+, CD11c-, CD123+ 
 
Myeloid DC: Lin-, HLA DR+, CD11c+, CD123- 
 
Basophils: HLADR-, CD123+, CD63, CD203c, psyk, mTOR, pS6 
 
Innate Immunity: TLR9 
 
Plus Tetramer Positive T cells to be gated 
   Typical Intracellular Staining: 
 
Ki-67  
 
IFNgamma  
 
IL-4 
 
IL-5 
 
IL-9 
 
IL-13 
 
IL-10  
 
TGF-beta 
 
IL-17  
 
pSTAT-1 
 
PSTAT-3 
 
pSTAT-5 
 
pSTAT-6 
 
Helios 
 
Foxp3 
 
GATA-3 
 
Tbet 
 
Psyk 
 
pS6 
 
mTOR 

40 
 
Table 7: Expected Results for Cell Parameters 
Parameter 
On Therapy 
Tolerance 
Desensitization 
Refractory 
Th2 
Progressive 
decrease in Th2 
absolute numbers 
and ICS 
transcription 
factors and Th2 
cytokines 
Low Th2 cell 
numbers and 
decreased ability 
to proliferate in 
response to peanut 
which persists 
despite the 3 
month period of 
abstinence 
Low Th2 cells 
and low ability to 
proliferate in 
response to 
peanut which 
does not persist 
within the 3 
month period of 
abstinence 
No change 
(compared to 
placebo or to 
baseline) 
Th1 
Progressive 
increase in Th1 
absolute numbers 
and ICS 
transcription 
factors and Th1 
cytokines 
HighTh1 cell 
numbers and 
increased ability to 
proliferate in 
response to peanut 
which persists 
despite the 3 
month period of 
abstinence 
High Th1 cell 
numbers and 
ability to 
proliferate in 
response to 
peanut which 
does not persist 
within the 3 
month period of 
abstinence 
No change (ibid) 
Th17 
Do not expect 
change 
Do not expect 
change 
Do not expect 
change 
Do not expect 
change (ibid) 
Treg 
Progressive 
increase in 
absolute counts of 
Treg but then 
decline by 12 mo. 
High Treg cell 
numbers and 
decreased ability 
to proliferate in 
response to peanut 
which persists 
despite the 3 
month period of 
abstinence 
Intermediate 
Treg cell 
numbers and 
decreased ability 
to proliferate in 
response to 
peanut which 
does not persist 
within the 3 
month period of 
abstinence 
No change  (ibid) 
NKT 
Progressive 
increase in 
absolute counts of 
NKT cells 
High NKT cell 
numbers 
associated with 
tolerance 
Intermediate 
NKT cell 
numbers 
associated with 
desensitization 
No change (ibid) 
DC 
Progressive 
decrease of TSLP 
receptor in mDCs, 
progressive 
increase in CD103 
and CCR9 in DCs 
Low TSLP receptor 
expression in 
mDCs, 
High DC expression 
of CD103 and CCR9  
Intermediate 
TSLP receptor 
expression in 
mDCs and 
intermediate DC 
expression of 
CD103 and CCR9 
No change (ibid) 
Cell death 
markers 
Progressive 
increase in cell 
death of allergen-
Highest cell death 
of allergen-specific 
Th2 memory cells 
Intermediate cell 
death of 
allergen-specific 
No change (ibid) 

41 
 
specific Th2 
memory cells 
Th2 memory 
cells 
Chemokine 
receptors 
Progressive 
increase in CCR4 
and CCR8 in Treg 
Highest expression 
of CCR4 and CCR8 
in Treg 
Intermediate 
expression of 
CCR4 and CCR8 
in Treg 
No change (ibid) 
Allergen 
specific cells 
Switch from mostly 
Th2 to Th1 or Treg 
subset over course 
of therapy 
Lack of Th2 
cytokines and 
transc. factors in 
gated tetramer 
positive population 
(i.e. no pSTAT6, no 
IL-4, no IL-13, no 
IL-5, no GATA-3 
expression upon 
peanut 
stimulation) 
Intermediate 
decrease in Th2 
cytokines and 
transc. factors in 
gated tetramer 
positive 
population  
No change (ibid) 
Note: Compared to placebo, in which we assume no changes will occur. 
III)          Sample Basophil Assay: 
Table 8: Expected Results for Basophil Activation Parameters 
Parameter 
On Therapy 
Tolerance 
Desensitization 
Refractory 
CD203c/CD63 
During course of 
therapy, will see 
decrease in 
basophil 
reactivity sooner 
than lowering of 
specific IgE 
Lack of basophil 
reactivity to 
peanut 
stimulation 
persists after 3 
mo abstinence 
Basophil 
reactivity returns 
during the 3 mo 
abstinence. 
No change in 
basophil 
reactivity (ibid) 
Logistics: Blood samples will be collected every 12-13 weeks during the subject’s participation in the study.  Volumes 
collected will follow NIH guidelines (for children: 5 ml/kg at any single draw, no more than 9.5 ml/kg over an 8-week 
period; adults: the smaller of 10.5 ml/kg or 550 ml total at any single draw). 
IV) GI biopsy assays: 
We will perform three major procedures on the GI biopsies: 
a. 
immunohistochemistry to identify cells-inflammatory and regulatory (mast cells, basophils, eosinophils, T cells, 
B cells, dendritic cells, and epithelial cells and associated markers –for example  TSLP, IL-33, IL-18, IL-10,  CD103, 
IL-4, IL-13, histamine, STAT6, GATA3, T-bet, IFN-g, TGF-b) 
b. 
single cell sorting with RNA Seq 
c. 
cryopreservation for future analysis outside the scope of the proposal 
 
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 

42 
 
11.1. Participant Completion 
Completion of the study will be defined as reaching the Week 117 (or equivalent) visit and participating in at least 90% 
of CFRU visits. 
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  
a. Missing >7 consecutive days of OIT therapy (e.g., concurrent illness such as gastroenteritis) 
b. Missing >3 consecutive days of OIT therapy on 3 occasions without consulting with study staff   
c. Anaphylaxis resulting in hypotension, neurological compromise or mechanical ventilation secondary to 
OIT dosing or any peanut food challenge 
d. Any allergic reaction to study drug requiring more than 2 doses of epinephrine due to single event 
e. The subject develops biopsy-documented eosinophilic esophagitis (EoE) with symptoms or other 
eosinophilic gastrointestinal disease 
f. 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.   
g. Other circumstances including, but not limited to, the following: 
i. Poor control or persistent activation of secondary atopic disease (e.g., AD, asthma)  
ii. Started on beta-blockers, or other prohibited medications, with no alternative medications 
available per the prescribing physician 
iii. Pregnancy  
11.3. Participant Replacement 
Subjects who initiate therapy (i.e., who do not fail the Initial Dose Escalation Day AND also initiate home dosing) in this 
trial 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 156.  
All willing subjects will be followed every 13 weeks for the duration of the study to monitor safety and efficacy 
parameters.  These visits will include skin testing and a blood draw for mechanistic studies. 
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. 
11.5.  Study Stopping Rules 
During the course of 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, 
including notification of the FDA and IRB. 

43 
 
If any of the stopping rules listed below are met, study enrollment will be suspended, the Initial Dose Escalation days will 
be suspended, dose escalation during Build-up will be stopped, and all enrolled participants will remain on their current 
dose pending expedited review of all pertinent data: 
• 
Any death related to peanut 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 peanut dosing or to oral food challenge. 
• 
More than 2 cases of hypotension related to peanut dosing or to oral food challenge. 
• 
More than 3 participants require more than 2 injections of epinephrine for anaphylaxis during a single dosing 
event of the peanut product. 
• 
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 clinical symptoms and confirmatory biopsy findings 
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.  
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, an adverse event will include any untoward or unfavorable medical occurrence associated with:   
• 
Study therapy regimen:  
Home OIT Dosing 
• 
Food allergy episodes in response to home dosing that are objective Grade 1 or 2 by Modified Bock’s 
Criteria (APPENDIX 4) will be recorded on the paper AE CRFs and graded by CTCAE v 4.03 criteria. 
• 
Food allergy episodes in response to home dosing that are Grade 3 by Modified Bock’s Criteria 
(APPENDIX 4) 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 CTCAE v 4.03 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 
 

44 
 
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 
 
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.  GI biopsies 
• 
GI biopsies will be performed on a voluntary subset of participants via an endoscopy.  Adverse 
events will be monitored and documented per the AE listings. Any adverse events related to the 
procedure or medications used and that meet the criteria for SAE will be reported per the SAE 
matrix to the FDA and the NIAID medical monitor.  
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 package insert or is not listed at the specificity, severity or rate of occurrence 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 or protocol. 
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) 
An adverse event or suspected adverse reaction is considered “serious” if 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 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 

45 
 
The study physician will grade the severity of adverse events experienced by the study subjects according to the 
criteria set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. 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 paper AE case report form for this study. 
Anaphylaxis will be defined when there is: 1) Symptomatic bronchospasm, with or without urticaria, 
with parenteral intervention indicated with edema and hypotension; or 2) Life-threatening 
consequences with urgent intervention indicated. 
 
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/study physician and recorded on the appropriate AE/SAE paper 
case report form and according to SUSAR guidelines 
(http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf)Final determination of attribution of SAE 
for safety reporting will be determined by DAIT/NIAID.   
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web site: 
http://ctep.cancer.gov/reporting/ctc.html. 
       
 
12.4.  Collection and Recording of Adverse Events 
12.4.1.  Collection Period 
Adverse events will be collected from the 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. 
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. 

46 
 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, 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 Sponsor 
This section describes the responsibilities of the site investigator to report serious adverse events to the 
sponsor. Timely reporting of adverse events is required by 21 CFR and ICH E6 guidelines.  
The site investigator will report to the NIAID Medical Monitor 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 MONITOR:  
, MD 
Division of Allergy, Immunology, and Transplantation – NIAID/NIH 
 
Rockville, MD 20852
, USA 
Phone: 
  
Cell Phone: 
 
E-mail: 
 
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 paper CRF will be updated and submitted. 
12.5.1.1.  Reporting of Unexpected Non-Serious Adverse Events 
An unexpected, non-serious adverse event that is of Grade 2 severity or higher and study related will be 
recorded and reported to the NIAID Medical Monitor and the Independent Medical Monitor.     
12.5.2.  Reporting to Health Authority 
Dr. Nadeau 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. Nadeau’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.  IND sponsor must report the event to the appropriate health 
authorities using one of these two options: 
12.5.2.1.  Standard Reporting (IND Annual Report) 
 
This option applies if the AE is classified as one of the following:  
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  
• Expedited reporting is required.  
This option applies if the AE is classified as one of the following:  

47 
 
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 312.32(c)(1)i 
o The IND sponsor, Dr. Nadeau, must report any suspected adverse reaction that is both serious and 
unexpected. The IND sponsor must report an adverse event as a suspected adverse reaction only if there 
is evidence to suggest a causal relationship between the study drug and the adverse event, such as: 
 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure.  
 
One or more occurrences of an event that is not commonly associated with drug exposure, but 
is otherwise uncommon in the population exposed to the drug  
o Aggregate analysis of specific serious adverse events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical control group. 
o Any findings from clinical or epidemiological studies, analysis of data pooled across multiple studies, 
published or unpublished scientific papers, or from animal or in vitro testing that would result in a 
safety-related change in the protocol, informed consent, General Investigational Plan section of the IND 
or other aspects of the overall conduct of the trial. 
SUSARs must be reported to the FDA within FDA calendar days; fatal or immediately and must be 
reported to the FDA within 7 calendar days. All of these must also be reported to the NIAID medical 
monitor within 24 hours so that s/he can report to the NIAID/DAIT DSMB within the same 15 or 7 day 
timeframe. The site principal investigator must report SAEs to their respective IRBs as mandated by 
them. The site principal investigator must report SAEs to their respective IRBs as mandated by them. 
To report a SUSAR, a finalized, initial SAE case report form (Appendix 2) and a MedWatch 3500A form 
will be generated by the site Principal Investigator and must be approved by the NIAID Medical Monitor.   
  
Any findings from studies that suggests a significant human risk  
 
The IND sponsor, Dr. Nadeau,  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.   
 
12.5.3.  Reporting of Adverse Events to IRBs/IECs 
The site investigator 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. Nadeau.  
   12.6.   
Pregnancy Reporting 
The investigator shall be informed immediately of any pregnancy in a study subject who has initiated study 
treatment. 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: 

48 
 
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. 
Any complication to pregnancy such as a congenital abnormality or birth defect shall be submitted as an SAE to 
the DAIT/NIAID using the SAE reporting procedures described above and to the FDA. 
12.7.  Reporting of Other Safety Information 
The site 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 chair compiling new and 
accumulating information on AEs, SAEs, and pregnancies recorded by the study site(s) on appropriate paper 
CRFs. 
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 NIAID Allergy and Asthma 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 submitted to the FDA. 
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 NIAID Medical Monitor. In addition, the following events will trigger an ad hoc comprehensive 
DSMB Safety Review:  
o 
Any death that occurs in the study. 
o 
The occurrence of the same unexpected SAE in 3 or more of the study participants who have 
received a study treatment. 
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 and/or Drug Dosing for ad hoc DSMB Safety 
Review  
A temporary halt in enrollment and/or 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.   

49 
 
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 double blind, randomized, placebo controlled study in peanut-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. 
The 120 enrolled subjects will be randomized 2.4:1.4:1. Thus, there will be three arms: (1) Arm A (60 subjects) 
on peanut OIT until week 104 and once meeting criteria [i.e.  1) assigned to OIT treatment for minimum 104 weeks, 2) 
reaching maintenance 13 weeks prior to DBPCFC at week 104 3) no severe reactions (Grade 3, APPENDIX 4) to home dosing 
from Week 92-Week 104, and/or 4) no objective reactions, (Appendix 4) at the Week 104 DBPCFC]   has been assigned to 
avoid peanut (i.e. 600 mg oat flour). (2) Arm B (35 subjects) on peanut OIT until week 104 and once meeting 
criteria, has been assigned to be maintained on 300 mg peanut protein (i.e. 600 mg peanut flour). (3) Arm C (25 
subjects) that is maintained on placebo (oat flour) and once meeting criteria, will receive 600 mg oat flour 
beginning on week 104. This will be true even if a subject in the placebo group meets criteria at week 104. This 
way all participants will receive approximately the same volume of flour so that the subject blinding will be 
easier to maintain. The decision to maintain subjects on only 300 mg peanut protein after week 104 is for ease 
of eating peanut for so long.  This upfront randomization is performed because our statistical analysis plan is 
focused on intent-to-treat principles.     
The primary analysis is an intent-to-treat comparison of success rates between arms A and C, where success is 
defined by reaching and passing the DBPCFC at both 104 weeks and 117 (or equivalent) weeks. 
 
 
 
13.2. Endpoints 
 
Primary Endpoint 
• 
Proportion of peanut allergic subjects who pass a DBPCFC after the 3 month avoidance period 
(Week 117 or equivalent) following the end of active treatment phase.  
 
Measurement: A DBPCFC is considered a “pass” if the subject has no clinical reactivity during the challenge 
(from administration of first dose through observation period lasting 2 hours after administration of the final 
dose). 
Secondary Endpoints: 
• 
Proportion of PA subjects who pass a DBPCFC after a 6 month avoidance period. 
• 
Proportion of PA subjects who pass a DBPCFC after a 9 month avoidance period. 
• 
Proportion of PA subjects who pass a DBPCFC after a 12 month avoidance period. 
• 
Proportion of PA subjects who can successfully complete the build-up phase of peanut OIT to the 
highest dose (4,000 mg of peanut protein) with only mild (Objective, APPENDIX 4) symptoms  

50 
 
• 
Proportion of PA subjects who can successfully undergo the build-up and maintenance phases of 
peanut OIT with only mild symptoms. 
• 
Comparison of the proportion of subjects in placebo, avoidance, and 300 mg peanut protein groups 
who are able to undergo DBPCFCs with no clinical reactivity after initiating OIT. 
 
Measurement of Secondary Endpoints:  For measurement of Bullets 1-3 and Bullet 6, see Measurement of 
Primary Endpoint above.  Data for measurement of Bullets 4 and 5 will be collected from subject diaries, 
reviewed at every updosing visit attempt and DBPCFC visit conducted after successful completion of the Initial 
Dose Escalation Day. 
13.3. 
Measures to Minimize Bias 
This study will employ a randomized, double-blind, placebo controlled design (peanut OIT vs. placebo OIT).  
13.4. Analysis Plan 
13.4.1 Analysis Populations 
• 
Intent-to-treat (ITT) sample: All subjects who are randomized will comprise the ITT sample. 
 
• 
Safety sample: All enrolled subjects who receive at least one dose of OIT or placebo.  Participants in the 
safety sample will be analyzed according to the treatment they actually received, regardless of their 
randomized assignment. 
13.4.2 
Primary Analysis of Primary Endpoint(s)/Outcome(s)   
The primary analysis is an ITT comparison of success rates between arms A and C (defined in Section 
13.1), where success is defined by reaching and passing the DBPCFC at Week 117 (or equivalent).  An 
unevaluable test will be considered a failure.  The analysis will be performed using the binomial test of 
proportions.  A two-sided alpha level of 0.05 will be used.  The success rate in each of the three arms will 
also be estimated, with 95% exact binomial confidence interval. 
13.4.3 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s)  
If any relevant covariates are imbalanced between arms A and C, the primary comparison will also be 
performed using a multivariable logistic regression model controlling for those variables. 
The primary comparison will be repeated between arms A and B, using the binomial test of proportions 
with two-sided alpha level of 0.05. 
13.4.4 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) 
The following proportions will be estimated, with 95% exact binomial confidence intervals: 
• 
Proportion in arm A who pass the DBPCFC week 130, 143, and 156 of peanut avoidance,  
• 
Proportion, in arms A and B combined, who can successfully complete the build-up phase of 
peanut OIT to the highest dose (4,000 mg of peanut protein) with only mild (Objective, 
APPENDIX 4) symptoms, 
• 
Proportion, in arms A and B combined, who can successfully undergo the build-up and 
maintenance phases of peanut OIT with only mild symptoms, 
• 
Proportion, in arms A and B combined, defined as treatment failures at initial dose escalation or 
at 1000 mg protein,   
• 
Proportions, in arms A and B separately, who are defined as desensitization failures at week 117 
(or equivalent), 130, 143, and 156, and 

51 
 
• 
Proportion, in arm A who are defined as tolerance failures at week 117 (or equivalent), 130, 143, 
and 156. 
Adverse events will be tabulated, using the safety sample. 
13.4.5 
Analyses of Exploratory Endpoint(s)/Outcome(s) 
We will use blood samples and clinical outcome measurements from this study to identify specific 
features of the immune response that are associated with ”clinical tolerance” at week 104, 117 (or 
equivalent), 130, 143, and 156.  We will also determine special immune features associated with 
subjects who are desensitized at week 104, 117 (or equivalent), 130, 143, and 156. It will be important 
to compare any of the immune features to those of the placebo arm, treatment failures, tolerance 
failures, and desensitization failures.  This exploratory objective may be examined prior to study 
closeout.  In such a case, only the statisticians will have access to identity of study arm.  Study arm, 
however, will not be a variable in the analysis prior to study closeout.  Instead the outcome of interest 
will be clinical tolerance/desensitization across study arms and the interest will lie in correlating 
molecular features to the outcome. 
A number of post-hoc analyses for predicting clinical outcomes will be completed looking at clinical and 
mechanistic variables. 
13.4.6 
Descriptive Analyses  
Descriptive statistics (proportions for categorical variables, means and standard deviations for 
continuous variables) will be reported for all key participant variables, including baseline and 
demographic characteristics, use of medications, compliance, and study completion status. 
13.5.1 Interim Analyses  
N/A – There will be no interim analyses in this protocol. 
Although no formal interim analyses are specified, we will examine one set of exploratory 
objectives prior to study closeout that do not involve our primary efficacy endpoint, nor do they 
reveal data by study arm.  Specifically, the outcome of interest will be clinical 
tolerance/desensitization aggregated across study arms and the interest will lie in correlating molecular 
features to the outcome. 
 
13.6. Statistical Hypotheses  
For the primary comparison, the following will be tested: 
• 
Null hypothesis: The success rate (where success is passing the DBPCFC at both 104 and 117 (or 
equivalent) weeks) is equal in arms A (active treatment followed by 3 months of avoidance) and C 
(placebo). 
• 
Alternative hypothesis: The success rate differs between arms A and C. 
As a secondary comparison, the following will be tested: 
• 
Null hypothesis: The success rate is equal in arms A and B (active treatment followed by 3 months of 
300mg peanut protein treatment). 
• 
Alternative hypothesis: The success rate differs between arms A and B. 
13.7. Sample Size Considerations  
In the previous trial by Burks et al, 2013 the rate of success among subjects treated as in arm A was 0.35.  
Literature (Sampson, et al. 2013) suggests that the rate of success among subjects on placebo (as in arm C) is 

52 
 
0.05 or less.  Using a binomial test of proportions with two-sided alpha level 0.05, the sample size of 60 
subjects on arm A and 25 subjects on arm C yields 90% power to detect that difference (between rates of 0.35 
and 0.05).  According to the definition of the endpoint – passing the DBPCFC at both 104 and 117 (or 
equivalent) weeks – subjects who drop out of the study are included in the analysis (counted as failures).  
Therefore, the analysis will include all subjects randomized to arm A or arm C, and the sample size is not 
decreased due to drop-outs. 
The following table displays the power for other possible success rates in the two arms. 
 
Arm C Population Success Rate 
0.025 
0.05 
0.075 
Arm A 
Population 
Success 
Rate 
0.25 
76% 
59% 
44% 
0.30 
89% 
77% 
64% 
0.35 
96% 
90% 
80% 
0.40 
99% 
96% 
91% 
0.45 
100% 
99% 
97% 
 
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, assessments 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 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 investigator and site staff will make all source data available to the PPD Monitor, DAIT/NIAID, as well as to the 
FDA.  Authorized representatives as noted above are bound to maintain the strict confidentiality of medical and 
research information that may be linked to identify 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, approved by the 
NIAID and then implemented promptly. 
 
Major Protocol Deviation - A major protocol deviation 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, 
major protocol deviations 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 

53 
 
regulations, policies, or procedures.  This also includes departures from GCPs and pharmacy handling of the 
investigational product and accountability. 
 
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 NIAID (Appendix 3).  However, protocol deviations may also be identified during site monitoring visits 
conducted by the PPD monitor, or during other forms of study conduct review.  
Deviations from the protocol will be reviewed by the NIAID project manager, on a case-by-case basis, to determine if the 
deviation meets major or non-major criteria.  All protocol deviations and the reasons for such deviations must be noted 
on the appropriate CRF. 
Protocol Deviation reports will be submitted by study site personnel in accordance with requirements from the local IRB, 
the FDA, and the NIAID.  Action plans to prevent deviations going forward will be reviewed and approved by the NIAID 
Project Manager and Medical Monitor. 
16. Ethical Considerations and Compliance with Good clinical Practice 
16.1. Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance, and according to the criteria specified in this study protocol.  Before study 
initiation, the protocol and the informed consent documents will be reviewed and approved by the 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 study physician listed on the FDA 1572 
will review the consent and answer questions with the potential participant and the study physician must sign the 
consent form with the participant and document the informed consent process.  For minors participating in this study, 
informed consent will be obtained from their parent(s) or legal guardian(s).  Minors participating in this study will 
provide assent if they are capable.  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 

54 
 
Every possible effort will be made for the primary outcome of the trial to be published in a peer-reviewed journal within 
12 months after the database is locked.  The DAIT/NIAID will review and comment on any manuscript derived from this 
trial prior to submission and the NIH data sharing policy 
(http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals).  Data from this trial will be 
shared in accordance to the specific plan that was included in the grant application.]     
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Nadeau KC, Egholm M, Miklos DB, Zehnder JL, Fire AZ: Measurement and clinical monitoring of human lymphocyte 
clonality by massively parallel VDJ pyrosequencing. Sci Transl Med 2009, 1:12ra23. 2819115 
42. Gernez Y, Tirouvanziam R, Reshamwala N, Yu G, Weldon BC, Galli SJ, Herzenberg LA, Nadeau KC: Modulation of 
mTOR Effector Phosphoproteins in Blood Basophils from Allergic Patients. J Clin Immunol 2012, DOI: 
10.1007/s10875-10012-19651-x.  

56 
 
43. Gernez Y, Tirouvanziam R, Yu G, Ghosn EE, Reshamwala N, Nguyen T, Tsai M, Galli SJ, Herzenberg LA, Nadeau KC: 
Basophil CD203c levels are increased at baseline and can be used to monitor omalizumab treatment in subjects with 
nut allergy. Int Arch Allergy Immunol 2011, 154:318-327. 3214954 
44. Ta V, Weldon B, Neale-May S, Yu G, Humblet O, Nadeau KC: Use of Specific IgE and Skin Prick Test to Determine 
Clinical Reaction Severity. British J  Med 2011, 1:410-429.  
45. Ewenstein BM, Hoots WK, Lusher JM, DiMichele D, White GC, 2nd, Adelman B, Nadeau K: Inhibition of CD40 
ligand (CD154) in the treatment of factor VIII inhibitors. Haematologica 2000, 85:35-39.  
46. Huang J, and Nadeau, K.: Oral Presentation. "mTOR inhibition increases pSTAT5 in Treg in Immunodeficiency". 
Primary Immunodeficiency Conference 2010, Clinical Immunological Society:Penn.  
47. Nadeau K, McDonald-Hyman, C., Pratt, B., Noth, B., Hammond, K.,Balmes, J. and Tager, I: Ambient air pollution 
impairs regulatory T-cell function in asthma. J Allergy Clin Immunol 2010, 126:845-852.e810.  
48. Nguyen KD, Vanichsarn C, Nadeau KC: Increased cytotoxicity of CD4+ invariant NKT cells against 
CD4+CD25hiCD127lo/- regulatory T cells in allergic asthma. Eur J Immunol 2008, 38:2034-2045.  
49. Kim YM, Munoz A, Hwang PH, Nadeau KC: Migration of regulatory T cells toward airway epithelial cells is 
impaired in chronic rhinosinusitis with nasal polyposis. Clin Immunol 2010, 137:111-121.  
50. Nguyen KD, Vanichsarn C, Nadeau KC: Impaired IL-10-dependent induction of tolerogenic dendritic cells by 
CD4+CD25hiCD127lo/- natural regulatory T cells in human allergic asthma. Am J Respir Crit Care Med 2009, 180:823-
833 
 
 
 
 

57 
 
Appendix 1: Schedule of Events  
Study Stage 
Screening 
IDED* 
Build-up Phase  
 
Time  
Week**** 
Day -300 
to Day 0 
Day 0 
2 
4 
6 
8 
10 
12 14 16 18 20 22 24 
26 
28 
Visit # 
X 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 
13 
14 
Informed Consent** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peanut/Placebo Dosing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total IgE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peanut Specific IgE and 
IgG4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peanut skin testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mechanistic labs 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Serum or urine test*** 
pregnancy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Spirometry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening DBPCFC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-Study DBPCFC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diaries 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EpiPen® Training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Initial Dose Escalation Day 
**Informed consent obtained prior to completion of any study procedures ^Subjects return for up-dosing every 2 weeks.  Blood to be obtained every 12 weeks 
***Urine pregnancy test to be performed preferentially.  Serum pregnancy test to be performed to confirm positive urine results, if any. 
****Week number may be + or – 2 weeks. 
 
 
 
 
 

58 
 
Appendix 1 (cont’d) 
Study Stage 
Build-up Phase (Week #) 
Maintenance Phase  
Early Completion 
Time 
Week**** 
30 
32 
34 
36 
38 
40 
42 
44 
52 
65 
78 
91 
104 
117
^ 
130 
143 
156 
Withdrawal/ 
Early Termination 
Visit # 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
Informed Consent** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peanut/Placebo Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Total IgE 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peanut Specific IgE and IgG4 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peanut skin testing 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mechanistic labs 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum or urine pregnancy*** 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Spirometry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Screening DBPCFC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-Study DBPCFC† 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Diaries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EpiPen® Training 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
†First On-study DBPCFC to 4,000 mg performed at Week 104 in all subjects. Participants meeting criteria at week 104 (Part IV, Figure 1) may also have DBPCFCs at 
Weeks 117 (or equivalent), 130, 143, and 156. 
 
^ Possible  early completion visit for those participants who demonstrate objective allergic reactions (Appendix 4) at week 104 DBPCFC.

59 
 
Appendix  2: 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): 
 
 
 
 
 
 
 
 
 
 

60 
 
 
 
 
 
 
 
 
 
 
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:   

61 
 
 
 
 
 
 
 
Action taken:  Describe action taken in regard to Investigational Product (s) and the management of the event) 
 
 
 
 
 
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 

62 
 
Appendix  3: 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) : 
      
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) : 
 
      

63 
 
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 
 
 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
9. Was continuation form used? 
YES  
   NO  
 
 
 
 
 
 
_______________________    _______           ___________________________   _______ 
Principal Investigator 
 
          Date  
 
Independent Medical Monitor      Date 
 
 
 
 
 
 
 
 
 
   (if applicable) 
 
For NIAID Use 
 
Date Notified 
NIAID Project Manager 
      
Independent Medical Monitor (if applicable) 
      
IRB (if applicable) 
 
      

64 
 
 
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 4: Scoring of Clinical Food Allergic Reactions using objective criteria 
Symptoms and/or Signs of an Objective (in bold) Allergic Reaction (Bock Scoring Challenge).  
Category  
 
Grade and Symptom(s)  
Skin  
 
 
           Rash  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Few areas of faint erythema  
 
Grade 2:  
Areas of erythema, macular and raised rash  
 
Grade 3:  
Generalized marked erythema (>50%); extensive  
 
 
raised lesion (>25%); vesiculation and/or  
 
 
piloerections  
           Pruritus  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Occasional scratching  
 
Grade 2:  
Scratching continuously for >2 minutes at a time  
 
Grade 3:  
Hard continuous scratching leading to excoriations  
           Urticaria  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
<3 Hives  
 
Grade 2:  
3 to <10 Hives  
 
Grade 3:  
Generalized involvement  
           Angioedema  Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
One site of angioedema  
 
Grade 2:  
Two or more sites of angioedema  
 
Grade 3:  
Generalized involvement, including airway  
 
 
involvement  

65 
 
Nasal  
 
 
          Sneezing  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Rare bursts of sneezing  
 
Grade 2:  
<10 bursts of sneezing  
 
Grade 3:  
Continuous rubbing of nose and/or eyes; periocular 
swelling &/or long bursts of sneezing  
 
 
 
 
Grade 1-mild, Grade 2-moderate, Grade 3-severe 

66 
 
Appendix 4 (cont’d) 
Symptoms and/or Signs of an Allergic Reaction (Bock Scoring Challenge)  
 
Category  
 
Grade and Symptom(s)  
      Nasal itching  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Mild itching  
 
Grade 2:  
Intermittent rubbing of nose or eyes  
 
Grade 3:  
Continuous rubbing of nose and/or eyes; periocular  
 
 
swelling and/or long bursts of sneezing  
      Nasal congestion  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Some hindrance to breathing  
 
 Grade 2:  
Nostrils feel blocked, breathes through mouth most  
 
 
of the time  
 
Grade 3:  
Nostrils occluded  
      Rhinorrhea  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Occasional sniffing  
 
Grade 2:  
Frequent sniffing, requires tissues  
 
Grade 3:  
Nose runs freely despite sniffing and tissues  
    Airway obstruction  Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Voice change mild  
 
Grade 2:  
Voice change moderate  
 
Grade 3:  
Voice change severe  
Chest  
 
 
     Wheezing  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Expiratory wheezing to auscultation or 15% decrease  
 
 
from highest FEV1 value observed on study or FEV1 
≤65%  
 
Grade 2:  
Dyspnea, inspiratory, and expiratory wheezing  
 
Grade 3:  
Dyspnea, use of accessory muscles, audible  
 
 
wheezing  
 

67 
 
Appendix 4 (cont’d) 
 
 
 
Symptoms and/or Signs of an Allergic Reaction (Bock Scoring Challenge)  
Category  
 
Grade and Symptom(s)  
Abdomen  
 
 
     Nausea  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
Mild complaint of nausea  
 
Grade 2:  
Frequent complaint of nausea  
 
Grade 3:  
Nausea causing notable distress  
   Abdominal pain  
Grade 0:  
Sign or symptom not observed  
 
    Grade 1:  
Complaint of abdominal pain  
 
Grade 2:  
Frequent complaints of abdominal pain, decreased 
activity   
 
Grade 3:  
In bed, crying, or notably distressed  
     Emesis  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
1 Episode of emesis  
 
Grade 2:  
2–3 Episodes of emesis or 1 of emesis and 1 of  
 
 
diarrhea  
 
Grade 3:  
>3 Episodes of emesis or ‡2 of emesis and ‡2 of  
 
 
diarrhea  
     Diarrhea  
Grade 0:  
Sign or symptom not observed  
 
Grade 1:  
1 Episode of diarrhea  
 
Grade 2:  
2–3 Episodes of diarrhea or 1 of emesis and 1 of  
 
 
diarrhea  
 
Grade 3:  
>3 Episodes of diarrhea or ≥2 of emesis and ≥2 of  
 
 
diarrhea  
 
 
Bock SA, Sampson HA, Atkins FM, Zieger RS, Lehrer S, Sachs M, et al.  Double-blind, placebo-controlled food challenge 
(DBPCFC) as an office procedure: a manual. J Allergy Clin Immunol 1988;82:986–97. 
 
 
 
 

68 
 
 
 
 
 
 
 
Appendix 5: EpiPen Training Form 
 
EpiPen Training Form 
By signing the EpiPen 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 
 
 
____________________________________________ 
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) 
 

69 
 
Appendix 6: Evaluation of Asthma 
The evaluation of asthma severity will be assessed using the NHLBI classification published August 18, 2007 as described 
in the table below. 
Classification 
Symptoms 
Nighttime 
awakenings 
Lung Function 
Interference 
with normal 
activity 
Short acting beta-
agonist use 
Intermittent 
(Step 1) 
< 2 days per week 
< 2x /month Normal FEV1 between 
exacerbations 
FEV1>80% predicted 
FEV1/FVC normal* 
None 
<2 days /week 
Mild 
Persistent 
(Step 2) 
> 2 days per week 
but not daily 
 
3-4x 
/month 
FEV1 > 80% predicted 
FEV1/FVC normal* 
Minor 
limitation 
>2 days  /week but not 
>1x/day 
Moderate 
Persistent 
(Step 3 or 4) 
Daily  
> 1x /week 
but not 
nightly 
FEV1 >60% but <80% 
predicted 
FEV1/FVC reduced 
5%* 
Some 
limitation 
Daily 
Severe 
Persistent 
(Step 5 or 6) 
Throughout the day 
Often 7x 
/week 
FEV1<60% predicted 
FEV1/FVC reduced 
>5%* 
Extremely 
limited 
Several times per day 
*Normal FEV1/FVC: 8-19 yr = 85%; 20-39 yrs = 80 
 
 
 
 
 
 
 
 
 
 
 
 

70 
 
Appendix 7: Sample Certificate of Analysis for Peanut Flour 
 
 
Appendix 8: Open Label Follow-Up 
 

71 
 
An open label protocol will be offered to placebo subjects, desensitization failures, and treatment failures.   This 
separate study will mainly focus on collecting safety data and will be conducted as per IND 14830. 
List of Tables 
Table 1: Peanut Protein or Oat Protein (Placebo) Dosage Escalation Schedule on the Initial Dose Escalation Day 
 
Table 2: Daily Peanut Protein Dosing and Increase Schedule for Build-Up Phase 
 
Table 3: Visit Windows 
Table 4: Serum Assays 
Table 5: Expected Results for Serum Parameters 
Table 6: Cell Components for CyTOF Parameters 
Table 7: Expected Results for Cell Parameters 
Table 8: Expected Results for Basophil Activation Parameters 
 
 
List of Figures 
 
Figure 1: Study Flow Chart 
 
Figure 2: Manufacturing Flow Diagram 
Figure 3: Management of Symptoms During Initial Dose Escalation Day 
 
List of Appendices 
Appendix  1: Schedule of Events 
Appendix  2: Sample Serious Adverse Event Form 
Appendix  3: Sample Deviation Report Form 
Appendix 4: Scoring of Clinical Food Reactions  
Appendix 5: EpiPen Training Form 
Appendix 6: Evaluation of Asthma 
 
Appendix 7: Sample Certificate of Analysis for Peanut Flour 
 
Appendix 8: Open Label Follow-Up