Clinical trial NCT00932828
Conditions: Food Hypersensitivity
Keywords: Peanut allergy
Sponsor: University of North Carolina, Chapel Hill
Start date: 2009-06-22; Completion date: 2017-02-01
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Peanut allergy is known to cause severe anaphylactic reactions.The goal of this proposal is to produce a new treatment that would benefit young subjects who have recently been diagnosed with peanut allergy by lowering the risk of anaphylactic reactions (desensitization), and changing the peanut-specific immune response in subjects who have peanut allergy (tolerance).

Detailed description:
Peanut allergy is known to cause severe anaphylactic reactions. Compared with other food allergies, it tends to be more persistent and its prevalence seems to be rising. Currently, there is no proven treatment other than strict avoidance. We are attempting to decrease the risk of anaphylaxis on accidental ingestion by desensitizing subjects to peanut using peanut mucosal immunotherapy (PMIT) more commonly called oral immunotherapy (OIT). We are also studying the effect of PMIT on the peanut-specific immune response to determine if tolerance to peanut protein will develop. Based on our preliminary work and recent studies supporting the importance of early oral exposure in tolerance induction, we propose that early treatment of peanut allergy with PMIT will be safe and effective. Children ages 9 to 36 months with peanut allergy will be randomized to receive high or low dose PMIT using peanut flour. Subjects will undergo desensitization on the first day and then increase the doses gradually to a maintenance dose. Doses will be taken daily at home except for dose increases which will be done on the research unit. Subjects will undergo a double-blinded, placebo-controlled food challenge (DBPCFC) if challenge criteria are met. Subjects passing the first challenge will stop PMIT and repeat the DBPCFC to assess tolerance. Outcome variables of interest include response to oral food challenges (OFC), skin prick testing, peanut specific serum immunoglobin E (IgE), immunoglobin G (IgG), and immunoglobin G4 (IgG4) and stool immunoglobin A (IgA), T and B cell responses, quality of life, and adverse events. As secondary and exploratory outcomes, these longitudinal results will be compared between high and low dose PMIT groups and controls using appropriate statistical analysis.

Arms: arm 1: Newly diagnosed allergic children receiving peanut flour as oral immunotherapy for the treatment of peanut allergy.
Interventions: intervention 1: Peanut oral immunotherapy
Intervention descriptions: intervention 1: Defatted peanut in flour form to be used as treatment for peanut allergy

Protocol documents:
Prot_000.pdf: 
  
 
 
Determining the Efficacy and Value of Immunotherapy on the 
likelihood of peanut tolerance: The DEVIL Study 
 
NCT number NCT00932828 
Document Date 04/08/2013 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 2 of 32 
Date: 4/08/2013 
 
 Determining the Efficacy and Value of Immunotherapy on the Likelihood of 
peanut tolerance: The DEVIL Study 
PI: Wesley Burks, MD 
Co-investigator: Brian Vickery, M.D. 
University of North Carolina at Chapel Hill 
PURPOSE OF THE STUDY 
 
Peanut allergy is an increasingly common and potentially severe problem, and no active 
treatment is currently available. The current standard of care is strict dietary elimination and 
emergency preparedness with an anaphylaxis kit in the event of an accidental reaction. Despite the 
constant state of vigilance required by families, accidental reactions are common and can be severe, 
leading to anxiety and impaired quality of life.  Because the disease is life-long in over 80% of 
affected patients, an active form of therapy is needed. Traditional injection immunotherapy (allergy 
shots) with peanut has been studied as a treatment option. Although effective, the rate and severity of 
significant systemic side effects was unacceptably high, and this approach has been abandoned. 
Mucosal immunotherapy (MIT), which takes advantage of the normally suppressive environment of 
the gut, has been used for the treatment of nasal allergies and food allergy, as well as drugs such as 
antibiotics and biological agents. In recent case reports and uncontrolled studies on oral 
immunotherapy in patients with milk, nut, egg, or fish allergy the majority of patients successfully 
completed the treatment regimen, and the mild side effects associated with treatment were generally 
controlled by the occasional use of antihistamines.  However, many of these studies were simply 
descriptive and did not employ rigorous study design or immunologic investigation, and the long-
term effectiveness of such treatments are unknown. Many unanswered questions remain about the 
possible mechanism(s) and optimal treatment schedule (dose, timing, route, duration) of food 
allergen immunotherapy,   
 
This randomized, double blinded, dose-finding study proposal is designed to find out if we 
can use peanut mucosal immunotherapy (PMIT) in young subjects allergic to peanuts, and to better 
characterize the appropriate dose of PMIT.  Our hypothesis is that mucosal peanut immunotherapy 
will make subjects who have peanut allergy less allergic and induce changes in their immune system.  
The goal of this proposal is to produce a new treatment that would benefit these subjects by lowering 
the risk of anaphylactic reactions (desensitization), and changing the peanut-specific immune 
response in subjects who have peanut allergy (tolerance).  By initiating PMIT in infants and toddlers 
shortly after their initial reaction to peanuts, we aim to interrupt the allergic immune response to 
peanut prior to the development of life-long immunologic memory. We anticipate being able to make 
these subjects less allergic to peanuts and cause long-term immune changes in their peanut allergic 
response.  The specific aims for this proposal are to: (1) use PMIT to treat subjects with peanut 
allergy to lower the risk of anaphylactic reactions and induce tolerance to peanut (2) determine the 
effect that PMIT has on the peanut-specific immune response. 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 3 of 32 
Date: 4/08/2013 
 
BACKGROUND AND SIGNIFICANCE 
Food allergic reactions have generated increasing concern in the U.S., with prospective 
studies indicating that 6-8% of children less than four years of age experience IgE-mediated food 
allergic reactions.  These data were recently confirmed by a Centers for Disease Control report, 
which also documented an 18% increase in food allergies among U.S. children over the past 10 
years. A recent survey in the U.S. found that 1.3% of the total population is allergic to peanuts or tree 
nuts, and the average age at peanut allergy diagnosis in our local population is 14 months, a 
significant decrease over the past 5 years. Despite increased recognition and understanding of food 
allergies, food-induced anaphylaxis remains the single-most common cause of anaphylaxis in 
hospital emergency departments, accounting for about one third of anaphylaxis cases seen.  Each 
year in the US, food allergy causes an estimated 125 000 emergency department visits, with 
anaphylaxis occurring in approximately 15 000 cases, leading to 3100 hospitalizations. Though 
food-induced anaphylaxis-induced deaths are rare, they do continue to occur, and remain the 
fundamental threat to all families dealing with food allergy. Fatal reactions are caused by peanut 
or tree nut allergy in over 80% of cases, and not surprisingly peanut allergy causes significant 
anxiety and impairment in quality of life for patients and their families.    
PROJECT DESCRIPTION 
 
We expect to develop a treatment that lowers the risk of anaphylactic (allergic) reactions and 
alters peanut-specific immune responses in peanut-allergic children.  This proposal seeks to 
determine the effect that peanut mucosal allergen immunotherapy (PMIT) has on the allergic 
response to peanuts in young children.  Our ultimate goal is determine whether PMIT will protect the 
allergic child from a potentially fatal reaction (by desensitization) and induce children to outgrow 
their allergy to peanuts (by tolerance). 
GOALS, HYPOTHESIS AND OBJECTIVES 
 
The goal of this proposal is to produce a new treatment that would benefit these subjects by 
lowering the risk of anaphylactic reactions (desensitization), and changing the peanut-specific 
immune response in subjects who have peanut allergy (tolerance). This project is designed to study 
the innovative idea that PMIT, begun early in life, will desensitize subjects with peanut 
hypersensitivity by regulating their mucosal and systemic immune reactivity and cause long-term 
tolerance. 
 
The present research plan draws upon our extensive knowledge of the allergens involved in 
peanut hypersensitivity; it is also based upon evidence demonstrating the effectiveness of peanut oral 
immunotherapy (OIT) in preliminary research studies.  Previous attempts to utilize peanut-specific 
immunotherapy (IT) subcutaneously have failed primarily because of the side effects of therapy.  We 
expect PMIT to have fewer side effects than the non-mucosal systemic desensitization method, and 
this proposal will compare a high dose regimen to a low dose regimen, which may improve the safety 
profile of PMIT. We propose to test the efficacy of PMIT in young peanut-allergic subjects; we 
believe that early intervention with PMIT, prior to the development of sustained immunologic 
memory, may offer an optimal treatment for affected subjects.   


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
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Date: 4/08/2013 
 
Our hypothesis is that mucosal peanut immunotherapy will make subjects who have peanut 
allergy less allergic and induce changes in their cellular and humoral immune system.  
 
The proposed study has two primary objectives: 
Objective #1:  To treat peanut-allergic subjects with PMIT and to determine whether this 
protocol lowers their risk of anaphylactic reactions and causes long-term 
tolerance. 
Objective #2:  To determine the effect that PMIT has on the peanut-specific cellular and 
humoral response in peanut-allergic subjects. 
Objective #1: To determine whether PMIT reduces peanut induced anaphylactic reactions and 
induces long-term tolerance in peanut-allergic subjects.   
 
Purpose and expectations:   
 
These studies are designed to test the feasibility and effectiveness of using PMIT to 
desensitize subjects with peanut allergy, and to optimize the appropriate treatment dose. We expect 
to demonstrate the effectiveness of PMIT by showing that subjects on PMIT will have negative 
double-blind placebo-controlled food challenges (DBPCFC) to peanuts following completion of a 
36-month course of PMIT. We will compare the effects of high-dose PMIT (3000mg) and low-dose 
PMIT (300mg) against untreated controls, and we expect that PMIT will induce a significant 
decrease in: (a) wheal (swelling) size from a titrated skin prick test to peanut protein, (b) serum-
specific IgE to peanut, and (c) adverse effects with accidental peanut ingestion. In this study we will 
test the hypothesis that low-dose PMIT is as successful in tolerance induction as high-dose PMIT in a 
young cohort of newly diagnosed subjects. 
 
The studies under Objective #1 will determine the feasibility of utilizing PMIT for peanut-
allergic subjects early in life, and help to define an optimal treatment dose, which will minimize 
potential side effects and thus enhance the safety of PMIT.  At the present time, strict avoidance of 
food allergens and ready access to self-injected epinephrine is the “standard of care” for food allergy.  
Unfortunately, this method does not work well for young patients with peanut allergy.  The ubiquity 
of peanut-containing foods, especially in children’s diets, makes the possibility of inadvertent 
ingestion great; moreover, children are often in circumstances in which epinephrine injection would 
prove logistically difficult.  If, however, we can demonstrate that PMIT is effective for peanut-
allergic children, the treatment would provide an immediate and feasible preventive option for 
averting potentially life-threatening reactions to accidental peanut exposure (desensitization).  
Additionally, we may be able to cause peanut-allergic children to lose their allergic reactivity to 
peanuts (tolerance). 
Objective #2: To determine the effect that PMIT has on the peanut-specific cellular and humoral 
activity/response in peanut-allergic subjects.  
Purpose and expectations: 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
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Date: 4/08/2013 
 
 
Objective #2 seeks to understand the mechanism(s) of PMIT’s effect on the cellular and 
humoral response to peanut. To do this, we will: (a) analyze the regulatory T-cells (types of white 
blood cells) induced following PMIT, (b) measure the cytokines (chemicals) produced by peanut-
specific T-cells after PMIT, (c) determine the type and quantity of peanut IgE-specific B cells 
(antibody-producing white blood cells), and (d) examine the peanut-specific IgE, IgG and IgG4 
response (in blood) and secretory IgA response (in stool). We anticipate that the effect of PMIT will 
occur by one or both of the following mechanisms: (1) the induction of regulatory T-cells, or (2) a 
shift from a Th2 (allergic) to Th1 (non-allergic) lymphocyte response (as evidenced by cellular 
changes and changes in peanut-specific IgE and IgG).  The induction of regulatory T-cells would 
modify the subject’s immune response to peanuts by modifying peanut-specific T cell proliferation 
and cytokine production. Both CD4+/CD25+ and CD4+/CD25+/CTLA+ T cells have been 
demonstrated in humans after mucosal antigen delivery, and there is extensive evidence in animals 
that T cells with regulatory properties develop upon repeated exposure to antigen and form the basis 
of low dose tolerance.  The conversion from a Th2 to Th1 lymphocyte response would have a similar 
clinical effect of making the subject less sensitive to peanuts, but would accomplish this by a 
different immune mechanism. These mechanisms may have overlapping effects and both have been 
reported to occur following allergen specific immunotherapy.   Additionally, stool analysis will 
evaluate the potential of PMIT to induce the production of allergen-specific secretory IgA antibodies 
in the gastrointestinal tract that prevent allergens from accessing the systemic immune system and 
inducing allergic symptoms.  
Our expectation is that the balance of immunoglobulin isotype response and the epitope diversity 
within each isotype (IgE, IgG subtypes, and IgA) is reflective of the antigen-specific immune 
response.  We anticipate that the identification of antigen-specific immunoglobulin responses may 
give better insight into mechanisms of immediate hypersensitivity reactions (e.g., “blocking” 
antibodies) and mediators of immune tolerance induction (e.g., IL-10 induced IgG4 as a marker of a 
modified Th2 response).  
STUDY DESIGN, DOSAGE SCHEDULE, AND ACCIDENTAL REACTIONS 
 
We will utilize a modified MIT schedule for this PMIT study with a randomized, double-
blinded study based on our previous experience with peanut-allergic subjects. Active peanut allergy 
will be confirmed in all interventional subjects with open oral food challenge prior to entry into the 
study. Control subjects may be offered a confirmatory food challenge if the diagnosis is uncertain. 
We will enroll 80 children in the intervention group. The active subjects will be randomized into 
either a high dose group (final maintenance dose of peanut 3000mg, N=40) or a low dose group 
(final maintenance dose of peanut 300mg, N=40) (see Figure 1). Forty additional subjects will be 
followed as control subjects and will not receive any type of study protein. All subjects in the active 
group will undergo a one-day peanut desensitization protocol designed to enable the subject to 
tolerate  a daily dose of peanut  protein (modified rush phase) (Table 3). If the subject has a mild 
reaction to one of the doses, the next dose would 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, or repeat the current dose. Once this determination of the 
dosage amount is made, the desensitization process resumes as outlined. Upon completion of the 
modified rush 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.   


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
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Date: 4/08/2013 
 
 
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.  
 
After the first day of desensitization, subjects will return to the research unit to begin the 
build-up phase of the study. The subject will ingest 6 mg, or a lower amount based on the reaction to 
the modified rush 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 for a minimum of ten to fourteen days (+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., applesauce).  Subsequently, subjects will return to the clinical 
research unit every ten to fourteen days to monitor their adherence to the dosage administration and 
increase the dose to the next escalation amount (see Table 4). The subject’s response to the new dose 
escalation amount will be monitored for a minimum of 30 minutes after dose administration. Vital 
signs are performed prior to the dose administration, prior to the completion of the observation 
period before discharge, and anytime symptoms occur. If attempts at blood pressure 
measurement have been very disturbing and traumatic to a young child, the study team will rely 
on observation, heart rate and respiratory rate and the physical assessment to determine the 
subject’s response. 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 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. Subjects will then take that dose 
daily for a period of 10 to 14 days (+ 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 (3000mg) is consumed. All active subjects will build up to 3000mg of study protein. To 
maintain blinding, the subjects randomized to the 300mg peanut dose will have additional placebo 
flour added to the study protein during buildup by unblinded study personnel. Laboratory studies will 
be done at the beginning of the study, when the subject reaches the 156 milligram dose, when the 
subject reaches the 749 milligram dose, and when the subject reaches the 3000mg dose, and annually 
thereafter until the end of the study. The laboratory studies will consist of blood tests to monitor the 
immune response to the peanut protein. Stool studies will be performed at the beginning of the study 
and the end of the study. Control subjects will have visits for medical history, physical exam, titrated 
skin prick testing and blood and stool laboratory studies associated with the study at entry and then 
yearly. This control group will be seen yearly over the length of the study.    
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 office phone number, pager number, and email 
address of the PI’s, study coordinators, and research nurses in addition to the pager number of  


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
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Date: 4/08/2013 
 
the on-call allergist who has the personal cell numbers of the study staff. Subjects who have any 
symptoms during observed dosing, food challenges, or those who express any specific concerns 
are given a follow up phone call on the day after dose escalation.     
 
After completing the escalation schedule (build up phase to 3000 mg study protein), the 
subjects will continue to receive their maintenance dose of study protein daily for the next 36 months 
of the study (maintenance phase). Once subjects enter the maintenance phase, assessment of the 
primary endpoint will occur conditionally (i.e., upon achievement of defined immunological 
benchmarks), and/or at the chronological end of 36 months of maintenance. These two possible 
scenarios are discussed further below. After 12 months of maintenance, the subject will have the 
peanut-specific IgE measured. In the first conditional scenario, at any point after this measurement, if 
the peanut IgE is 15 kU/L or less, the skin test is 8mm or less, and there have been no severe 
symptoms following PMIT doses or accidental peanut exposure in the previous 6 months, at the 
discretion of the investigator, the subject will stop the daily dosing and have a DBPCFC the next day. 
This cohort of subjects will then stop the daily dosing for the next 4 weeks and then return for a 2nd 
DBPCFC to peanut to assess long term tolerance to peanut. If these food challenges are negative (i.e., 
successfully completed), they will be followed by an open peanut challenge. The open challenge will 
occur in a 1 to 2 hour window after the successful completion of the tolerance challenge, and the 
study will be completed for that participant if the open challenge is successful. If any of the 
challenges are positive or inconclusive (i.e., not successful), the participant will resume OIT dosing 
until the next 12 months, or at the end of the 36 month treatment period. In the second (i.e. 
chronological) scenario, all remaining subjects will be assessed for the primary endpoint once they 
have completed 36 months of maintenance treatment, regardless of their immunologic parameters 
and/or their performance in past challenges, if applicable. If either challenge at the end of 36 months 
are positive or inconclusive (i.e., not successful), the participant will be considered as having 
completed the study and will return to standard of care. 
 
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 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 a dosing level previously 
tolerated by the subject, or a change from active subject to control subject . 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 on page 16 of the protocol. 
 
We will monitor accidental reactions to peanuts in each subject during the PMIT trial.  We 
will note any reaction that occurs in a subject after the ingestion of peanuts, and record the type of 
symptoms (i.e., skin, respiratory, gastrointestinal, or cardiovascular). Pilot data from our previous 
studies indicate that home dosing is safe, with infrequent 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 after dosing. Families of subjects will be asked to 
administer the study protein with additional food such as at snack or meal times, and during illness to 
hold the study protein and contact study personnel for instruction.  


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
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Date: 4/08/2013 
 
Because of the extreme risk to subjects, those experiencing severe symptoms during dosing or 
challenges such as respiratory failure, hypotension or other symptoms requiring ICU care will be 
withdrawn from the study.  Additionally any subjects who have had an accidental peanut 
ingestion and developed anaphylaxis with respiratory failure or hypotension during the time on 
PMIT will be dropped from the active portion of the study.  Subjects that do not complete the 
study because of an accidental reaction to peanut will be followed in the control group.   
Study Stopping Rules 
 
The following stopping rules will be used throughout the study.  If a subject at any time point 
experiences a serious adverse event as described by the FDA or an unanticipated event of grade 3 
or above as defined by the CTC III scale, the trial will be halted and the IRB and FDA will be 
consulted. If symptoms as noted above occur in 2 or more subjects, the study will be stopped and 
the situation reviewed.  In addition, the study will not resume until the FDA has been notified 
and given the approval for the study to continue. 
 
Subjects will come to the UNC Food Allergy Study Center (FASC) for a double-blind, 
placebo-controlled food challenge (DBPCFC) at the end of the 36 month maintenance treatment 
period, or sooner if challenge criteria are met. The DBPCFC may either occur on 1 day or over a 
2 day period. The food challenges will be administered by the study coordinators or research 
nurses associated with the study.  In a double-blind, placebo controlled challenge, two 
challenges, one containing placebo (which will be oat flour) and one containing peanut, will be 
performed in the same day Randomization and preparation of the challenge materials will be 
performed by the dietitian or a representative from Dr. Burks’ laboratory. Prior to the food 
challenge, subjects will be asked to restrict the use of antihistamines (short acting, 72 hours: long 
acting, 7 days), beta-agonists (12 hours), theophylline (12 hours), and cromolyn (12 hours).  One 
challenge will consist of six doses of peanut given every 10-20 minutes in increasing amounts up 
to a total weight of 5 grams of peanut protein.  The other challenge will consist of placebo 
material given also in six doses.  The cumulative dose of peanut protein given is 5 grams (10 
gram weight of peanut flour). Both challenges will start by first touching the patient’s lip/tongue 
with a small amount of the test material. The first ingested dose will be 0.5 grams (5 %), then 
increasing to 1 gram (10%), 2 grams (20%), 2.0 grams (20%), 2 grams (20%), and 2.5 grams 
(25%). During food challenges, vital signs will be performed prior to the challenge, between the 
two parts of the challenge, at the end of the challenge day, and anytime symptoms occur. Prior to 
each challenge, the patient will have a medical history and physical exam performed, during 
which emphasis will be placed on active respiratory symptoms such as wheeze and cough.  The 
challenge will be administered by a nurse or physician who is blinded to the testing material.  
The supervising investigator will also be blinded to testing material.   
If the subject ingests all of the challenge material without significant symptoms, the 
treatment will be stopped for 4 weeks, and the DBPCFC will be repeated, using the same 
procedure as described above. At the end of these challenges, all negative challenge results will 
be confirmed by open challenge to peanut.  Approximately 5 grams of peanut protein will 
be the quantity of peanut given in the open challenge.  


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
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Date: 4/08/2013 
 
After each challenge the patient will be observed for a minimum period of 1 hour. 
Reactions will be scored using a Food Challenge Symptom Score sheet (page 24 and 25 of the 
protocol).  If the patient begins to have any objective symptoms or subjective symptoms deemed 
clinically significant, the food challenge will be terminated and the patient will be given 
appropriate treatment. Symptoms which would result in discontinuation of the ongoing part of 
the DBPCFC include diffuse hives, throat/tongue swelling, wheezing, respiratory distress, 
emesis, moderate to severe abdominal pain and hypotension.  These would be treated with the 
appropriate emergency medication and the subject would enter a minimum 2 hour observation 
period or until symptoms resolve.  If no symptoms are reported during the first part of the 
DBPCFC, the subject would enter the observation period.  If the subject is stable after the 
observation period, the second part of the DBPCFC would then commence.  If epinephrine is 
required to treat symptoms, the subject would be observed for a minimum of 4 hours and the 
second part of the challenge will be deferred until the next day. The subjects who are not 
symptomatic will be observed for a minimum of 2 hours after the challenges are completed 
before being discharged from the FASC. All food challenges will be performed under physician 
supervision. 
If the subject fails the tolerance challenge after being off the study protein for 1 month, 
the subject will be discharged home to continuing daily dosing on the highest tolerated dose of 
the challenge. The subject will continue this dose and have the desensitization and tolerance 
challenges repeated in one year or at the chronological end of their 36 month maintenance 
period, whichever comes first. 
 
Individual Stopping Rules 
 
Subjects will be dropped from the arm of the study ingesting daily maintenance dose of 
peanut protein if they are having moderate to severe clinical symptoms (GI, respiratory or skin) 
at home after taking the daily dose of peanut protein.  Additionally, any subjects who have an 
accidental peanut ingestion and have anaphylaxis during the time on oral desensitization, will be 
dropped from the arm of the study ingesting daily maintenance dose of peanut protein. Subjects 
who experience peanut-related hypotension as evidenced by a 15 % drop in their blood pressure 
from their baseline, nontransient oxygen desaturation below 90%, recurrent abdominal pain, or 
recurrent emesis which is felt by the PI to be potentially dose related will be stopped from 
participating in the study.  
 
Any subject who has a serious adverse event which is felt by the PI to be potentially a result 
of participation in the study will be dropped from the study.     
 
SAFETY MONITORING  
 
This section defines the types of adverse events that should be reported. It outlines the 
procedures for the appropriate collection, grading, recording and reporting of the events. 
 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
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Date: 4/08/2013 
 
Procedures and Monitoring 
 
All unexpected serious adverse events related to the experimental procedures will 
be reported to the IRB, DCRU, DSMB, and FDA in a manner consistent with 21 CFR 
312.32.  All other adverse events related to the experimental procedures will also be 
reported to the IRB and DCRU in an expedited manner if they are Grade 3 and above in 
severity. Participant deaths are reportable within 24 hours.  The expedited report sent to 
other organizations will be copied to the DCRU.  The investigator will continue to follow 
or obtain documentation of the resolution course of such an event.  A copy of the 
annual report of adverse events submitted to the IRB will be copied to the DCRU.  
Reactions to dosing of the study product will be recorded on a dosing log and will not be 
reported separately as adverse events.  Any reaction that meets the criteria for a serious 
adverse event will be reported both on the dosing log and on an adverse event case report 
form. 
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 treatment and throughout 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.   
Potential adverse reactions seen in subjects treated with peanut OIT and subjects 
undergoing DBPCFC include the following: skin manifestations such as pruritus, 
urticaria, or angioedema; respiratory symptoms such as wheezing, coughing, nasal 
congestion/rhinorrhea, cough and hoarseness; and gastrointestinal manifestations such as 
vomiting, diarrhea, or abdominal pain.  Anaphylaxis is a potential risk involving any of 
the above symptoms plus hypotension and circulatory collapse. 
Serious Adverse Event 
A serious adverse event is defined as any adverse therapy experience occurring at any 
dose that results in the following (21 CFR 312.32): 
1. Death: A death occurring during the study, or which comes to the attention of the 
investigator during the protocol-defined follow-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 or prolongation of existing hospitalization. 
4. Persistent or significant disability or incapacity. 


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5. Congenital anomaly/birth defect. 
6. An event that required intervention to prevent permanent impairment or damage. 
Unexpected Adverse Event 
An adverse event is considered “unexpected” when its nature (specificity) or severity is not 
consistent with applicable product information, such as safety information provided in the 
protocol or consent. 
TOXICITY GRADING 
Toxicity grades are assigned by the study site to indicate the severity of adverse 
experiences and toxicities using the NCI-CTCAE version 3.0.  Toxicity grading for 
allergic reactions including anaphylaxis is modified from the NCI-CTCAE system to be 
more appropriate for this study population, and is displayed in Appendix 2.  The NCI-
CTCAE has been reviewed specifically for this protocol and is otherwise appropriate for 
this study population.  The purpose of using the NCI-CTCAE system is to provide 
standard language to describe toxicities and to facilitate tabulation and analysis of the 
data and assessment of the clinical significance of treatment-related toxicities. 
 
Adverse events not included in the CTCAE listing should be recorded and graded 1-5 
according to the General Grade Definition provided below: 
 
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 medical/therapy intervention required, 
hospitalization or hospice care probable. 
Grade 5 
Death 
Death. 
 


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Relationship 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 finitely 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 (positive rechallenge: and 
by reappearance of the reaction after repeat exposure [positive rechallenge]); 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 rechallenge; 
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 
participant’s 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. 
 
1. 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, a negative rechallenge to the test article and/or procedure would support 
an unrelated relationship. 
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 
to the principal investigator.  Adverse events will be reported as described above.  The 
Principal Investigator will determine relationship of the event to the study intervention 
and decide course of action for the study participant. 


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Recording and Reporting Procedures 
Monitoring will be conducted semi-annually via Internal Audits with a Research Safety 
Committee known as the UNC Food Allergy Initiative (UNC FAI) Data Safety 
Monitoring Board DSMB).  Yearly reports will be made to the proper Institutional 
Committees, as required.  All adverse events will be kept in a file by numerical identifier. 
SAE Recording and Reporting Procedures 
 
All serious adverse events are recorded on the appropriate case report forms. 
SERIOUS ADVERSE EVENT NOTIFICATION 
The research staff will notify the sponsor/investigator of any serious adverse event 
immediately on learning about the event. 
 
SIZE OF POPULATION (AGE, GENDER, ETHNICITY, SOURCE OF SUBJECTS, 
RECRUITMENT PROCESS) 
 
We will recruit 120 subjects between 9 to 36 months of age who have EITHER diagnosed 
peanut allergy, based on (1) the presence of IgE specific to peanuts (a positive skin prick test >3mm 
wheal size) to peanuts or a positive in vitro IgE [CAP-FEIA] > 0.35 kU/L and (2) a convincing 
history of an allergic reaction (defined as significant clinical symptoms occurring within 60 minutes 
after ingesting peanuts) within 6 months prior to enrollment, OR probable peanut allergy, defined as 
(1) positive skin prick test and (2) CAP-FEIA ≥ 5 kU/L, in a child with no known history of peanut 
ingestion. We will confirm the diagnosis of peanut allergy in all interventional subjects with graded 
open (unblinded) oral food challenge to 4 grams of peanut protein prior to enrollment. Subjects with 
a known wheat food allergy will be excluded because of cross contamination of oat with wheat. We 
will recruit subjects from the Duke Pediatric Allergy Clinics and subjects from colleagues of the 
investigators in the surrounding community based on our clinic’s demographics; we expect to enroll 
subjects in equal numbers of females and males, with approximately 20% under-represented 
minorities.  Subjects will participate in the study for a period of up tp 72 months.   
 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment as study 
participants: 
• 
Age 9-36 months of either sex, any race, any ethnicity at the time of the initial visit 
• 
EITHER a positive skin prick test to peanuts (diameter of wheal ≥ 3.0 mm) or positive in 
vitro IgE [CAP-FEIA] > 0.35 kU/L] PLUS a history of a clinical allergic reaction (defined as 
significant clinical symptoms occurring within 60 minutes after ingesting peanuts) within 6 
months of screening  


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• 
OR a positive prick skin test to peanuts and CAP-FEIA > 5 kU/L when there is no history of 
allergic reaction and no known peanut exposure 
• 
Provision of signed informed consent 
• 
Development of symptoms characteristic of IgE-mediated food allergy (urticaria, 
angioedema, respiratory distress/wheeze/cough, vomiting/diarrhea, anaphylaxis) during 
initial open oral food challenge 
 
Exclusion Criteria 
 
Subjects who meet any of these criteria are not eligible for enrollment as study 
participants: 
• 
History of severe anaphylaxis to peanut as defined by hypoxia, hypotension, or neurological 
compromise (Cyanosis or SpO2 < 92% at any stage, hypotension, confusion, collapse, 
loss of consciousness; or incontinence) 
• 
Currently participating in a study using an investigational new drug 
• 
Participation in any interventional study for the treatment of food allergy in the past 12 
months 
• 
Subjects with a known wheat food allergy will be excluded because of cross contamination of 
oat with wheat 
• 
Subjects with a known oat allergy will be excluded because oat flour will be added to the 
peanut flour for those subjects who are randomized to receive the dose of 300 mg of peanut    
• 
Severe atopic dermatitis 
• 
Currently being treated with greater than medium daily doses of inhaled corticosteroids, as 
defined by the NHLBI guidelines  
• 
Inability to discontinue antihistamines for skin testing and OFCs 
EXPECTED IMPACT 
 
The significance of this proposal is several-fold.  First, a treatment for peanut-allergic 
children is badly needed.  A therapeutic option such as PMIT would greatly benefit subjects both 
immediately, by preventing anaphylactic or significant allergic reactions to small amounts of peanuts 
in other foods, and long-term, by laying the groundwork for development of an optimal vaccine for 
peanut allergy.  Second, an understanding of the cellular and humoral dynamics following PMIT will 
allow us to determine if this is an appropriate initial step in the eventual development of a safe and 
efficacious vaccine/treatment for peanut-allergic subjects. This proposed study would also generate 
important new pharmacodynamic information about PMIT by targeting newly diagnosed young 
patients. We believe that the initiation of treatment soon after diagnosis and early in life, as well as 
the comparison of doses, will generate novel data that are likely to impact the safety and efficacy of 
future PMIT therapies. Additionally, targeting young populations with PMIT may also generate 
useful insights about tolerance that could be applied to implementation of primary prevention 
strategies before peanut allergy develops. If PMIT does not induce complete tolerance, it may be 
partially effective and useful in augmenting other types of therapy including antihuman IgE or other 
peanut-specific vaccines.  Finally, a better understanding of the immunologic process by which 
allergen desensitization occurs during PMIT can later be applied to other food allergies. 
1.  Urgent need for an effective treatment/prevention strategy 


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It is estimated that over 50% of individuals who are allergic to peanuts will have an 
accidental reaction to peanuts over a two-year period.   Previous studies have examined traditional 
and rush allergen IT in peanut-allergic subjects.   Given the partial rate of response and the high rate 
of adverse reactions in these studies, and considering the frequent occurrence of accidental peanut 
ingestion, alternative forms of immunotherapy are necessary for this potentially fatal allergy. 
 
Novel immunotherapeutic strategies designed to alter the immune system’s response to food 
allergens are being examined as potential treatment modalities for food allergy.  These include 
cytokine-modulated immunotherapy, immunostimulatory sequence-modulated immunotherapy, 
plasmid DNA immunotherapy, allergen-peptide immunotherapy, and “engineered” (mutated) 
allergen protein immunotherapy. All of these approaches strive to elicit a Th1-type response or 
tolerance from the immune system in response to a specific food allergen.  Unfortunately all of these 
therapeutic options are costly, technically demanding, and several years from becoming available to 
peanut-allergic subjects. Data from our preliminary studies indicate that PMIT is effective in creating 
a state of desensitization, whereby treatment raises the threshold for clinical reactivity to peanut 
ingestion. This PMIT-induced change can protect subjects in the event of an accidental peanut 
exposure, which could be potentially dangerous.  The proposed project is designed to develop a 
peanut-specific MIT that could be made immediately and readily available to peanut-allergic infants, 
toddlers, and older children. 
2.  Importance of elucidating cellular and humoral mechanisms in order to develop vaccine/treatment 
 
Understanding the cellular and humoral dynamics following PMIT will allow us to determine 
if this strategy represents an appropriate initial step toward developing a safe and efficacious vaccine 
for peanut allergy.  Even if PMIT does not induce complete tolerance, it may nonetheless be partially 
effective.  Delineating its specific effects on the immune response will enable us to determine its 
utility and define its role in conjunction with other types of therapy,  
 
Ultimately, we hope to develop a vaccine that lowers the risk of anaphylactic reactions and 
down-regulates peanut-specific IgE and peanut-specific T and B cells in peanut-allergic children.  By 
specifically targeting patients who are at risk for life-long peanut sensitivity, we intend to develop a 
therapy that permanently desensitizes patients or that induces long-term immune modulation of their 
allergic response to peanuts.  Beginning PMIT early in life and shortly after diagnosis may promote 
reshaping of the immune response to peanut prior to the development of long-lasting immune 
memory. Targeting newly diagnosed subjects early may also permit lower dosing which could 
improve the safety and effectiveness of PMIT.   
3.  Relevance of project results for treatment/prevention of other food allergies 
 
If PMIT proves effective, then there is reason to believe that a similar approach could be used 
to treat individuals with allergies to other common food allergens such as milk, egg, tree nuts, fish, 
shellfish, wheat, and soy. Additionally, if PMIT is effective in infants and toddlers, and if we can 
understand the immune responses that cause it to be effective, we will be able to design clinical trials 
for young children prior to their development of food allergy, to prevent the emergence of food 
allergy. Mucosal immunotherapy may also modify the systemic responses to non-food allergens and 
possibly affect the development of new respiratory allergies and asthma, as has been shown for 
traditional subcutaneous injection immunotherapy in children with dust mite allergy. 


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SPECIFIC LABORATORY PROCEDURES.  
Overview 
 
We hypothesize that PMIT will induce immunologic changes characterized by either (1) 
a conversion from a Th2 to Th1 response or (2) the induction of regulatory T cells, or both. The 
specific laboratory procedures are outlined in the section below. In brief, peripheral blood 
mononuclear cells (PBMCs) will be isolated from whole blood drawn at all time points.  PBMCs 
will be cultured with the major peanut allergen Ara h 2, crude peanut extract (CPE), and the 
positive control Concanavalin A and assessed for proliferative responses to these various stimuli. 
In addition, supernatants from these stimulated PBMCs will be analyzed for the production of 
the cytokines IFN-γ, IL-4, IL-5, IL-10, IL-13, TGF-β and TNF-α. In addition to measuring the 
composite cytokine profile in the circulation, the ELISPOT technique will allow us to follow the 
cytokine levels of peanut-specific T cells on a per-cell basis over time. Using flow cytometry, we 
will determine the presence of regulatory T cells in a subject’s blood sample from each time 
point, and we will assess their function with additional coculture techniques.  In the event that a 
subject’s blood sample from any given time point does not have enough cells to perform all 
studies outlined, we will prioritize our studies to focus first on the cytokine and initial 
proliferation studies, then assessing the presence of  T regulatory cells, then functional regulatory 
T cell assays. 
 
We expect to find one or both of the two patterns described below.   
Th2 to Th1 conversion: Protective responses to PMIT mediated by a shift from a Th2 response to 
a Th1 response would be expected to result in decreased concentrations of Th2 cytokines IL-4 
and IL-5, and increased concentration of the Th1 cytokine IFN-γ in cells cultured at later time 
points compared to cells cultured at entry.  However, Th2 to Th1 conversion will result in no 
significant change in the magnitude of allergen-specific proliferative responses from cells 
isolated at entry compared to cultures of cells from follow-up time points.    
Induction of regulatory T cells:    The pattern from the studies described in the overview section 
that would suggest a role for T regulatory cells would include proliferation data demonstrating 
hyporesponsiveness of desensitized allergen-specific T cells in conjunction and/or elevated 
levels of regulatory cytokines (IL-10 and/or TGF-β).  If suppression is indeed observed, we will 
concentrate on the role of regulatory T cells by phenotypic and functional analyses.    
Allergy Skin Tests   
Allergy prick skin testing with standard 1:20 peanut allergen extract will be performed at the 
beginning of the study and yearly thereafter. The wheal will be outlined in ink on transparent 
tape and then transferred to the permanent record. Skin prick testing to environmental allergens 
(dust mites, cat, grass mix, tree mix, and weed mix) and pecan will be performed at entry into the 
study and at the end of the study as well.  


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Skin testing is routinely done in the Allergy Clinic for patients with possible allergies. 
Measurement of serum peanut specific IgG and IgE levels  
 
Sera will be collected and stored at –80°C.  Levels of peanut-specific IgE and IgG will be 
measured by ELISA. Briefly, plates will be coated with CPE incubated overnight at 4oC, and 
then blocked and washed.  Samples (1:10 dilutions for IgE, 1:500 dilutions for IgG) will be 
added to the plates and incubated overnight at 4oC. For IgE measurement, plates will be washed 
and sheep anti-human IgE will be added and incubated for 1 h. After washing, biotinylated 
donkey anti-sheep IgG will be added for 1 h. After washings, avidin peroxidase will be added for 
an additional 15 min at room temperature. The reactions will be developed and read at 405 nm. 
For peanut specific IgG measurements, biotinylated rat anti-human IgG1, and IgG2 monoclonal 
antibodies (0.25 g/ml) will be used as the detection antibodies. Subsequent steps will be done as 
same as those in IgE measurement. Equivalent concentrations of PN-specific IgE and IgG will be 
calculated by comparison with a generated reference curve.(15) Additionally, a CAP-FEIA 
(Pharmacia) for peanut specific IgE and IgG4 will de done at each time point. 
Stool peanut-specific secretory IgA 
 
We will utilize ELISA assays to evaluate host antibody responses to Ara h 2 in stool and 
serum in samples collected before, during and after completion of PMIT. Stool samples will be 
tested at an initial dilution of 1:4 followed by serial 2-fold dilutions until we are able to 
determine an endpoint titer. An endpoint titer will be calculated as the last sample dilution that 
has an ELISA reading (fluorescent relative light units) 3-fold great than the RLU of the same 
sample tested against ELISA plates that are not coated with antigen.  Once the antigen-specific 
endpoint titers are calculated, we will quantitate the total concentration (µg/ml) of  IgA in each 
stool sample and report the antigen-specific responses as a “titer/µg of total antibody”. 
Cytokine Measurements 
Cells will be collected, isolated, and suspended in complete medium containing RPMI 
1640 plus 10% FBS, 1% penicillin/ streptomycin, and 1% glutamine.  Cell suspensions will be 
cultured in 24-well plates (4 x 106 /well/ml) in the presence or absence of Ara h 2, CPE (10 
μg/ml) or Con A (2 μg/ml).  Culture supernatants will be harvested after 24-, 48- and 96-hrs of 
culture.  Levels of cytokines IFN-γ, IL-4, IL-5, IL-10, IL-13, TGF-β and TNF-α will be 
determined by either Cytometric Bead Array (Becton Dickinson, CA) or ELISA according to the 
manufacturer’s instructions (R&D systems, Minneapolis for IL-13; PharMingen, San Diego for 
all others).  All analyses will be performed in duplicate with cytokine concentrations calculated 
by comparison with standard curves generated using reference cytokine preparations. Samples 
will be analyzed on a Bio-Mek 1000 Automated ELISA Workstation or Luminex multiplex 
analyzer.   
Protection from anaphylaxis mediated by conversion from a Th2 response to a Th1 
response would be expected to result in decreased concentrations of the Th2 cytokines IL-4, IL-5, 
and IL-13, and increased measured concentration of the Th1 cytokine IFN-γ in cells isolated at 


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Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
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entry compared to cultures in follow up every 4 months.  Alternatively, protection mediated by 
tolerance induction would likely result in low levels of all cytokines tested. Elevated levels of IL-
10, TGF-β, and or IL-4 in conjunction with proliferation data demonstrating suppression of 
allergen-specific T cell proliferation in treated subjects would suggest a mechanism of tolerance 
involving regulatory cells.  
T cell phenotype and proliferation 
Cells isolated at entry and every 4 months from individual patients will be incubated for 6 
days in triplicate (1 x 106/well in 0.2 ml complete medium) in the presence or absence of Ara h 
2, CPE (10 µg/ml) or Con A (2 µg/ml).  Cells will then be pulsed for 18 h with 1 µCi [3H] 
thymidine, harvested, and incorporated radioactivity measured in a β-scintillation counter.  
Results will be expressed as geometric mean cpm +/- SE with significant proliferation above 
background (p<0.05) determined by a t test.  Protection from anaphylaxis due to Th2 to Th1 
conversion will result in no significant change in the magnitude of allergen-specific proliferative 
responses from cells isolated at entry compared to cultures in follow up every 4 months.  
However, protection mediated by tolerance induction will result in diminished proliferation in 
peanut-desensitized patients.  If diminished proliferation is observed, cultures will be setup in the 
presence of exogenous IL-2 to distinguish whether decreased proliferation is due either to 
anergy, which should respond to exogenous IL-2, or due to tolerance, which should not.  The 
presence of CD4+ CD25+ FoxP3+ regulatory T cells will be assessed by flow cytometry. 
Additionally, we will use ELISPOT kits to quantify the number of IL-10+ peanut-specific T cells 
over time to determine if this inducible Tr1 type of regulatory T cell develops in treated subjects.   
PRELIMINARY RESULTS 
 
Preliminary data from current trials suggest that oral and mucosal immunotherapy for food 
allergy is safe and effective. 28 subjects (mean age 4.8 years) were enrolled in an initial study of 
unblinded peanut oral immunotherapy at Duke and the University of Arkansas Medical Sciences 
Center. Comorbid allergic disease was prevalent in this cohort, with 68% having asthma, 64% atopic 
dermatitis, and 61% allergic rhinitis. 20 of 28 have completed the three phase protocol; four subjects 
dropped out of the study for personal reasons, one due to the development of eosinophilic 
esophagitis, and three remain in the build-up or maintenance phase.    
  
The final dose of the initial modified rush desensitization in this study was 50 mg. In this 
study, the risk of experiencing some symptoms during the initial desensitization was 93%, but most 
were mild. Three subjects were treated with epinephrine for cough &/or mild wheeze (Tables 1 & 2). 
None of the subjects had any cardiovascular symptoms such as hypotension or bradycardia. 
Subsequent study designs have capped the top dose on initial desensitization day at 6 mg of peanut to 
minimize reactions.  
 
The risk of developing any symptoms during subsequent buildup doses at DCRU was less 
than 50%, and fewer than 2% required any treatment. Home doses were very well-tolerated, with 
fewer than 1% of over 10,000 home doses requiring any treatment (Tables 1&2).   


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Table 1: Risk of Symptom Occurrence with 95% Confidence Intervals during the Initial 
Escalation Day, the Build-up Phase and the Home Dosing Phase 
 
Initial Escalation Day 
Build-up Phase 
Home Dosing 
Phase 
Any Symptom 
93% 
(77%, 99%) 
46%  
(37%, 56%) 
3.5%  
(2.3%, 5.1%) 
Upper Respiratory 
79% 
(59%, 92%) 
29%   
(20%, 41%) 
1.2% 
(0.6%, 2.5%) 
Skin 
61%  
(41%, 79%) 
24%   
(17%, 32%) 
1.1%  
(0.7%, 1.8%) 
Abdominal 
68%  
(48%, 84%) 
5.5%   
(3.2%, 9.2%) 
0.9%  
(0.6%, 1.4%) 
Chest 
18%  
(6%, 37%) 
1.7%   
(0.6%, 5.1%) 
0.3% 
(0.1%, 0.4%) 
Table 2: Frequency of Treatment during the Initial Escalation Day, Build-up Phase and Home 
Dosing Phase of Peanut Oral Immunotherapy 
Treatment 
Percent of Initial 
Escalation Days 
Percent of Build-
up Doses 
Percent of Home 
Doses 
Any 
71% (20/28) 
1.7% (5/301)) 
0.7% (67/10,184) 
Diphenhydramine Alone 
50% (14/28) 
1% (3/301) 
0.4% (45/10,184) 
Albuterol Alone 
0% 
0% 
0.04% (4/10,184) 
Diphenhydramine + 
Albuterol 
7% (2/28) 
0.7% (2/301) 
0.2% (18/10,184) 
Diphenhydramine + 
Epinephrine 
11% (3/28) 
0%  
0% 
Diphenhydramine + 
Albuterol +Epinephrine 
4% (1/28) 
0% 
0.02% (2/10,184) 
 
100% (9/9) of the subjects who have undergone follow-up food challenges after maintenance 
OIT treatment have become clinically desensitized. Of these nine subjects, six had IgE levels < 2, 
suggesting they may have become tolerant. 100% (6/6) of these subjects passed a follow-up food 
challenge after discontinuing treatment, indicating tolerance to peanut. These subjects now freely 
consume peanut in their diet without symptoms. Median peanut IgE of all subjects treated to date has 
significantly decreased over time while median peanut IgG4 has significantly increased, indicating 
that peanut OIT may actively reshape the immune response to peanut. A double-blinded, placebo-
controlled PMIT study is currently underway to better assess the contribution of peanut 
immunotherapy on the immune response, and further mechanistic work is ongoing.  


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DATA STORAGE AND CONFIDENTIALITY 
 
All records generated during the visits will be stored in the Division of Allergy and 
Immunology Food Allergy data base or the individual subject’s research study binder. The 
subject’s information is accessible only to the investigator or his designated colleagues by 
individual password or direct viewing of the research record.  In addition, patients will be 
assigned a unique subject identification number that will be used to assure anonymity for any 
data retained in the research record or stored in the microcomputer. The research records will be 
kept in a locked closet in the investigator’s office suite. Subject information which will be shared 
with the other institution participating in the research will only be shared using the unique 
subject identification number. All other identifiers of the subject will be removed prior to the 
release of the information. If the results of the trial are published, the participant’s identity will 
remain confidential. Study records will be retained until the subject reaches age 21. At that point, 
any data not in the medical record will be destroyed. 
 


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3000mg 
300mg 
Randomization 
4 wk  
off tx  
Baseline 
 
 
OFC  
10 gm  
 
OFC     
10 gm  
Lab studies annually, or at 
the discretion of the PI 
from this time forward  
 1 
Figure 1.  Peanut Study Overall Schematic  
2 
 
3 
 
4 
 
5 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
Enrollment  
14 
 
15 
 
16 
 
17 
 
18 
  
19 
 
 
 
 
 
 
 
 
 
 
 
                                                                 
20 
 
21 
 
22 
 
23 
 
24 
Red – Indicates lab studies 
25 
 
26 
N=40 
N=40 
Maintain 3 gm or highest dose achieved 
12-36 months 
Week 1-40* 
See Dosing Schedule Below 


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Table 3 – Modified Rush and Daily Home Schedule 
Modified Rush – Day One 
Dose # 
Dose 
Interval (minutes) 
% Increase 
1 
0.1mg 
30  
100 
2 
0.2mg 
30 
100 
3 
0.4mg 
30 
100 
4 
0.8mg 
30 
100 
5 
1.5mg 
30 
100 
6 
3mg 
30 
100 
7 
6mg 
30 
100 
Daily Dosing and Increase 
Dose # 
Dose 
Interval (weeks) 
 
%  Increase 
7 
6mg 
 
Rush escalation  to         
6 mg 
8 
12mg 
       2 
100% 
9 
25mg 
       2 
108% 
10 
50mg 
       2   
50% 
11 
75mg 
       2 
33% 
12 
100mg 
       2 
25% 
13 
125mg 
       2 
25% 
14 
156mg 
       2 
25% 
15 
195mg 
       2 
25% 
16 
245mg 
       2 
25% 
17 
306mg 
       2 
25% 
18 
383mg 
       2 
25% 
19 
479mg 
       2 
25% 
20 
599mg 
       2 
25% 
21 
749mg 
       2 
25% 
22 
936mg 
       2 
25% 
23 
1170mg 
       2 
25% 
24 
1463mg 
       2  
25% 
25 
1829mg 
       2        
25% 
26 
2286mg 
       2  
25% 
27 
3000mg 
       2 
31% 
 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 23 of 32 
Date: 4/08/2013 
 
Tolerance of Daily Study Protein Dose Diary 
 
Child’s Name_______________________________________ 
 
Date 
 
 
 
 
 
 
 
 
 
 
Dose 
taken (Yes 
or No) 
 
 
 
 
 
 
 
Accidental 
ingestion 
(Yes or 
No) 
 
 
 
 
 
 
 
 
 
 
 
Using the following scale, please enter the appropriate number in each box 
0 = None       1 = Mild     2 = Moderate     3 = Excessive 
 
Vomiting 
 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
Hives 
 
 
 
 
 
 
 
 
 
Itching 
 
 
 
 
 
 
 
 
 
Runny 
Nose 
 
 
 
 
 
 
 
 
Wheezing 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Comments: 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 24 of 32 
Date: 4/08/2013 
 
DEVIL Screening Form 
 
Screening    
 
 
 
 
      Date____________________ 
Recorded by _________________________ 
 
Informed consent obtained and witnessed prior to obtaining information:  Yes   No 
 
Copy of informed consent given to parent:   Yes   No 
 
Name____________________________________        Unit #____________________ 
 
Parent’s Name__________________________________________________________ 
 
Address_______________________________________________________________ 
 
 
Telephone number that we can personally reach you: (H)_______________________ 
(W)_________________________ (Cell) ___________________________________ 
 
DOB___________________      Age_________ ( between 9 and 36 months of age) 
 
Sex:  Male  Female  Race: Afr-American   Caucasian   Hispanic   Other 
 
Weight_____________ ( lb  kg ) Height_____________ ( in   cm) 
 
Ever eaten peanut?   Yes    No    Not Sure 
Describe reactions to peanut and other foods: 
______________________________________________________________________ 
______________________________________________________________________ 
 
Eligibility Criteria 
_______ Subject between 9 and 36 years of age 
_______ Peanut allergy diagnosis within the last 6 months:  CAP > 0.35 or PST > 3mm with history 
of peanut ingestion &  
   convincing IgE-mediated symptoms within 60 minutes  
               date of reaction: ___________ 
   date of testing (and results): PST________(________)_ CAP_________(________) 
Or  
_______ Probable peanut allergy diagnosis within the last 6 months: CAP > 5 and PST > 3mm 
with NO history of peanut ingestion  
   date of testing (and results): PST________(________)_ CAP_________(________) 
 
     
Exclusion  
_______Subjects with a history of severe, anaphylaxis to peanut 
_______Medical history that would prevent a DBPCFC/OFC to peanut 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 25 of 32 
Date: 4/08/2013 
 
Desensitization Day 
 
Initial Medical History & Physical Exam 
 
 
Subject Name: 
 
 
 
 
 
D.O.B:  
 
 
 
Subject  # 
 
 
 
 
 
 
Race:  
 
 
 
Atopic History: (Symptoms, triggers, current treatment, date of onset/diagnosis) 
 
Rhinitis 
 
 
 
 
 
 
 
 
 
 
 
 
Atopic Dermatitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
Food Allergy  
 
 
 
 
 
 
 
 
 
 
 
Drug/Venom allergy  
 
 
 
 
 
 
 
 
 
 
Asthma 
 
 
 
 
 
 
 
 
 
 
 
 
Patient has a current in-date EpiPen   
Yes:  □        Date expires ___________ 
No:   □ 
Patient was given an EpiPen 
Yes:  □         Date expires ___________ 
No:  □  
Episodic symptoms/brief and intermittent with complete clearing/ greater than twice a 
week/continuous? 
 
  
Coughing  
 
Chest Tightness 
 
Wheezing 
 
SOB 
Peak Flow: 
>80% baseline 
 
60-80% baseline  
 
<60% 
PF variability :  
 
 
 
 
Nighttime symptoms:   
 
always  
 
exacerbations only 
 
never 
ER visits in past 6 months 
 
 
Exercise symptoms:   
routine activities 
 
vigorous exercise 
 
none 
 
Significant Medical History: (Skin/skeletal, neuro, endocrine, respiratory, cardiac, renal, 
gastrointestinal), Hospitalizations, surgeries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family History of Atopy: (Immediate family members) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________ 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 26 of 32 
Date: 4/08/2013 
 
Physical Exam: 
 
General: 
 
 
 
 
 
 
 
 
 
 
 
 
HEENT: 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory: 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac: 
 
 
 
 
 
 
 
 
 
 
 
 
Abdomen: 
 
 
 
 
 
 
 
 
 
 
 
 
Skin/Extremities: 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic Tests: 
PST 
 
 
 
 
 
 
 
 
 
RAST  
 
 
 
 
 
 
 
 
 
 
 
 
PFT’s  
 
 
 
 
 
 
 
 
 
 
 
Lab 
 
 
 
 
 
 
 
 
 
Other  
 
 
 
 
 
 
 
 
 
All Current Medications: 
Medication 
 
 
Dose  
 
Indication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator Signature:  
 
 
 
date:  
 
 
 
Investigator Signature: 
 
 
 
 
 
date:  
 
 
 
 
 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 27 of 32 
Date: 4/08/2013 
 
Follow-Up Visit History 
     & 
      Physical Exam 
 
 
 
Subject Name: 
 
 
 
 
 
DUMC# 
 
 
 
 
Interval History:  
 
 
 
 
 
 
 
 
 
 
 
___________ 
____________________ 
 
 
 
 
 
 
 
 
_____  
 
 
_____________ 
 
 
 
 
 
 
 
_____ 
____________________________________________________________________________ 
Accidental ingestion/reaction: __________________________________________________ 
____________________________________________________________________________ 
 
Physical Exam: 
General: 
 
 
 
 
 
 
 
 
 
 
 
HEENT: 
 
 
 
 
 
 
 
 
 
 
 
Respiratory: 
 
 
 
 
 
 
 
 
 
 
 
Cardiac: 
 
 
 
 
 
 
 
 
 
 
 
Abdomen: 
 
 
 
 
 
 
 
 
 
 
 
Skin/Extremities: 
 
 
 
 
 
 
 
 
 
 
 
All Current Medications: 
Last antihistamine given/indication________________________________________ 
Medication 
 
 
Dose  
 
Indication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
_____ 
 
 
 
 
 
 
 
 
 
 
 
 
_____ 
Study Coordinator Signature:  
 
 
 
date:  
 
 
Investigator Signature: 
 
 
 
 
 
date:  
 
 
 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 28 of 32 
Date: 4/08/2013 
 
DEVIL 
Desensitization/ Challenge Sheet 
(*Record time in 24 hour clock) 
Subject Number___________           
Date of visit____/_____/______        Randomization number: ___________________ 
 
Date of Desensitization____/____/____ 
 
Food used for desensitization___________________; Use 1 Tablespoon per dose of peanut. 
Clock 
time* 
Running 
time 
(Minutes) 
Amount 
Food 
Challenge 
SKIN 
% Area   Rash  Pur.  Urt/Ang. 
Rash IA    IB      IC       ID 
UPPER RESPIRATORY 
Sneez/   Nasal/     Rhin    Laryn. 
Itch IIA  Cong IIB   IIC      IID 
CHEST 
Wheeze 
IIIA 
ABDOMEN 
Subj     Obj Comp 
Comp IVA    IVB 
   :  
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 29 of 32 
Date: 4/08/2013 
 
(Continued)  
 
 
 
 
 
DEVIL 
Desensitization/ Challenge Sheet  
(*Record time in 24 hour clock) 
Subject Number___________           
Date of visit____/_____/______        Randomization #____________________ 
Clock 
time* 
Running 
time 
(Minutes) 
Amount 
Food 
Challenge 
SKIN 
% Area   Rash  Pur.  Urt/Ang. 
Rash IA    IB      IC       ID 
UPPER RESPIRATORY 
Sneez/   Nasal/     Rhin    Laryn. 
Itch IIA  Cong IIB   IIC      IID 
CHEST 
Wheeze 
IIIA 
ABDOMEN 
Subj     Obj Comp 
Comp IVA    IVB 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1Mucosaldose approximately doubled every 30 minutes. 
2If the subject has a clinical reaction to one of the doses, the next dose is the previously tolerated dose. 
 
Skin:                +        -               Time of the initial response after food challenge: ___________(minutes) 
Respiratory:     +       -                Antihistamine administered        Yes      No         Route:    PO    IV 
GI:                   +         -               Epinephrine administered          Yes      No         Route:    IM     IV 
 
 
 
                Time (minutes from initiation of challenge):___________ 
Comments:________________________________________________________________________________________________
_________________________________________________________________________________________________________ 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 30 of 32 
Date: 4/08/2013 
 
DEVIL 
Dosage Escalation Sheet 
(*Record time in 24 hour clock) 
 
Subject Number___________           
Date of visit____/_____/______ 
Date of Desensitization____/____/____          
Randomization #:____________________ 
Current Daily Dose ______________ 
Dose to be given today ___________ 
 
Food used for dosage escalation___________________; Use 1 Tablespoons per dose of peanut. 
Clock 
time* 
Running 
time 
(Minutes) 
Amount 
Food 
Challenge 
SKIN 
% Area   Rash  Pur.  Urt/Ang. 
Rash IA    IB      IC       ID 
UPPER RESPIRATORY 
Sneez/   Nasal/     Rhin    Laryn. 
Itch IIA  Cong IIB   IIC      IID 
CHEST 
Wheeze 
IIIA 
ABDOMEN 
Subj     Obj Comp 
Comp IVA    IVB 
   :  
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
   : 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments:________________________________________________________________________________________________
_________________________________________________________________________________________________________ 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 31 of 32 
Date: 4/08/2013 
 
 
Symptom Scoring Sheet for Desensitization, Dosage Escalations, and Oral  Food Challenges 
 
I. Skin 
A.  Erythematous rash - _____% area involved 
B. Rash 
0 Absent 
1 Mild – few areas of faint erythema 
2 Moderate – areas of erythema, macular and raised rash 
3 Severe – generalized erythema (>50%), extensive raised lesions (>25%) 
C. Pruritus 
0 Absent 
1 Mild – occasional scratching 
2 Moderate – scratching continuous for more than 2 minutes at a time 
3 Severe – generalized involvement 
D. Urticaria/Angioedema 
0 Absent 
1 Mild – less than 3 hives 
2 Moderate – greater than 3 but less than 10 hives 
3 Severe – generalized involvement 
 
II. Upper Respiratory 
A. Sneezing/Itching 
0 Absent 
1 Mild – rare bursts 
2 Moderate – less than 10 bursts, intermittent rubbing of nose and/or  
eyes 
3 Severe – continuous rubbing of nose and/or eyes, periocular swelling  
and/or long bursts of sneezing 
B. Nasal Congestion 
0 Absent 
1 Mild – some hindrance to nasal breathing 
2 Moderate – nostrils feel blocked; breathes through mouth most of the time 
3 Severe – nose runs freely despite sniffling and tissues 


DUKE  IRB# 00016160 
UNC IRB# 11-2307 
Principal Investigator: Wesley Burks, MD     
Co-Investigator: Brian Vickery, MD  
 
Protocol Version # 5 
 
Page 32 of 32 
Date: 4/08/2013 
 
C. Rhinorrhea 
0 Absent 
1 Mild – occasional sniffling 
2 Moderate – frequent sniffling, requires tissues 
3 Severe – nose runs freely despite sniffling and tissues 
D. Laryngeal 
0 Absent 
1 Mild – throat clearing, cough 
2 Moderate – hoarseness, frequent dry cough 
3 Severe – inspiratory stridor 
 
III. Chest 
A. Wheezing 
0 Absent 
1 Mild – expiratory wheezing to auscultation 
2 Moderate inspiratory and expiratory wheezing 
3 Severe – dyspnea, use of accessory muscles, audible wheezing 
 
IV. Abdomen 
A. Subjective complaints 
0 Absent 
1 Mild – complaints of nausea or abdominal pain, no change of activity 
2 Moderate – frequent complaints of nausea or pain, decreased activity 
3 Severe – patient in bed; crying or notably distressed 
 B. Objective complaints 
0 Absent 
1 Mild – 1 episode of emesis or diarrhea 
2 Moderate – 2 to 3 episodes of emesis or diarrhea or 1 of each 
3 Severe- more than 3 episodes of emesis or diarrhea or greater than 1 of each       
 
 
 
 

SAP_001.pdf: 
 
 
Determining the Efficacy and Value of Immunotherapy on the 
likelihood of peanut tolerance: The DEVIL Study 
Statistical Analysis Plan 
NCT number NCT00932828 
Document Date 04/08/2013 
 
 


Sample size 
No placebo-controlled studies have been published that evaluated the development of 
tolerance/SU after years of treatment with peanut OIT. Published data from our own 
uncontrolled pilot study in older children with long-standing disease suggest that SU developed 
in 12 of 24 (50%) peanut-allergic subjects completing high-dose OIT. (Vickery, et al. Sustained 
unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J 
Allergy Clin Immunol. 2014 Feb;133(2):468-75. doi: 10.1016/j.jaci.2013.11.007). On the basis of 
preliminary data that were available to us at the time this study was conceived in 2008, and 
according to our hypothesis, we predicted before the study that 70% of low-dose subjects 
would develop SU, compared with the expected rate of spontaneous peanut allergy resolution 
of 20% as shown in multiple cohort studies. At a 2-sided significance level of .05, 15 subjects in 
each treatment arm would have at least 80% power to detect a 50% absolute average 
difference between the proportion of subjects in each arm passing the exit SU OFC and the 20% 
rate of spontaneous tolerance expected in untreated controls. On the basis of a prestudy 
assumption of 15% to 20% dropout, we enrolled 20 subjects per arm to ensure adequate 
power. 
 
Practical considerations prevented a trial large enough to show definitive comparisons of high- 
and low-dose therapy directly. Twenty subjects in each arm would have 63% power to identify 
a 40% difference in SU acquisition between regimens. Even if underpowered to show a 
difference between low-dose and high-dose therapy, we reasoned a priori that a type II error in 
this setting may still be clinically meaningful so long as the proportion achieving SU in the low-
dose group significantly exceeded 20%. This would be especially true if low-dose therapy offers 
other advantages (fewer visits, better safety profile, improved palatability, etc). 
 
Randomization 
For the primary outcome analysis, subjects were considered a single intervention group on 
open label peanut OIT. For exploratory analyses, subjects were randomized 1:1 to be on either 
low dose OIT (300mg peanut protein) or high dose (3000mg peanut protein). Masking was 
achieved by the addition of oat flour to the low dose OIT in order to match the weight of the 
high dose OIT product. Patients, patient families, study coordinators and investigators were 
blinded to the dose allocation. Randomization was conducted by unblinded laboratory staff in 
the Burks lab using a block randomization scheme. 
 
Statistical Analysis 
We computed averages, variances, frequencies, proportions, and graphical displays for all 
variables and examined them to ensure parametric distributional assumptions were met. 
Nonparametric test statistics were used as appropriate. Baseline demographics and categorical 
peanut consumption outcomes were compared between E-OIT and controls using Fisher’s exact 
test. Analyses were performed with GraphPad Prism 6 for Mac (La Jolla, CA) or Stata/SE 13.1 
(College Station, TX). To achieve approximate normality and variance stabilization for 
longitudinal immune analyses, psIgE and psIgG4 were log-transformed, while for SPT raw data 
were employed. Models were fit separately for each group in R (www.r-project.org) for each 
outcome with functions of time using generalized estimating equations. Linear and quadratic, 


and cubic models in time were considered, with the best fitting model selected for each group 
for each outcome selected using QIC. All hypothesis tests were two-sided, with p<0.05 
considered significant.