Conditions: Peanut Allergy
Keywords: Peanut
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
The purpose of this trial is to study the safety of rescue peanut oral immunotherapy followed by the introduction of dietary peanut for patients with peanut allergy who have lost desensitization during a peanut immunotherapy trial.

Detailed description:
Salvage Peanut Oral Immunotherapy Study is a single-arm, open label trial of peanut flour oral immunotherapy (OIT) administered for 6 months followed by introduction of dietary peanut for an additional 6 months.

The peanut OIT phase will involve approximately 3 months of dose escalation up to a maintenance dose of 300 mg peanut protein. This is followed by 3 months of daily maintenance dosing with 300 mg of peanut protein. Patients are then transitioned to the dietary peanut phase ingesting common foods containing approximately 300 mg of peanut protein daily.

Safety will be assessed during both peanut OIT and dietary peanut phases with adverse events recorded including gastrointestinal side effects. They will also be monitored for any anaphylaxis or injectable epinephrine administration. Data regarding compliance with peanut OIT will be collected as well.

Arms:
arm 1: Single arm study with all subjects receiving peanut OIT study drug for the initial 6 months. This is followed by daily ingestion of common dietary foods containing approximately 300 mg of peanut protein for an additional 6 months.

Interventions: intervention 1: Peanut OIT
Intervention descriptions: intervention 1: Participants will be given increasing doses of the peanut flour as peanut oral immunotherapy (OIT) with increasing doses every 2 weeks over a period of 3 months up to a 300 mg target dose. This 300 mg peanut OIT maintenance dose is then continued daily for 3 months. Participants will then introduce dietary peanut of approximately 300 mg of peanut protein and continue daily ingestion for an additional 6 months.

Protocol document:
Prot_SAP_000.pdf: 
STUDY PROTOCOL 
 
Salvage Peanut Oral Immunotherapy Study: A single-arm, open label  
trial of peanut flour with 6 month active treatment and 6 month  
follow-up 
 
 
NCT number NCT03251508 
Document Date 07/17/2018 
 


 
Page 1     
 
 
Salvage Peanut Oral Immunotherapy Study: A single-arm, open label 
trial of peanut flour with 6 month active treatment and 6 month 
follow-up 
 
 
PRINCIPAL 
INVESTIGATOR   
Dr.  Edwin Kim 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to 
investigators, potential investigators, consultants, study staff, and applicable 
independent ethics committees or institutional review boards.  The contents of 
this document shall not be disclosed to others without written authorization 
from Dr. Kim, unless it is necessary to obtain consent from potential study 
participants. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 2     
 
 
 
 
 
Version  3.0 
Date: July 17, 2018  
 
Principal Investigator 
Dr. Edwin Kim 
Short Title:    Salvage peanut oral immunotherapy  (SOIT)  
 
I have read protocol and I approve it. As the principal investigator, I agree to conduct this protocol according to Good 
Clinical Practice (GCP), as delineated in the United States Code of Federal Regulations (CFR) – 21 CFR Parts 50, 54, 56 
and 312 and in the International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) “Guidance for Industry: E6 Good Clinical Practice Consolidated Guidance” 
(June 1996 (R1) and November 2016 (R2)), and according to the criteria specified in this protocol. Furthermore, I will 
conduct this protocol in keeping with local, state and federal requirements 
 
_______________________________                                     
Principal Investigator (Print)                                                     
 
_______________________________                                    _______________ 
Principal Investigator (Signature)                                            Date 
 
 
 
 


 
Page 3     
 
TABLE OF CONTENTS 
Synopsis .................................................................................................................................................... 5 
Glossary of Abbreviations .................................................................................................................. 8 
1.BACKGROUND AND RATIONALE ................................................................................................... 9 
A.Background ...................................................................................................................................................... 9 
B.Rationale ........................................................................................................................................................... 9 
2.POTENTIAL RISKS AND BENEFITS ............................................................................................. 11 
A.Risks ................................................................................................................................................................ 11 
B.Benefits ........................................................................................................................................................... 12 
3.OBJECTIVES AND OUTCOME MEASURES .................................................................................. 12 
A.Objectives ...................................................................................................................................................... 12 
B.Outcome Measures ..................................................................................................................................... 12 
4.SELECTION AND WITHDRAWAL OF PARTICIPANTS ........................................................... 13 
A. Inclusion Criteria ....................................................................................................................................... 13 
B. Exclusion Criteria ...................................................................................................................................... 13 
C. Premature Withdrawal Criteria ........................................................................................................... 14 
D. Study termination criteria ..................................................................................................................... 15 
5.STUDY DESIGN AND SCHDULE ..................................................................................................... 15 
A. Location ......................................................................................................................................................... 15 
B. Duration of enrollment ............................................................................................................................ 16 
C. Duration of the study per participant ................................................................................................. 16 
D. Study visits ................................................................................................................................................... 16 
1. Screening and baseline visit ................................................................................................................................ 16 
2. Escalation phase ....................................................................................................................................................... 16 
3. Build up phase ........................................................................................................................................................... 17 
4. Maintenance phase .................................................................................................................................................. 18 
5. Peanut food equivalent phase ............................................................................................................................. 19 
E. Handling adverse reactions and follow up during home dosing .............................................. 19 
F. Managing missed doses............................................................................................................................ 20 
G. Monitoring of side-effects, adverse events, and clinical changes ............................................. 20 
6. STUDY PROCEDURES ..................................................................................................................... 20 
A. History taking, physical exam and peanut oral immunotherapy administration .............. 20 
B. Skin Prick Testing (optional) ................................................................................................................ 21 
C. Blood draw: .................................................................................................................................................. 21 
Venous blood may be obtained during the study for serum based assays (including but 
confined to serum peanut specific IgE). No more than 2 cc/kg of body weight will be 
collected during any blood draw. ............................................................................................................. 21 


 
Page 4     
 
D. Spirometry ................................................................................................................................................... 21 
E. Saliva collection (optional-subject to the investigator discretion) ......................................... 22 
F. Compliance sheets ..................................................................................................................................... 22 
G. Urine pregnancy test ................................................................................................................................ 22 
7. Study agent ....................................................................................................................................... 23 
A. Formulation, packaging and labeling ................................................................................................. 23 
B. Preparation, administration and dosage .......................................................................................... 23 
C. Starting dose and escalation schedule ............................................................................................... 23 
D. Dose adjustment ........................................................................................................................................ 23 
E. Duration of therapy ................................................................................................................................... 24 
F. Rescue medication and concomitant medication ........................................................................... 24 
8. SAFETY MONITORING ................................................................................................................... 24 
A. Definitions .................................................................................................................................................... 24 
B. Toxicity Grading ......................................................................................................................................... 25 
C. Relationships to Procedure Definitions ............................................................................................. 28 
D. Adverse Events Collection Procedures .............................................................................................. 29 
E. Serious Adverse Event Notification ..................................................................................................... 30 
F. Notifying the IRB and DSMB ................................................................................................................... 31 
G. Reporting Criteria ..................................................................................................................................... 31 
9. MECHANISTIC ASSAYS ................................................................................................................... 31 
10. Statistical Considerations and Analysis Strategy.............................................................. 32 
A. Interim and Final Analyses .................................................................................................................... 32 
B. Plans for Each Specific Aim .................................................................................................................... 33 
C. CHOICE OF SAMPLE SIZE .......................................................................................................................... 35 
11. Data management and data handling: .................................................................................. 35 
A.  RESEARCH DATA MANAGEMENT ........................................................................................................ 35 
B.  Plan for Ensuring Confidentiality ....................................................................................................... 36 
C. Plan for Ensuring Data Security ............................................................................................................ 36 
D. Plan for Quality Assurance ..................................................................................................................... 36 
E. Data Handling Procedures ...................................................................................................................... 37 
F. Risk of Deductive Disclosure ................................................................................................................. 38 
12. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE
 ................................................................................................................................................................... 39 
A.Statement of Compliance ......................................................................................................................... 39 
B.Consent and Assent .................................................................................................................................... 39 
C.Privacy and Confidentiality ..................................................................................................................... 39 
 
 


 
Page 5     
 
 
SYNOPSIS 
 
Title 
Salvage Peanut Oral Immunotherapy Study: A single-arm, open 
label trial of peanut flour with 6 month active treatment and 6 
month follow-up 
Short Title 
Salvage peanut oral immunotherapy  (SOIT) 
Clinical Phase 
Phase II  
Sponsor 
Wesley Burks MD 
Principal 
Investigator  
Dr. Edwin Kim 
Participating Site 
The University of North Carolina at Chapel Hill 
Accrual Period 
2 years  
Purpose 
The primary purposes of the study are (1) to provide salvage 
therapy for individuals who previously participated in a peanut 
immunotherapy trial but did not demonstrate clinically 
significant desensitization, (2) to investigate the safety and 
tolerability of the salvage therapy regimen including both 
peanut flour and peanut flour equivalent, and (3) to explore 
mechanisms responsible for long-term desensitization and/or 
tolerance to food allergens induced by immunotherapy.   
Study Design 
This uncontrolled, observational, prospective, open-label study 
will be used to assess the safety and tolerability of a two-stage 
salvage therapy regimen:  (a) peanut oral immunotherapy (OIT) 
followed by (b) extended maintenance with a peanut food 
equivalent.           
Participants 
We will enroll up to 100 eligible subjects who (1) did not 
demonstrate clinically significant desensitization in previous 
peanut immunotherapy trials, or (2) previously endured an 
extended time on placebo therapy, or (3) previously developed 
desensitization and then subsequently lost this protection due to 
time off from therapy.  
Choice of Sample 
Size 
The choice of sample size is based entirely on the ethical 
necessity of providing therapy to a pre-defined number of 


 
Page 6     
 
individuals in need of salvage therapy.  We anticipate that up to 
100 eligible subjects will be enrolled to receive the salvage 
therapy treatment regimen. 
Study Duration 
Approximately 12 months for each participant.  
Primary Outcomes 
• Overall incidence rate of adverse events (including both AEs 
and SAEs) during the entire 2-stage treatment sequence  
• Overall number of days of treatment missed during the entire 
2-stage treatment sequence 
Secondary 
Outcomes 
• Stage-specific incidence rate of all adverse events  
• Days of treatment missed during each stage of treatment.  
• Overall incidence rate of gastrointestinal AEs during the 
entire 2-stage treatment sequence.  
• Overall incidence rate of Epipen use 
•  Overall incidence rate of drop-outs due to gastrointestinal 
AEs during the entire 2-stage treatment sequence.  
Exploratory 
Measures 
• Changes in basophil, T cell, and antibody responses in 
peripheral blood and saliva samples (to explore the 
mechanisms responsible for long-term desensitization and/or 
tolerance to food allergens induced by immunotherapy.) 
Inclusion Criteria 
• Subjects who have completed an immunotherapy trial for 
peanut allergy within the last 18 months and are unable to 
tolerate ≥ 300mg of peanut. 
• Age 1-65 years of either sex, any race, any ethnicity. 
• Written informed consent from patient or parent/guardian (if 
< 18 years) with participant’s assent.  
Exclusion Criteria 
• Current participation in an interventional study for peanut 
allergy  
• History of a severe anaphylactic reaction to peanut, defined as 
hypoxia, hypotension, or neurologic compromise (cyanosis or 
SpO2 < 92% at any stage, hypotension, confusion, collapse, 
loss of consciousness, or incontinence) 


 
P a g e 7     
 
•  E osi n o p hilic or ot h er i nfl a m m at or y ( e. g. c eli ac) 
g astr oi nt esti n al dis e as e  
•  S e v er e ast h m a ( 2 0 0 7 N H L BI Crit eri a St e ps 5 or 6 – A p p e n di x 
2)  
•  Us e of -bl oc k ers ( or al), a n gi ot e nsi n -c o n v erti n g e n z y m e 
( A C E) i n hi bit ors, a n gi ot e nsin- r ec e pt or bl oc k ers ( A R B) or 
c alci u m c h a n n el bl oc k ers  
•  Si g nific a nt m e dic al c o n diti o n ( e. g., li v er, ki d n e y, 
g astr oi nt esti n al, c ar di o v asc ul ar, h e m at ol o gic, or p ul m o n ar y 
dis e as e) w hic h w o ul d p ut t h e s u bj ect at ris k f or i n d ucti o n of 
s e v er e f o o d r e acti o ns. 
•  Pr e g n a nc y or l act ati o n .  
St u d y P r o c e d u r e s  
T h e f oll o wi n g pr oc e d ur es will b e p erf or m e d:  
•  M e dic al a n d all er g y hist or y (i ncl u di n g di et ar y hist or y)  
•  P h ysic al e x a mi n ati o n  
•  P e a k fl o w r at es (if c a p a bl e)  
•  Or al i m m u n ot h er a p y ( OI T)  
•  S er u m a n al ysis f or p e a n ut -s p ecific i m m u n o gl o b uli ns 
(I m m u n o C A P) ( o pti o n al) 
•  P e a n ut s ki n pric k t esti n g ( o pti o n al)  
•  S ali v a c oll ecti o n ( o pti o n al)  
•  Pr e g n a nc y t est f or f e m al es i n c hil d b e ari n g a g e.  
 
 
 
 
 
 
 
 
 


 
Page 8     
 
 
 
 
GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse Event 
CTCAE 
Common Toxicity Criteria Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTRC 
Clinical Translational Research Center 
DBPCFC 
Double Blind Placebo Controlled Food Challenge 
DSMB 
Data Safety Monitoring Board 
FASC 
Food Allergy Study Center 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HRQL 
Health-Related Quality of Life 
ICH 
International Conference on Harmonization 
IND 
InvestigationalNew Drug 
IRB 
Institutional Review Board 
NIAID 
National Institute of Allergy and Infectious 
Diseases 
OFC 
Oral Food Challenge 
OIT 
Oral Immunotherapy 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SPT 
Skin Prick Test 
SU 
Sustained Unresponsiveness 
UNC 
The University of North Carolina at Chapel Hill 
 
 
 


 
Page 9     
 
 
 
 
1.BACKGROUND AND RATIONALE  
A.BACKGROUND 
Food allergy is a significant public health problem that is increasing in 
prevalence. According to recent CDC data, approximately 4% of children are 
affected by food allergy while 1.3% of the total population is allergic to 
peanut or tree nuts. Despite recent increased recognition and understanding 
of the disease, food allergy is the most common cause of outpatient 
anaphylaxis, and peanut allergy is the most common cause of fatal 
anaphylaxis. In the United States, it is estimated that emergency departments 
treat about 30,000 food-induced anaphylactic events each year, and that 
about 200 fatal cases occur annually.  
 
Currently the only available preventative treatment for food allergy is strict 
avoidance of the allergenic food. Food avoidance involves a lifestyle change 
for families, requiring careful reading of food labels, exercising caution when 
dining at restaurants, and carrying rescue medications at all times. For these 
reasons, food allergy is known to significantly impact the quality of life for 
both patients and their families. These findings stress the importance of 
developing improved therapies for food allergy. 
 
B.RATIONALE 
An increasing number of studies have proved the concept that peanut 
immunotherapy can desensitize subjects with peanut allergy by regulating 
their mucosal and systemic immune reactivity. This has culminated in the 
development of a large phase 3 study of peanut OIT that is currently 
underway with guidance from the US Food and Drug Administration (FDA). 
However, there are important aspects of peanut OIT that remain to be 
studied and are the subject of more recent studies. These include questions 
about the durability of the desensitization effect termed sustained 
unresponsiveness (SU), the effect of peanut OIT in special populations such 
as very young children, and the prevalence of certain side effects such as 
eosinophilic esophagitis. With this gradual shift away from equipoise, a need 


 
Page 10     
 
for providing a salvage therapy option for those who continue to volunteer to 
participate in research studies has become apparent. Two populations of 
particular interest are those who have previously developed desensitization 
and then subsequently lost this protection and those who have been 
randomized to extended courses of placebo drug. 
 
In many current studies of peanut OIT, subjects are initially desensitized and 
then subsequently asked to avoid peanut for a discrete amount of time in 
order to assess the durability of the desensitization effect (sustained 
unresponsiveness). This research is critical to understanding the clinical and 
immunologic changes induced by peanut OIT and longer term implications of 
therapy. However, in the course of these investigations, the potential exists 
for subjects to lose their desensitization to peanut and their protection 
against accidental exposures to peanut. 
 
The majority of current studies of OIT utilize a placebo group, some for 
extended periods of time (> 1 year). These extended placebo courses are vital 
to understanding the efficacy of OIT as up to 20% of peanut-allergic patients 
are thought to naturally develop tolerance to peanut. These subjects are not 
thought to be at any higher risk than those who are strictly avoiding peanut 
which is the current standard of care. However, concerns remain with 
withholding potentially protective treatment for these extended periods of 
time.  
 
The use of investigational drugs to induce and maintain desensitization has 
been and continues to be the subject of numerous ongoing studies. However, 
there has been growing interest in the use of food products to maintain this 
effect with the thought that these readily available foods may allow for 
superior compliance. The safety and compliance with transitioning to a non-
drug equivalent amount of peanut food has not been well studied. 
 
The goals of this study protocol are several-fold.  First and foremost, we 
would like to provide a salvage therapy option for those previously involved 
in vital peanut allergy research.  Simultaneously, we will address three 
research aims: 
 
Aim 1 --Investigate the safety and compliance in the 2-stage protocol 
in subjects who either (a) have previously developed desensitization and 
then subsequently lost this protection due to a period of time off of therapy 
or (b) have previously endured an extended time on placebo therapy.   


 
Page 11     
 
 
Aim 2 -- Characterize and compare the two stages of the protocol in 
terms of safety and compliance.    
 
Aim 3 -- Explore the mechanisms responsible for long-term 
desensitization and/or tolerance to food allergens induced by 
immunotherapy.    
 
In doing this, we aim to add to the accumulating pool of data on the safety of 
OIT while providing a salvage option for these subjects. The data generated 
from our study can guide future research to identify high risk groups for 
peanut oral immunotherapy, and compare safety and compliance between 
peanut OIT and peanut food equivalents. A food equivalent of peanut 
containing food is an available food in the market with known doses of 
peanut protein ( e.g. Reese’s peanut butter cups, Peanut M&Ms, etc.) 
 
2.POTENTIAL RISKS AND BENEFITS  
A.RISKS 
The main risks for participating in this study include: 
1. Allergic symptoms during the initial escalation, build up or maintenance 
phase: including sneezing, rhinorrhea, urticaria, angioedema, flushing, 
eczema flare, nausea, vomiting, diarrhea, abdominal discomfort, cough, 
wheezing, dyspnea, pruritus (ocular, nasal, oral, throat) or anaphylaxis.  
2. Skin prick testing (SPT) is an optional procedure in the study and may 
result in a small, pruritic hive where the test is placed.  Usually, the hives 
resolve within 1-2 hours, but rarely a subject may have local swelling that 
takes two to three days to clear entirely. Very rarely, some individuals 
may develop a serious allergic reaction that is life threatening, but no 
deaths from prick skin testing using standard dosing techniques have 
been reported in fifty years. Skin prick testing will be supervised by a 
physician or nurse coordinator, and rescue medications will be readily 
available if any reaction occurs. 
3. Blood draws for mechanistic studies are an optional procedure in the 
study and result in pain and discomfort, bleeding, bruising where the 
needle is placed, and, in rare cases, fainting and infection.  In order to 
minimize the risk of anemia, the maximum volume of blood to be drawn 
will be less than 2 ml/kg of body weight per visit up to a maximum of 45 
ml in 8-week period for pediatrics and less than 550 ml in an 8-week 


 
Page 12     
 
period for adults. This maximum amount applies for both clinical or 
research purposes: clinical blood draw will be considered prior to 
research blood draw). Blood collection will not occur more than 2 times 
per week.  
 
 
B.BENEFITS 
The benefits from this study include: 
1. The potential of decreasing the participants’ reactivity to peanut after an 
accidental ingestion by developing desensitization to at least an 
equivalent of the daily tolerated maintenance dose (300 mg of peanut 
protein). Most accidental exposures to peanut protein are believed to be 
less than 200 mg. (Schäppi, GF et al. 2001). 
 
2. This study will expand the general knowledge of food allergy. This applies 
specifically to safety of peanut oral immunotherapy and identifying high 
risk groups. This may lead to new management and therapeutic protocols 
for individuals with peanut allergy, or food allergy in general. 
 
3.OBJECTIVES AND OUTCOME MEASURES 
A.OBJECTIVES 
1. The primary objective of this study is to place patients who have been 
involved in peanut immunotherapy research on salvage therapy while 
investigating safety and compliance of oral immunotherapy and food 
equivalent therapy in these patients.  
2. The secondary objectives include:  
a. Investigation of incidence of gastrointestinal adverse event, drop outs, 
and Epipen use.  
b. Investigation of the compliance of participation with peanut OIT and 
peanut food equivalent  
 
B.OUTCOME MEASURES 
1. Primary Outcomes  
• Overall incidence rate of adverse events (including both AEs and SAEs) 


 
Page 13     
 
during the entire 2-stage treatment sequence (OIT followed by peanut 
containing food equivalent) 
• Overall number of days of treatment missed during the entire 2-stage 
treatment sequence 
 
2. Secondary Outcomes 
• Stage-specific incidence rate of all adverse events  
• Days of treatment missed during each stage of treatment.  
• Overall incidence rate of gastrointestinal AEs during the entire 2-stage 
treatment sequence.  
• Overall incidence rate of Epipen use 
• Overall incidence rate of drop-outs due to gastrointestinal AEs during 
the entire 2-stage treatment sequence. 
 
4.SELECTION AND WITHDRAWAL OF PARTICIPANTS 
 
A. INCLUSION CRITERIA 
Anyone meeting all of these criteria is eligible for enrollment as study 
participants: 
1. Age 1-65 years of either sex, any race, any ethnicity. 
2. Subjects who have completed an immunotherapy trial for peanut 
allergy within the last 18 months and are unable to tolerate ≥300mg of 
peanut. 
3. Written informed consent from patient (if ≥ 18 years) or permission of 
parent/guardian with participant’s assent ( if between 7-17) 
 
B. EXCLUSION CRITERIA 
Participants who meet any of these criteria are not eligible for enrollment as 
study participants: 
1. History of a severe anaphylactic reaction to peanut, defined as hypoxia, 
hypotension, or neurologic compromise (cyanosis or SpO2 < 92% at 


 
Page 14     
 
any stage, hypotension, confusion, collapse, loss of consciousness, or 
incontinence) 
2. Eosinophilic or other inflammatory (e.g. celiac) gastrointestinal disease 
3. Severe asthma (2007 NHLBI Criteria Steps 5 or 6 – Appendix 2) 
4. Use of β-blockers (oral), angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin-receptor blockers (ARB) or calcium channel 
blockers 
5. Significant medical condition (e.g., liver, kidney, gastrointestinal, 
cardiovascular, hematologic, or pulmonary disease) which would put 
the subject at risk for induction of severe food reactions. 
6. Currently participation in an interventional study for peanut allergy. 
7. Pregnancy or lactation.  
 
C. PREMATURE WITHDRAWAL CRITERIA 
Participants may be prematurely withdrawn from the study if: 
1.  At any point in the study, the participant elects to withdraw consent 
from all future study activities. 
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 develops a medical condition that the investigator 
deems incompatible with participation in the trial. That includes 
specifically developing Eosinophilic Esophagitis (participants who 
develop symptoms compatible with Eosinophilic Esophagitis will be 
referred to a gastroenterologist).  
4. Severe atopic dermatitis requiring oral steroids or immunmodulatory 
agent, or severe asthma; requiring more than daily medium dose inhaled 
corticosteroids (more than Flovent 440 mcg daily or its equivalent) 
5. The use of systemic corticosteroids in the past 30 days.  
6. The participant experiences severe symptoms during the build-up or 
maintenance phases as a result peanut OIT dosing 


 
Page 15     
 
7. In the investigator’s discretion, there is poor compliance or any other 
concern that would create an unacceptable risk to the subject.  
8. The participant dies. 
9. The study ends. 
To the extent possible, participants who discontinue therapy will be followed 
to observe and record study outcomes.  
 
 
D. STUDY TERMINATION CRITERIA  
If any of the stopping rules listed below are met, study enrollment will be 
suspended, the initial dose escalation phase and build-up phase 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:  
1.  Any death related to peanut OIT dosing. 
          2. More than one event comprising systemic allergic symptoms with 
significant hypotension at any stage of the protocol. 
          3. More than 3 participants require more than 2 injections of 
epinephrine during dosing of the peanut product. 
          4. More than 3 of the following events: 
 Severe adverse event, other than anaphylaxis, related to 
investigational product. 
 Eosinophilic esophagitis. 
 
5.STUDY DESIGN AND SCHDULE 
A. LOCATION 
Visits will be done at the University of North Carolina-Chapel Hill Food 
Allergy Study Center (FASC), located in the CTRC building. The FASC is 
equipped as a clinic. In addition to MD and NP coverage, there are 24-hour 
adult and pediatric rapid response teams in case of emergencies. The study 


 
Page 16     
 
site is adjacent to the UNC Hospitals Emergency Department where subjects 
can be transferred for continued monitoring and acute care as needed.  
 
B. DURATION OF ENROLLMENT  
The study enrollment duration is for 2 years or until a commercial peanut 
OIT products is available to participants whichever is sooner.  
 
 
C. DURATION OF THE STUDY PER PARTICIPANT  
Each participant will be in the study for a total of 12 months. There will be 
three phases in the study: escalation phase for 1 day, build up phase up to 16 
weeks, and maintenance phase up to 3 months on peanut OIT followed by 6 
months of food equivalent to tolerated peanut protein. 
 
D. STUDY VISITS 
Participants will have: an initial study visit (screening), followed by one visit 
for the escalation phase, followed by visits every 1-2 weeks for the up dosing 
phase, a visit at the end of peanut OIT treatment at 6 months, a phone 
interview at 9 months and a final visit at the end of the study at 12 months. 
The screening visit may be combined with the initial escalation visit. 
 
1. SCREENING AND BASELINE VISIT  
We will perform screening during the initial study visit. We will determine if 
the patient is still eligible for the study, discuss the study and consent with 
the patient, perform physical exam and spirometry (participants ≥ 7 years 
old). A blood draw and skin prick test may also be performed. 
2. ESCALATION PHASE  
All subjects will undergo a one-day peanut desensitization protocol to enable 
them to tolerate a daily dose of peanut protein (3-6 mg) (Table I). If the 
participant has a reaction to one of the doses in the escalation, the next dose 
will be determined at the discretion of the investigator. The options open to 
the investigator are to administer the last previously tolerated dose, or wait 
an additional amount of time between doses. Once this determination of the 
dosage amount is made, the desensitization process resumes as outlined. 


 
Page 17     
 
Upon completion of the modified escalation phase to peanut, the subject is 
observed for a minimum of 2 hours.  If there is no evidence of an allergic 
reaction the subject is discharged home.  If the subject requires treatment for 
symptoms during the initial escalation protocol with antihistamines on one 
occasion, then the rest of the protocol may be followed. If the subject 
requires more than one medication or multiple doses of antihistamines or 
requires other rescue medications, the initial desensitization phase should be 
stopped. If the subject has tolerated either the 3 mg or 6mg dose, the subject 
will be eligible to return on Day 2 to proceed with the build-up phase 
Subjects must be able to tolerate the first two doses of escalation with mild 
or no symptoms to continue with build-up. 
 
Table I   
Dose # 
Dose 
Interval 
(minutes) 
% Increase 
1 
1.5mg 
30 
100 
2 
1.5mg 
30 
0 
3 
3mg 
30 
100 
4 
6mg 
30 
100 
3. BUILD UP PHASE  
After the first day of desensitization, subjects will return to the research unit the 
following day to begin the build-up phase of the study. The subject will ingest 6 
mg, or a lower amount based on the reaction during the escalation phase. After the 
subject is observed for a minimum of 30 minutes for symptoms to the study 
protein ingestion, he or she will be discharged from the research unit and will 
continue to consume the study protein at home daily fourteen days (-3/+7 days).  
The family receives the study protein doses as a powder that they give to the child 
each day by sprinkling it on a previously tolerated food (e.g., apple sauce).  
Subsequently, subjects will return to the clinical research unit every 2 weeks (-
3/+7 days) to monitor their adherence to the dosage administration and increase 
the dose to the next escalation amount (Table II). Vital signs are performed prior 
to the dose administration, prior to the completion of the observation period 
before discharge, and anytime symptoms occur. If the study team feels that a 
longer observation time is warranted based on the prior dosing history of the 
subject or their current physical status, the subject will be observed for a longer 
period of time. If symptoms occur that do not require treatment, the subject will 


 
Page 18     
 
be observed until they resolve.  If symptoms occur that require diphenhydramine 
or albuterol, the subject will be observed a minimum of 2 hours or until symptoms 
resolve.  If symptoms occur that require epinephrine, the subject will be observed 
at least 4 hours or until symptoms resolve.  If symptoms do not fully resolve after 
6 hours or if new symptoms occur, the subject will be transferred to UNC 
Children’s Hospital to be observed overnight.  Per individual stopping rules, 
participants experiencing severe symptoms during buildup will be terminated 
from the study.  
 
Subjects who tolerate dose escalations will take that dose daily for a period 2 
weeks (-3/+7 days) after which they will return to the clinical research unit to 
have the daily dose increased proportionately at each visit until the maximum 
daily dose of study protein (300 mg) is reached. Mechanistic studies may be done 
at the discretion of investigator to address any clinical symptoms for further 
studies.    
 
 
 
 
Table II 
Dose # 
Dose 
Interval(weeks) 
 
5 
6mg 
Day 2 
6 
12mg 
       2 
7 
25mg 
       2 
8 
50mg 
       2   
9 
75mg 
       2 
10 
100mg 
       2 
11 
150mg 
       2 
12 
225mg 
       2 
13 
300mg 
       2 
 
 
4. MAINTENANCE PHASE  
After completing build up phase to 300 mg study protein, the subjects will 
continue to receive their maintenance dose of study protein daily for the 
proceeding 3 months of the study (maintenance phase). After 3 months of 
maintenance, the subject may have mechanistic studies done at end of study visit. 
Data from our previous studies indicate that home dosing is safe, with infrequent 


 
Page 19     
 
reactions which are typically mild. These data have identified several risk factors 
for reactions, which include dosing on an empty stomach, fever/illness, and 
activity/exercise shortly before or after dosing. Families of subjects will be asked 
to administer the study protein with additional food such as at snack or meal 
times, and will be instructed to hold the dose during illness and contact study 
personnel for instruction. After 3 months of daily maintenance peanut protein 
OIT, subjects will have a follow up visit where they are assessed by study 
investigator and if qualified they will be switched to food equivalent of peanut 
protein for the following 6 months. 
 
 
 5. PEANUT FOOD EQUIVALENT PHASE  
At the end of maintenance peanut OIT phase, subjects will be given instruction 
during their last study visit in maintenance phase to start a peanut food equivalent 
of 300 mg peanut protein: which include the following options: peanuts ( not dry 
roasted), peanut butter, powdered peanut butter, mini snickers, mini Reese’s cup, 
cheese peanut butter crackers, Reese’s pieces, Reese’s peanut butter chips or 
Goober. An instruction sheet will be provided on how much to take of one of 
these products on a daily basis This phase will last for 6 months. During this 
phase, subjects will continue to fill compliance sheets and they will receive phone 
calls from study coordinators at 9 months. This will be no study visits until the 
end of this phase to hand daily compliance sheets and fill a survey. At the end of 
the study the subjects may have the option to enroll in our peanut OIT follow up 
study if study investigator deemed they meet inclusion criteria for the study.  
 
E. HANDLING ADVERSE REACTIONS AND FOLLOW UP DURING HOME DOSING 
Each subject is given multiple ways to contact study staff when they are 
enrolled in the study. This is reviewed at the end of each visit. The families 
are told to contact the study staff if they have any questions or concerns 
before the next visit or at any time during the study. Study contact 
information given to families include the research clinic phone number, 
email addresses and office numbers of the, study coordinators, and 
instructions for how to get in contact with the pediatric on-call allergist who 
can reach the lead coordinator if needed. Subjects who have any symptoms 
during observed dosing, or those who express any specific concerns are 
given a follow up phone call on the day after dose escalation.  All subjects will 
be asked to carry an auto-injector epinephrine. If prescription is not 
provided by their physician, we will provide them with a prescription for an 
auto-injector epinephrine. We will ask subjects to fill their prescription and 


 
Page 20     
 
bring their epinephrine auto-injector with them before starting treatment to 
verify they have filled their prescription.  
 
F. MANAGING MISSED DOSES  
Subjects who miss one to two days of the daily dose will continue at their 
current dose at home. The PI will determine where the next dose of study 
protein is given for those who miss three to four days of the daily dose based 
on the length of time on study, the daily dose amount, the subject’s reaction 
history and the amount of time since the last reaction to a dose in order to 
assure safety with dosing.  Those who miss more than four consecutive days 
will return to the clinical research unit for evaluation by the study team in 
order to determine the best course of action for the subject. Options open to 
the investigator include repeat desensitization, observed dosing at the 
current level, or observed dosing at a dosing level previously tolerated by the 
subject.  All such management of missed doses will be carefully documented 
in the study database.  
 
G. MONITORING OF SIDE-EFFECTS, ADVERSE EVENTS, AND CLINICAL CHANGES 
• We will monitor accidental reactions to peanuts in each subject during each 
visit to the study center.  We will note any reaction that occurs in a subject 
within two hours after the ingestion of peanuts, and record the type of 
symptoms (i.e., skin, respiratory, gastrointestinal, or cardiovascular). A copy 
of the CRF is in the appendix.  
• To monitor subjects for adherence, any accidental ingestion, any symptoms 
related to daily dosing and any unintended side-effects of daily dosing, the 
families will be asked to keep a simple daily diary to record the requested 
information. A copy of the daily diary is included in the appendix of the 
protocol. 
• We will check mechanistic changes in the immune system by checking lab 
tests, skin testing or spirometry during the study.  
 
 
6. STUDY PROCEDURES 
 
A. HISTORY TAKING, PHYSICAL EXAM AND PEANUT ORAL IMMUNOTHERAPY 
ADMINISTRATION 


 
Page 21     
 
Please refer to 5.e for detailed description of study visits. In each study visit 
medical and allergy history will be reviewed (including dietary history) and 
physical exam will be performed before administering any treatment. Peanut 
OIT will be administered according to schedule provided in Table I and II.  
 
B. SKIN PRICK TESTING (OPTIONAL)  
Participants will have standard allergen skin prick tests (SPT) performed to 
peanut and possible other allergens based upon the subject’s history and at 
the discretion of the investigator.  The investigator will document in the 
database the rationale for performing the optional SPT.  Examples include: 
checking mechanistic studies for subjects who develop specific 
gastrointestinal side effects (e.g. EoE), subjects who are unable to tolerate 
desensitization to 300 mg or subjects with severe adverse events.  
 
If skin prick testing is schedule for a certain visit, the participant will be 
notified prior leaving appropriate length of time to stop any antihistamines 
at the discretion of the investigator (5 half-lives of the antihistamine that is 
being used). A skin test probe is loaded with extract (Greer) then used to 
prick the epidermis. Positive (histamine) and negative (saline-glycerine) 
controls are placed as well to establish that the response is not blocked and 
to determine if there is dermotagraphism, respectively. The tests are read 15 
minutes after placement, outlined in pen for wheal and flare and transferred 
by cellophane tape to paper to establish a record. SPTs are considered 
positive if there is a mean wheal diameter of 3 mm or greater, after 
subtraction of the saline control.  Histamine wheals should be 3mm larger 
than the saline, and any saline wheel measuring larger than 3mm would 
invalidate the test and should be repeated. 
 
C. BLOOD DRAW:  
Venous blood may be obtained during the study for serum based assays 
(including but confined to serum peanut specific IgE). Blood drawn will be 
less than 2 ml/kg of body weight per visit up to a maximum of 45 ml in 8-
week period for pediatrics and less than 550 ml in an 8-week period for 
adults. Blood collection will not occur more than 2 times per week.  
 
D. SPIROMETRY 
Spirometry will be done for every subject 7 years or older in screening visit. 


 
Page 22     
 
Afterwards, if clinical indicated, spirometry will be administered per clinic 
asthma standard of care as an assessment of lung function in subjects 7 years 
of age or older during study visits. Procedures follow American Thoracic 
Society criteria. Bronchodilation is not conducted and beta-agonists do not 
need to be withheld prior to the test. The test is administered while the 
subject is in a standing position and using a nose clip. We will reference the 
Hankinson predictive values for lung function.  Subjects between 7 and 11 
years who are unable to perform spirometry will be offered an attempt to 
use a peak flow meter.  Participants who are unable to maintain >80% PEFR 
of their predicted value will need to be evaluated by the NP or MD before 
proceeding. 
 
E. SALIVA COLLECTION (OPTIONAL-SUBJECT TO THE INVESTIGATOR DISCRETION)  
A 0.5 ml of saliva could be collected to run mechanistic assays as determined 
by the investigator. Examples include: checking mechanistic studies for 
subjects who develop specific gastrointestinal side effects (e.g. EoE), subjects 
who are unable to tolerate desensitization to 300 mg or subjects with severe 
adverse events.  
Samples may be obtained by the subject spitting independently or the 
coordinator using a plastic syringe to gather saliva. 
 
F. COMPLIANCE SHEETS 
Subjects will be given sheets to record their compliance with the medication 
that needs to be changed on a weekly basis. The sheets will also include 
reactions the subjects have, the symptoms they experienced and how they 
were treated. Subjects will hand the sheets to their study coordinator at each 
visit and at the end of the study. The data from these sheets will be used to 
assess compliance and adverse events in addition to information gathered 
from subjects from their follow up surveys.  
 
G. URINE PREGNANCY TEST  
All participating females of child bearing age will have pregnancy urine test 
in screening then for the last follow up visit within 30 days of the last 
pregnancy test.  Female subjects who become pregnant will be taken out of 
the study.  Sexual abstinence will be accepted as an effective method of 


 
Page 23     
 
contraception. 
Sexually active female subjects are to use either:  
• 
A highly effective method of birth control, defined as one that results 
in a low failure rate (i.e., less than 1 percent per year) when used 
consistently and correctly, such as implants, injectables, combined 
oral contraceptives, some intrauterine contraceptive devices (IUDs), 
sexual abstinence, or a vasectomized partner; or   
• 
Alternatively, if a highly effective method of birth control is not used, 
an effective, double barrier method of contraception (e.g., male 
condom with female condom, cervical cap, diaphragm, or 
contraceptive sponge) may be used.   
7. STUDY AGENT  
A. FORMULATION, PACKAGING AND LABELING 
Peanut flour will be packaged and labeled by the weight (mg) of the source 
material in each cup per dose at the University of North Carolina GMP 
manufacturing facility. Both the investigational drug as well as placebo (oat 
flour) are manufactured as described in Master File Type II MF2 15171.  
 
B. PREPARATION, ADMINISTRATION AND DOSAGE 
The investigational pharmacist will dispense the appropriate dose to the 
clinical staff. The peanut flour will be mixed into a food vehicle (applesauce, 
yogurt, or other tolerated food) for the subject to consume  
 
C. STARTING DOSE AND ESCALATION SCHEDULE 
Please refer to 5.E.  
 
D. DOSE ADJUSTMENT 
Please refer to 5.E, 5.F. and 5.G.  
 


 
Page 24     
 
E. DURATION OF THERAPY 
Total duration of therapy with peanut flour will be up to 6 months. This will 
be followed by 6 months of peanut equivalent.  
 
F. RESCUE MEDICATION AND CONCOMITANT MEDICATION  
Treatment of individual allergic reactions during OIT therapy will be with 
either an antihistamine and/or epinephrine, along with IV fluids, albuterol, 
and corticosteroids as indicated. Participants and parents are likely to have 
self-injectable epinephrine but for those who do not, self-injectable 
epinephrine will be prescribed in clinic. Participants will be trained in proper 
use of self-injectable epinephrine and will be able to demonstrate proper 
technique. All subjects will be given a food allergy action plan to follow while 
in this study.  
8. SAFETY MONITORING  
A. DEFINITIONS 
Adverse Event (AE) or Medical Event 
An adverse event is a new, undesirable medical event or occurrence or 
worsening of an existing condition (including an abnormal laboratory 
finding) in a subject that occurs during the study, whether or not it is 
considered to be study related.  Adverse events or medical events and 
toxicities are treatment emergent signs and symptoms. 
Serious Adverse Event (SAE) 
A serious adverse event is defined as any adverse therapy experience 
occurring at any dose that suggests a significant hazard, contraindication, 
side effect, or precaution.  This includes, but may not be limited to any of the 
following events: (This terminology is from Section B.2 on the FDA 
MedWatch form.  For a copy of the current MedWatch Form 3500, see the 
list of PDF forms on the Web at 
http://www.fda.gov/opacom/morechoices/fdaforms/cder.html) 
 
1) Death: A death occurring during the study or which comes to the 
attention of the investigator during the protocol-defined follow-


 
Page 25     
 
up after the completion of therapy whether or not considered 
treatment-related, must be reported. 
2) Life-threatening: Any adverse therapy experience that places the 
subject or subjects, in the view of the investigator, at immediate 
risk of death from the reaction as it occurred (i.e., it does not 
include a reaction that, had it occurred in a more serious form, 
might have caused death)  
3) In-patient hospitalizations. 
4) Persistent or significant disability or incapacity. 
5) Congenital anomaly/birth defect. 
6) An event that required intervention to prevent permanent 
impairment or damage 
Unexpected Adverse Events 
An adverse event is considered “unexpected” when its nature or severity is 
not consistent with the descriptions in the protocol or informed consents. 
For subjects who become pregnant during the study and whom we will 
withdraw from the study as stated above, we will continue to monitor them 
with phone calls every 3 months until delivery. We will use our phone 
interview questionnaire to report any adverse outcomes for these subjects 
and report the outcome of all pregnancies in our study report.  
B. TOXICITY GRADING 
Symptoms associated with systemic allergic reactions and/or anaphylaxis 
that occur during administration of peanut flour or peanut equivalent food 
will be graded according to table below, that was adapted from the grading of 
allergic reactions in the following article:  
Burks A, Jones S, Wood R, et al. 2012. Oral immunotherapy for treatment of egg 
allergy in children. N Engl J Med. Table 1 (Suppl): 367:233–43   
Grade 1 Mild  
Grade 2 Moderate  
Grade 3 Severe  
Grade 4 Life 
threatening  
Grade 5 
Death  
Transient or mild 
discomforts (< 48 
hours), no or minimal 
medical 
Symptoms that produce 
mild to moderate limitation 
in activity some assistance 
may be needed; no or 
Marked limitation in 
activity, some assistance 
usually required; medical 
intervention/therapy 
Extreme limitation in 
activity, significant 
assistance required; 
significant 
Death  


 
Page 26     
 
 
Other adverse events related to study procedures other than peanut flour or 
peanut equivalent  and adverse events that are not associated with study 
procedures will be graded according to the criteria in the National Cancer 
Institute  NCI –CTC,  as following: 
  
Grade 1 Mild 
Transient or mild discomforts (< 48 
hours), no or minimal medical 
intervention/therapy required, 
hospitalization not necessary (non-
prescription or single-use 
prescription therapy may be 
employed to relieve symptoms, e.g., 
aspirin for simple headache, 
acetaminophen for post-surgical 
pain). 
Grade 2 Moderate 
Mild to moderate limitation in activity 
some assistance may be needed; no or 
minimal intervention/therapy required, 
hospitalization possible. 
Grade 3 Severe 
Marked limitation in activity, some 
assistance usually required; medical 
intervention/therapy required, 
hospitalization possible. 
Grade 4 Life-threatening 
Extreme limitation in activity, significant 
assistance required; significant 
intervention/therapy 
required. These 
symptoms may include 
pruritus, swelling or 
rash, abdominal 
discomfort or other 
transient symptoms.  
minimal 
intervention/therapy is 
required. Hospitalization is 
possible. These symptoms 
may include persistent 
hives, wheezing without 
dyspnea, abdominal 
discomfort/ increased 
vomiting or other 
symptoms  
required, hospitalization is 
possible. Symptoms may 
include bronchospasm with 
dyspnea, severe abdominal 
pain, throat tightness with 
hoarseness, transient 
hypotension among others. 
Parenteral medication(s) are 
usually indicated.  
medical/therapy. 
Intervention is required; 
hospitalization is 
probable. Symptoms 
may include persistent 
hypotension and/or 
hypoxia with resultant 
decreased level of 
consciousness associated 
with collapse and/or 
incontinence or other life 
threatening symptoms.  


 
Page 27     
 
medical/therapy intervention required, 
hospitalization or hospice care probable. 
Grade 5 Death 
Death. 
 
Anaphylaxis: 
Anaphylaxis will be defined according to second  National Institute of 
Allergy and Infectious Disease/ Food Allergy and Anaphylaxis Network 
symposium ( Sampson H, Muñoz-Furlong A, Campbell R, et al. 2006. Second 
symposium on the definition and management of anaphylaxis: Summary 
report: Second NationalInstituteof 
AllergyandInfectiousDiseases/FoodAllergyand 
AnaphylaxisNetworksymposium.J AllergyClinImmunol.92:397–403) as 
following:  
 
Table I. Clinical criteria for diagnosing anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria 
are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, 
or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
 AND AT LEAST ONE OF THE FOLLOWING 
 a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
 b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure TO A LIKELY ALLERGEN FOR 
THAT PATIENT(minutes to several hours): 
 a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-
uvula) 
 b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
 c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 


 
Page 28     
 
Anaphylaxis is highly likely when any one of the following 3 criteria 
are fulfilled: 
 d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to KNOWN ALLERGEN FOR THAT PATIENT (minutes to several 
hours): 
 a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP∗ 
 b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's 
baseline 
PEF, Peak expiratory flow; BP, blood pressure. 
∗ Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 
month to 1 year, less than (70 mm Hg + [2 × age]) from 1 to 10 years, and less than 90 
mm Hg from 11 to 17 years. 
 
Eosinophilic Esophagitis: 
We will monitor subjects for the development of eosinophilic esophagitis 
using Modified Aceves Questionnaire for all of our patients. The 
questionnaire will be done at screening, then visits 4,6,9,10,11 and 12. The 
answers in the questionnaire will be scored and those who have a score of 5 
or more will be evaluated for possible Eosinophilic Esophagitis and will be 
referred to gastroenterology  
 
C. RELATIONSHIPS TO PROCEDURE DEFINITIONS 
Associated: There is a reasonable possibility that the adverse event may 
have been caused by the test product and/or procedure.  This definition 
applies to those adverse events that are considered definitely, probably or 
possibly related to the procedure. 
1)  Definitely related: An adverse event that follows a temporal 
sequence from administration of the test product and/or 
procedure; follows a known response pattern to the test article 
and/or procedure; and, when appropriate to the protocol, is 
confirmed by improvement after stopping the test product (and by 


 
Page 29     
 
reappearance of the reaction after repeat exposure); and cannot be 
reasonably explained by known characteristics of the subject’s 
clinical state or by other therapies. 
2)  Probably related: An adverse event that follows a reasonable 
temporal sequence from administration of the test product and/or 
procedure; follows a known response pattern to the test product 
and/or procedure, is confirmed by improvement after stopping 
administration of the test product or stopping the procedure; and 
cannot be reasonably explained by the known characteristics of the 
participant’s clinical state or other therapies. 
3)  Possibly related: An adverse event that follows a reasonable 
temporal; sequence from administration of the test product and/or 
procedure and follows a known response pattern to the test product 
and/or procedure, but could have been produced by the 
participants’ clinical state or by other therapies. 
 Not associated: An adverse event for which sufficient information exists to 
indicate that the etiology is not related to the test product and/or therapy. 
 Unrelated: An adverse event that does not follow a reasonable temporal 
sequence after administration of the test product and/or procedure; and 
most likely is explained by the participant’s clinical disease state or by other 
therapies.  In addition, no change in a reaction with stopping or restarting the 
test product or procedure would support an unrelated relationship. 
 
For additional information and a printable version of the NCI-CTCAE 
manual, consult the NCI- CTCAE website, 
http://ctep.cancer.gov/reporting/ctc.html. 
   
D. ADVERSE EVENTS COLLECTION PROCEDURES 
The Principal Investigator is responsible for collecting and recording all 
clinical data.  As these results are collected, all toxicities and adverse events 
will be identified and reported as described above.  The Principal 
Investigator will determine relationship of the event to the study activities 
and decide the course of action for the study participant. 
 


 
Page 30     
 
 Adverse events will be evaluated from the onset of the event until the time 
the event is resolved or medically stable or until 30 days after reporting of 
the event, whichever comes first. 
Adverse events may be discovered through any of these methods: 
1. Observing or questioning the participant during study visits.  
2.  Reviewing the forms given to the patient for home monitoring and 
documenting compliance.  
3. Receiving an unsolicited complaint from the participant. 
 
E. SERIOUS ADVERSE EVENT NOTIFICATION 
The research staff will notify the principle investigator of any serious adverse 
event immediately on learning about the event. Serious adverse events will 
be recorded on the adverse event CRF within 24 hours of their occurrence. 
The following attributes must be assigned: 
•     Description 
•     Date of onset and resolution (if known when reported) 
•     Severity 
•     Assessment of relatedness to test procedure 
•     Action taken 
 The principal investigator must apply their clinical judgment to determine 
whether an adverse event is of sufficient severity to require that the subject 
be removed from treatment.  If necessary, an investigator must suspend any 
trial procedures and institute the necessary medical therapy to protect a 
subject from any immediate danger. 
  
Subsequent review by the DSMB or IRB may suspend further treatment or 
procedures.  The DSMB retain the authority to suspend additional 
enrollment and treatments as applicable. 
  
A subject may also voluntarily withdraw from the study due to what he/she 
perceives as an intolerable adverse event, or for any other reason.  If 


 
Page 31     
 
voluntary withdrawal is requested, the subject should be asked to complete a 
study termination form, and be given appropriate care under medical 
supervision until the symptoms of any adverse event resolve or their 
condition becomes stable. 
F. NOTIFYING THE IRB AND DSMB 
A Data Safety Monitoring Board (DSMB) will monitor the study for safety. 
The DSMB will meet periodically to review accruing safety data. The 
committee will consist of individuals with clinical study experience drawn 
from the fields of clinical immunology (specifically food allergies) and 
biostatistics. These individuals will be entirely independent of the conduct of 
the study.  
The study investigator will provide the DSMB with listings of all AEs/SAEs on 
a periodic basis. The DSMB will meet annually to review all AEs/SAEs. 
Furthermore, the DSMB will be informed of all SAEs within 24 hours. 
Furthermore, the sponsor will inform the FDA, IRB, and DSMB of expedited 
reports of SAEs.    
G. REPORTING CRITERIA 
The investigator will ensure the timely dissemination of all AE information, 
including expedited reports, to the IRB in accordance with applicable local 
regulations and guidelines. 
9. MECHANISTIC ASSAYS 
Subjects may have blood drawn and saliva collected for laboratory studies at 
the discretion of the investigator throughout the study. The investigator will 
document in the database the rationale for each sample.   Examples include: 
checking mechanistic studies for subjects who develop specific 
gastrointestinal side effects (e.g. EoE), subjects who are unable to tolerate 
desensitization to 300 mg or subjects with severe adverse events.  
The overall goals of the mechanistic studies are to identify changes in 
basophil, T cell, and antibody responses using peripheral blood and saliva 
samples from study subjects.  We are especially interested in the changes in 
these immune compartments that are associated with treatment with oral 
immunotherapy for food allergy.  In other words, we aim to explore the 
mechanisms responsible for long-term desensitization and/or tolerance to 


 
Page 32     
 
food allergens induced by immunotherapy. Delineating its specific long-term 
effects on the immune reaction will enable us to determine its utility and 
define its therapeutic role.  
 
We have previously demonstrated changes in peanut-specific IgE, IgG, and 
IgA, as well as changes in basophil activation and T cell phenotypes in 
subjects on immunotherapy.  Peripheral blood samples from subjects will be 
collected in this protocol to further follow these subjects’ immune responses 
to the food.   
 
Blood collected in serum separator tubes will be centrifuged and serum 
collected and stored at -80°C until use.  Serum will be used to study allergen-
specific IgE, IgG, and IgA quantities, epitope specificity, and blocking function.  
Blood collected in heparin-containing tubes will be used to isolate peripheral 
blood mononuclear cells (PBMCs) using a Ficoll gradient.  PBMCs will be 
stimulated in vitro with allergens and used to assess changes in T cell 
frequency, phenotype, and function.  Heparinized blood will also be used to 
determine basophil activation responses by ex vivo stimulation and 
assessment via flow cytometric techniques. 
 
Saliva will be assessed for total and allergen-specific IgA and Secretory-IgA 
(sIgA) quantities. Saliva samples will be frozen it at -80 C until analysis. 
 
 
10. STATISTICAL CONSIDERATIONS AND ANALYSIS STRATEGY 
A. INTERIM AND FINAL ANALYSES 
 
An interim analysis will be performed when at least 50 patients have finished 
their peanut OIT treatment phase and at least 25 patients finished 6 months 
of food equivalent treatment phase.  
The interim analysis and the final analyses will include all subjects in the 
study who provided complete follow up information regarding their 


 
Page 33     
 
compliance and adverse events, and will also include those who dropped out 
or were withdrawn from the study before its completion.  
The final analyses will be performed when all subjects have completed the 
study. 
 
B. PLANS FOR EACH SPECIFIC AIM  
 
Aim 1.  Investigate the safety and compliance in the 2-stage protocol 
in subjects who either (a) have previously developed desensitization and 
then subsequently lost this protection due to a period of time off of therapy, 
or (b) have previously endured an extended time on placebo therapy.  
 
We will rely on the following methods to accomplish Aim 1: 
1. Our primary analysis will focus on estimates of incidence rates of adverse 
events and the proportion of days of treatment missed during the treatment 
protocol. 
2. Our secondary analyses will include estimation of  
o the overall incidence rate of gastrointestinal AEs during the entire 
2-stage treatment sequence.  
o the overall incidence rate of Epipen use 
o the overall incidence rate of drop-outs due to gastrointestinal AEs 
during the entire 2-stage treatment sequence. 
3. Exploratory analyses will be used to investigate potential candidate risk 
factors for AEs (using logistic regression models) and causes of missed 
treatment days (using generalized log-linear models for counts of days).    
4. Descriptive tabular and graphical methods will be used to visualize the 
data and examine the relationships among the measures of interest using 
graphical and descriptive methods.   
 
All statistical estimates will be tabulated with the corresponding 95% 
confidence intervals (CI). Interpretation of these CIs will be an integral part 
of the analyses.  For Aim 1  (and for all the aims) sensitivity analyses will be 
performed to evaluate the robustness of the main results to reasonable 
perturbations of the choices of statistical methods and statistical 
assumptions used.  For example, the influence of any extreme or 
questionable data value will be explored.  Results of the sensitivity analyses 
will only be used to guide our level of confidence in the main results. 


 
Page 34     
 
 
 
 
Aim 2. Characterize and compare the two stages of the protocol in 
terms of safety and compliance.  
 
We will rely on the following methods to accomplish Aim 2: 
1. Our main analyses will focus on stage-specific estimates of incidence rates 
of adverse events and the proportion of days of treatment missed.  
Comparisons of the two stages will rely on logistic regression models for 
rates,  and generalized log-linear models for counts of days.  The primary 
emphasis will be on point estimates and confidence interval estimates.  No 
hypothesis tests will be performed.  
2. Our secondary analyses will include estimation of  
o the stage-specific incidence rates of gastrointestinal AEs during 
the entire 2-stage treatment sequence.  
o the stage-specific incidence rates of Epipen use 
o the stage-specific incidence rates of drop-outs due to 
gastrointestinal AEs. 
Comparisons of the two stages will rely on logistic regression models for 
rates, and generalized log-linear models for counts of Epipen usages.  The 
primary emphasis will be on point estimates and confidence interval 
estimates.  No hypothesis tests will be performed. 
3. Exploratory analyses will be used to investigate potential candidate risk 
factors for AEs (using logistic regression models) and causes of missed 
treatment days (using generalized log-linear models for counts of days).    
4. Descriptive tabular and graphical methods will be used to visualize the 
data and examine the relationships among the measures of interest using 
graphical and descriptive methods.   
 
Statistical estimates of interest include stage-specific parameter estimates 
(e.g., incidence rates) as well as estimates of differences between stage-
specific parameters (e.g.,  odds ratios,  or rate differences).  All statistical 
estimates will be tabulated with the corresponding 95% confidence intervals 
(CI). Interpretation of these CIs will be an integral part of analysis.  For Aim 2, 
sensitivity analyses will be performed to evaluate the robustness of the main 


 
Page 35     
 
results to reasonable perturbations of the choices of statistical methods and 
statistical assumptions used. 
 
 
Aim 3. Explore the mechanisms responsible for long-term 
desensitization and/or tolerance to food allergens induced by 
immunotherapy.    
 
We will rely on the following methods to accomplish Aim 3: 
1. Our main analyses will focus on changes in basophil, T cell, and antibody 
responses in peripheral blood and saliva samples.  The exploratory analyses 
will be used to generate or refine hypotheses.   No hypothesis tests will be 
performed.      
2. Descriptive tabular and graphical methods will be used to visualize the 
data and examine the relationships among the measures of interest using 
graphical and descriptive methods. 
All statistical estimates will be tabulated with the corresponding 95% 
confidence intervals (CI). Interpretation of these CIs will be an integral part 
of analysis of the primary outcome.   
For Aim 3, sensitivity analyses will be performed to evaluate the robustness 
of the main results to reasonable perturbations of the choices of statistical 
methods and statistical assumptions used. 
 
C. CHOICE OF SAMPLE SIZE 
 
The choice of sample size is based entirely on the ethical necessity of 
providing therapy to a pre-defined number of individuals in need of salvage 
therapy.  We anticipate that up to 100 eligible subjects will be enrolled to 
receive the proposed salvage treatment regimen. 
11. DATA MANAGEMENT AND DATA HANDLING: 
A.  RESEARCH DATA MANAGEMENT 
 
Management of the research data for this study will involve collection, entry, 
processing, storage, retrieval, archival, distribution and documentation of 


 
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information collected according to a written protocol. The overall strategy 
for quality assurance in data management will be of a professional level as 
described in the following sections.  
 
B.  PLAN FOR ENSURING CONFIDENTIALITY 
Study records will be kept confidential as required by law and institutional 
policies. All research data and records are stored in the Food Allergy 
database, on the UNC Pediatric Allergy / Immunology server, and/or 
research study binders. Participants’ personal identifying information will be 
accessible only to the investigator and authorized study personnel.  Research 
data will be identified only by study identification numbers (IDs). These 
study IDs will be used to maintain relationships in the data between various 
tables.  All consent forms and any paper data collection instruments will be 
stored in a locked cabinet in a secure location. The list identifying subjects 
with their contact information will be kept separate from the scientific study 
data.  The database will be created within centralized files and maintained on 
University approved, encrypted, password protected, shared research drives 
and will be viewed only on approved devices by approved study personnel.   
To ensure PHI Security, procedures to maintain privacy and confidentiality 
will be followed rigorously.  For each subject, identifying information and 
protected health information (PHI) will be collected along with scientific 
study data.  Each research subject will be assigned a study identification 
number (ID).  The scientific study data will be stored in a digital file that does 
not include patient identifiers or PHI.  A separate data file will contain 
identifiers and PHI.   A master file linking patient identifiers to the study data 
will be kept under lock and key by principal investigator. The database will 
be password protected and will be stored on servers housed in a secure 
location. 
 
C. PLAN FOR ENSURING DATA SECURITY 
The research binders, including source documents, are kept locked in the 
study team’s office suite. The subject’s information is accessible only to the 
investigator and authorized members of his designated research study team 
by password protection or direct viewing of the research record.  
 
D. PLAN FOR QUALITY ASSURANCE 


 
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The investigators will keep accurate records to ensure that the conduct of the 
study is fully documented.  The investigator is responsible for regularly 
reviewing the conduct of the trial, for verifying adherence to the protocol, 
and for confirming the completeness, consistency, and accuracy of all 
documented data.  The P.I. will have overall responsibility for ensuring 
quality in the data and in the procedures that produce the data.  In addition 
to the master protocol document, written guidelines and detailed procedure 
manuals may be needed for uniform adherence to the detailed intent of the 
protocol.  The written record of how the study was performed will be 
completed prior to commencement of recruitment and will be updated 
during the course of the study. The P. I. will have overall responsibility for 
the definition and production of the documents necessary to describe all 
aspects of the study in sufficient detail to insure the study can be conducted 
in a scientifically sound, standardized manner. The P.I. will be assisted by 
members of the research team in monitoring adherence to protocol. 
 
E. DATA HANDLING PROCEDURES 
 
 
Case Report Forms (CRFs).   As it is not unusual for revisions to the 
CRFs to occur in clinical studies, each form will be clearly labeled with a 
version number. Transition to an updated version of a CRF will be 
communicated to all members of the research team. 
 
 
Data Collection.  Study data will be recorded at the point of care using 
data collection instruments provided by the study team. Paper forms will be 
stored in a designated folder securely maintained at the point of care and will 
be retrieved by the study team on a daily basis.  The subjects’ medical 
records will be retrospectively reviewed to obtain study data and the patient 
characteristics at admission.  The medical record data will be recorded on a 
patient-specific CRF.   Data collection will adhere to precise written 
instructions and will be monitored to insure adherence to the protocol.  
 
 
Data Entry.   All data entered into the database from the CRFs will be 
verified by comparing the original CRFs to the values in the database.  
 


 
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Data Editing.  The P.I. will be responsible for reviewing data-
monitoring results and investigating questions raised (i.e., “queries”) about 
remarkable or questionable data values. 
 
 
Database Documentation.  The names of the variables and their valid 
ranges or categorical values will be listed in a “data book”.  Documentation 
will also include an index of computer programs and an index of reports.  All 
programming for statistical computation will include comments providing 
internal documentation. 
 
 
Pilot Testing of Operations.   
All aspects of data management 
and project operation will be pilot tested prior to the commencement of the 
study in order to verify adequacy of the methods, materials and systems 
prepared.  Every clinical study collects such pilot data   −either intentionally 
prior to commencement of the study, or unintentionally after recruitment 
has begun.   
F. RISK OF DEDUCTIVE DISCLOSURE 
 
 
We will minimize the risk of unauthorized persons using the database 
to figure out a subject's identity and responses.    
 
(1) The database will comprise two separate files:   a TRACKING FILE  
(containing sensitive patient identifiers such as name, birthdate, date and 
time of admission to the ER, and Subject_ID)  and a de-identified RESEARCH 
FILE containing non-sensitive data such as Subject_ID,  age at admission to 
the ER,  elapsed time since admission to the ER,  treatment assignment,  pain 
scores,  questionnaire data,  etc.   Both database files contain Study_ID.   This 
allows the two sets of information to be linked together if necessary,   but 
prevents linkage as long as the two files are kept safely separated. 
 
(2)  The database will be secured on encrypted storage media to 
guard against hacking or other unauthorized access.   Paper forms will be 
stored in locked locations. 
 
(3)  Data will be retrieved from the RESEARCH FILE and distributed to 
specific personnel (e.g., the P.I., or co-investigators)  for purposes of 
statistical computations  for preparation of publications.   Storage, retrieval 
and distribution will be carefully and securely controlled.   Digital 


 
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transmission of the data will be encrypted.  Transportation of the data will 
use secure media.    
 
(4)   Selective data-entry will also be employed: Some of the study 
data does not need to be entered into an electronic file and will be 
maintained on paper forms in a locked storage location.          
12. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE 
A.STATEMENT OF COMPLIANCE 
This 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 consent documents will be reviewed and 
approved by the UNC IRB. Any amendments to the protocol or to the consent 
materials must also be approved before they are implemented. 
 
B.CONSENT AND ASSENT  
The consent process is a means of providing information about the study to a 
prospective participant and/or to the participant’s parent/guardian and 
allows for an informed decision about initial and continued participation in 
the study.  A copy of the consent will be given to a prospective subject or 
parent/guardian for review.  The study staff will review the consent and 
answer questions.  The prospective subject or parent/guardian will be told 
that being in the study is voluntary and that he or she may withdraw 
him/herself or his/her child from the study at any time, for any reason.  
Subjects or parents/legal guardians (if subject <18 years old) will be asked to 
read, sign, and date a consent form before entering the study or undergoing 
any study-specific procedures.   
Participants 7 years and older will be asked for assent to participate in the 
study. The consent form must be revised whenever the protocol is amended 
with a study design change.    
 
C.PRIVACY AND CONFIDENTIALITY 
Study personnel respect participant’s privacy and confidentiality throughout 
the study. Each participant will be assigned a unique study identification 
number. The participant’s study identification number is used for purposes 
of data and specimen collection and storage. The study identification number 


 
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is used for specimen labeling, including specimens sent to laboratories for 
assays. The participant’s study identification number may be used when 
information is shared with collaborators for research purposes, for scientific 
meeting presentations, and/or for publications. 
 
Study participants’ information will only be shared using the unique study 
identification number; all other personal identifiers will be removed prior to 
the release of information. Information and data resulting from this study 
may be presented at scientific meetings or published and, the participant’s 
identity will not be revealed, but the participant's unique identifier may be 
used. 
 
Study participation may involve testing that is considered clinical standard of 
care, as well as testing that is solely for research. Specimens sent to clinical 
laboratories for testing may contain the participant’s name. Standard of care 
clinical test results may be entered in the participant’s medical record. The 
results of tests and assays conducted solely for research will not be entered 
in the patient’s medical record. 
 
Except for when required by law, participants will not be identified by name, 
social security number, address, telephone number, or any other direct 
personal identifier in study records disclosed outside of UNC.