Clinical trial NCT04090203
Conditions: Peanut Hypersensitivity
Keywords: Peanut Allergy
Sponsor: Alton Melton
Start date: 2019-11-05; Completion date: 2021-05-20
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Prospective Phase 1 clinical trial providing proof of concept data on boiled peanut oral immunotherapy (OIT) for the treatment of peanut allergy in children. The investigators hypothesize that the proportion of subjects successfully desensitized with boiled peanut OIT is greater than the theoretical placebo rate of 20%.

Detailed description:
Oral Immunotherapy will be administered utilizing a powder derived from boiled peanuts. Treatment will begin with an initial escalation day in which dosing is begun at 0.1 mg peanut protein and escalated to a final dose of 6 mg peanut protein. Doses are ingested orally. Participants will continue daily oral ingestion of doses at home and return for updosing every 2 weeks to a final maintenance dose of 300 mg peanut protein. Participants will continue daily oral ingestion of the peanut product for a minimum duration of 28 days before undergoing exit double blind placebo controlled food challenge. At the conclusion of the study, participants will be offered continued maintenance therapy off study in line with current specialty standards.

Arms: arm 1: Boiled Peanut Powder
Interventions: intervention 1: Boiled Peanut Powder
Intervention descriptions: intervention 1: Oral Immunotherapy will be administered utilizing a powder derived from boiled peanuts. Treatment will begin with an initial escalation day in which dosing is begun at 0.1 mg peanut protein and escalated to a final dose of 6 mg peanut protein. Doses are ingested orally. The subjects will continue daily oral ingestion of doses at home and return for updosing every 2 weeks to a final maintenance dose of 300 mg peanut protein. The subjects will continue daily oral ingestion of the peanut product for a minimum duration of 28 days before undergoing exit DBPCFC. At the conclusion of the study, patients will be offered continued maintenance therapy off study in line with current specialty standards.

Protocol documents:
ICF_002.pdf: 
Boiled Peanut Oral Immunotherapy for the Treatment of Peanut Allergic 
Pediatric Patients 
NCT04090203 
Informed Consent Form v04/06/2020 
Assent Form v05/29/2019 


Consent Version:  4/06/2020 
 
Page 1 of 13  
Protocol Version: 2/12/2020 
The Cleveland Clinic Foundation 
Consent to Participate in a Research Study 
 
Study title: Boiled Peanut Oral Immunotherapy 
Sponsor: Dr. Alton Melton 
PI:  Dr. Jaclyn Bjelac  (216) 445-1449 
Study Coordinator: Navneet Singh  (216) 445-2246 
After hours phone contact #: (216) 445-1449 
Pediatric Allergy Research Pager# (216) 207-3704 
 
You are being invited to participate in a research study.  A research study is designed to answer 
specific questions about new ways to prevent, detect, and treat disease.  Being in a research study 
is different from being a patient.  The purpose of this document is to provide a written summary 
of the discussion and exchange of research information you had with the research team.  It is also 
for use as a reference during the study.   
 
Please note: 
• You are being asked to participate in a research study 
• Ask as many questions as needed so you can make an informed decision. 
• Carefully consider the risks, benefits, and alternatives of the research 
• Your decision to participate is completely voluntary and will have no effect on the 
quality of your medical care if you choose not to participate. You can also withdraw 
from the study at anytime. 
• For the purposes of this document, “you” refers to “your child” if you are a parent 
providing consent. 
 
 
1. INFORMATION ON THE RESEARCH 
Why is the research study being done? 
Peanut allergy is becoming more common. Being a child with peanut allergy can be 
stressful .As parents, having a child with a peanut allergy can be very stressful. Trying to 
avoid peanut entirely can be very difficult. Worrying that your child might accidentally 
eat peanut and have an allergic reaction can make many people feel anxious. Right now, 
the only way to treat the allergy is to avoid peanuts and have emergency medications 
close by in case peanuts are eaten accidentally. Some new treatments are being studied.  
 
One of these treatments is called oral immunotherapy (OIT). This means that over a 
number of weeks or months, you will eat tiny amounts of peanut every single day. The 
amount will slowly be increased until you can eat a larger amount of peanut without 
having an allergic reaction. This treatment is still being studied and is not widely 
available because there are still some problems that need worked out. One problem is a 
lot of side effects, like itchy mouth or upset stomach. The purpose of this study is to see 
if we can find a way to give oral immunotherapy with less side effects. 
 
Based on previous research, we think that there will be less side effects if we use a boiled 
peanut for oral immunotherapy instead of roasted peanuts. This study will help us find 


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Protocol Version: 2/12/2020 
out if this is true. If it is true, this will help us treat more children with peanut allergy in 
the future.  
 
This study will use peanut as an investigational agent. We will use 2 different kinds of 
peanut, roasted peanut and boiled peanut. Both kinds of peanut are commercially 
available, meaning you can buy these kinds of peanuts in the store or online. However, 
using peanut as a drug to treat peanut allergy is investigational. This means it has not 
been approved by the FDA.  
 
If your child is enrolled in the study, he/she will receive roasted peanut material to 
consume at the Oral Food Challenges during the first and last visits. In addition, he/she 
will receive boiled peanut material to consume throughout the remainder of the trial.  
 
What is involved if you decide to take part in this research study? 
 
 
If you decide to take part in this study, your enrollment will consist of 10 study visits 
over an 18 week period. 
SCHEDULE OF VISITS 
Visit Number 
When 
Where 
Time Needed 
What Happens 
1 
Week 1 
CCF Main Campus  
 
Pediatric Allergy 
Clinic 
 
4-6 hours 
Oral food 
challenge to 
confirm your child 
is allergic to 
peanut 
2 
1-4 weeks later  
CCF Main Campus 
 
Clinical Research 
Unit (M51) 
 
4-6 hours 
-Initial Escalation 
day to start tiny 
doses of peanut 
-Allergy skin test 
-Blood draw  
3 
2 weeks later 
CCF Main Campus  
 
Clinical Research 
Unit (M51) 
 
2 hours 
Updosing (where 
your child eats a 
little bit higher 
dose of peanut) 
4 
2 weeks later 
CCF Main Campus  
 
Clinical Research 
Unit (M51) 
 
2 hours 
Updosing (where 
your child eats a 
little bit higher 
dose of peanut) 
5 
2 weeks later 
CCF Main Campus 
 
Clinical Research 
Unit (M51) 
 
2 hours 
Updosing (where 
your child eats a 
little bit higher 
dose of peanut)  
6 
2 weeks later 
CCF Main Campus 
 
Clinical Research 
Unit (M51) 
 
2 hours 
Updosing (where 
your child eats a 
little bit higher 
dose of peanut) 
7 
2 weeks later 
CCF Main Campus 
 
Clinical Research 
Unit (M51) 
 
2 hours 
Updosing (where 
your child eats a 
little bit higher 
dose of peanut) 
 


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Protocol Version: 2/12/2020 
8 
2 weeks later 
CCF Main Campus 
 
Clinical Research 
Unit (M51) 
 
2 hours 
Updosing (where 
your child eats a 
little bit higher 
dose of peanut) 
9 
2 weeks later 
CCF Main Campus 
 
Clinical Research 
Unit (M51) 
 
 
2 hours 
Updosing (where 
your child eats a 
little bit higher 
dose of peanut) 
10 
4 weeks later 
CCF Main Campus 
 
Clinical Research 
Unit (M51) 
 
 
2 hours 
-Oral food 
challenge 
-Allergy skin test 
-Blood draw 
 
Screening Visit 
This is the visit where we determine if your child is a good fit for the study. At this visit 
you will be going over and signing this document (in addition to the assent form if 
applicable). Additionally, we will collect vital, ask basic demographic information, ask 
about any medications you are taking at home, ask you to fill out a questionnaire and if 
applicable perform a test called spirometry (all patients ages 5+ and/or at the physicians 
discretion) and a urine pregnancy test (on all females of childbearing potential). 
 
Visit 1: /Peanut Challenge 
To find out if your child qualifies for this study, first we will perform a peanut challenge. 
Your child will come to the clinic and we will give them small doses of peanut. Then the 
dose will be increased several times. If your child has an allergic reaction, we will treat 
the allergic reaction and will invite you to participate in the study. Spirometry will also 
be performed at this visit, before the oral food challenge, on children ages 5 and up or if 
the physicians feels  the child is developmentally capable of the test. 
 
If your child reacts to peanut challenge and you and your child agree to participate in the 
study, you will be assigned to receive oral immunotherapy using boiled peanut material 
and scheduled to come in for your Initial Dose Escalation Visit.  
 
 
 
 
 
Visit 2: Initial Dose Escalation Visit 
The Initial Dose Escalation Visit will take place at the Clinical Research Unit (CRU) at 
Main Campus. The CRU is an area specifically designed for research studies where your 
child can be monitored very closely. We will give a very small amount of peanut (even 
less than the amount during the food challenge). Then the dose will be slowly increased. 
We will find out the highest dose that your child can eat without having an allergic 
reaction. Then we will have your child continue eating this amount at home once a day 
until the next study visit. During visit two a blood draw and skin prick test will also 
occur. Before any dose is given we will also measure your ability to push air out of your 
lungs with a test called a “peak flow test.”  
 
Visits 3-9: Updosing Visits  


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During visits 3-9, you will return to the clinic every 2 weeks. Each time we will increase 
the amount of the peanut you are to consume. You will continue eating that higher dose of 
peanut daily (at home) until your next study visit. So you will come to the clinic 
approximately 7 times over approximately 12 weeks. This part of the study might last a 
little longer if you are having side effects. In this case, we might have to increase the dose 
slower.  Before any dose is given we will also measure your ability to push air out of your 
lungs with a test called a “peak flow test.” 
 
*Visit 10: Final Study Visit (2 part or 2 day visit) and Beginning of Optional Maintenance 
At this Visit an oral food challenge similar to the one given at visit 1 will be repeated. 
The difference in this challenge is that this food challenge will be blinded, meaning 
neither you nor the study team will know if your child is receiving peanut powder or a 
placebo. You will be asked to come back to clinic with your child either later in the day 
or the following day to receive an additional food challenge (either peanut powder or the 
placebo).   A blood draw and skin prick test will occur as well. These are identical to the 
ones that were done at visit 2. Spirometry will also be performed at this visit, before the 
oral food challenge, on children ages 5 and/or at the physician’s discretion. Additionally, 
a urine pregnancy test will be done on all females of child bearing potential.  
 
Once you have reached the maximum dose of peanut, you will be offered the opportunity 
for ongoing once daily consumption of the maintenance dose. This ongoing maintenance 
is optional and will not be paid for by the study. If the ongoing maintenance is done, the 
therapy will be one dose down of roasted peanut from the exit dose of boiled peanut 
Additionally, someone from the physician’s office will contact you via phone every 3 
months to make sure the continued therapy is acceptable and to talk about the benefits of 
continuing/stopping the therapy. 
 
What tests will be performed as part of your participation in the study? 
 
You will have a total of 1.6mL of blood drawn at study visit 2 and study visit 10 to test 
for: peanut specific IgE concentration, peanut component testing (peanut specific IgE 
concentration for Ara h 1, 2, 3, 8 and 9), and peanut specific IgG4  concentration.  
You will have skin prick testing with peanut extract, a negative control, and a positive 
control (histamine) performed at study visit 2 and study visit 10. This skin prick testing 
will provide evidence of immediate IgE mediated peanut hypersensitivity. 
If you are a female of childbearing potential. You will have a urine pregnancy test  
            performed before the start of study participation and before the final oral food challenge.  
 
Spirometry will be done on all patients ages 5 and up and/or at the physician’s discretion 
at the screening visit and at the final food challenge visit.  
A Peak Flow Test (blowing into a device) will be done at the initial dose escalation visit 
as well as all study visits after that. 
 
 
 
 
 


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Protocol Version: 2/12/2020 
What are your responsibilities during the study? 
 
You will need to come to the Cleveland Clinic Main Campus for each of the visits 
listed in the Schedule of Visits above 
 
If you are sexually active you must use two forms of contraceptive while receiving 
study therapy and for thirsty days after therapy has stopped. 
 
You will consume a dose of the provided peanut every single day at home. We will 
send you with doses of the peanut in small medicine cups. Each day, you will mix the 
peanut with another food, such as applesauce or pudding and eat this mixture. Every 
effort should be made to consume the peanut at the same time each day using the 
same method of ingestion.  
 
At Visit 1, you will review and update your FARE's Food Allergy & Anaphylaxis 
Emergency Care Plan. This plan will outline the recommended treatment in case of 
an allergic reaction occurs during your enrollment in the study. This plan is signed by 
a physician, and includes emergency contact information. Keep your plan in a place 
where others can find it, and make sure you and others understand what to do in case 
of an emergency.   
 
You will be provided with a take home Dosing/Adverse Events Recording Sheet to 
record the time you consume the dose of peanut each day. You will also record any 
allergic reactions that may occur, the symptoms associated with those reactions, and 
any treatments required. . You will be instructed to look for objective signs of a 
reaction for up to 2 hours after ingestion including: rash/hives, lip/mouth itching, 
nausea/upset stomach, vomiting, cough/wheeze, or other.  
 
When an allergic reaction occurs at home, your parent/caregiver should 
administer the rescue medication available that corresponds with the severity 
of the reaction. All subjects will be prescribed an epinephrine auto-injector to 
have available for rescue at home. All subjects will also be prescribed an oral 
antihistamine, cetirizine (Zyrtec), to have available for rescue at home. If 
patient is allergic to cetirizine (Zyrtec), patient will be instructed to take 
diphenhydramine (Benadryl).  All subjects with an underlying diagnosis of 
asthma will be prescribed a short acting beta-agonist (albuterol or 
levalbuterol) to use for rescue at home.  
All potential allergic reactions should be recorded on the Dosing/Adverse 
Events Recording Sheet. The nature and severity of the AE as well as the 
implications for ongoing treatment will be discussed by a physician 
investigator with you at the next in-person study visit. If you have concerns 
about the reaction, you can contact a study team member at any time using the 
contact information provided within this form.  
In the event a reaction symptom occurs that is life threatening in the opinion 
of your parents and/or caregivers, you should call 911 and seek medical care 
immediately.  
 


Consent Version:  4/06/2020 
 
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Protocol Version: 2/12/2020 
At enrollment and after completion of the study, you will be asked to complete 
previously validated, age specific food allergy quality of life questionnaires27 
 
You will have to return the used medicine cups and completed Dosing/Adverse 
Events Recording Sheet to the clinic at each follow up visit.  
 
If your child is having serious side effects, you will need to call study personnel to let 
them know. If you child is ill or there is any other reason that you are unsure whether 
to give them peanut that day, you will need to call study personnel. You will be 
provided with this contact information.  
 
     A Dosing/Adverse Event Recording Sheet should be filled out for each day  
 
enrolled in the study. If a dose is missed for any reason, a Dosing/Adverse Event 
 
Recording Sheet should still be filled out documenting the date and a dose of “0” 
 
at the top. Subject nonadherence to OIT, specifically defined by 12 
 
(approximately 10%) nonconsecutive missed doses could lead to discontinuation 
 
of study intervention and removal from the study.  
 
 
 
2. ALTERNATIVES 
 
   What are the alternatives to participation in the research study?   
 
Your participation in this study is voluntary. You do not have to be in this study to 
receive treatment for your peanut allergy. If you choose not to participate, you can 
still receive treatment using standard of care treatment options, which could include 
oral immunotherapy with roasted peanut product.  
 
Standard care for peanut allergy is to avoid peanut. There are no FDA approved 
treatment options currently available for peanut allergy. This means you will be 
instructed to have your child completely avoid peanut and use the appropriate rescue 
medications as needed.  
As part of standard care, your doctor may recheck allergy tests in the future to see if 
there is any sign that you are outgrowing the peanut allergy. We only expect about 
20% of children with peanut allergy to outgrow it.  
 
 
 
3. RISKS 
 
   What are the risks of participating in the research study? 
 
There is a risk for children to have an allergic reaction to the peanut powder used in 
this study. This is most often mild symptoms such as mouth itching or stomach upset. 
Sometimes the allergic reaction be severe and life-threatening.  
 


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Protocol Version: 2/12/2020 
Common symptoms: mouth itching, nausea, vomiting  
 
Less common symptoms: sneezing, hives, itching, diarrhea, coughing, 
wheezing 
 
Rare symptoms: lightheadedness or loss of consciousness, difficulty breathing 
 
If you experience an allergic reaction in the clinic, you will be treated with 
medications. If the reaction is mild, they may be treated with an antihistamine like 
Zyrtec or Benadryl. If the reaction is severe, they may be treated with an EpiPen. 
Other treatments could include albuterol (a breathing treatment) or fluids in an IV.  
 
You will be prescribed medications to have available at home as well. All subjects 
will be prescribed an epinephrine auto-injector and an oral antihistamine, cetirizine 
(Zyrtec), to have available for rescue at home. All subjects with an underlying 
diagnosis of asthma will also be prescribed a short acting beta-agonist (albuterol or 
levalbuterol) to use for rescue at home.  
 
It is also possible that the peanut allergy can come back after the peanut powder is 
stopped and the child is no longer eating peanut every day. We don’t yet know how 
often this happens.  
 
Finally, some children treated undergoing oral immunotherapy develop EoE or 
eosinophilic esophagitis. This is a condition where there is inflammation in the 
esophagus. It can cause symptoms like difficulty swallowing, the feeling of food 
getting stuck, or heartburn.  
 
In the other studies using peanut oral immunotherapy, EoE happens in 3-4% of 
patients. 
 
Symptoms suggestive of Eosinophilic Esophagitis (EoE) will prompt 
discontinuation of oral immunotherapy and begin once weekly symptom 
monitoring phone calls with study staff. If symptoms fail to resolve after 1 
month off therapy, consultation with Gastroenterology will be considered for 
further evaluation and management. In most oral immunotherapy studies, 
when children develop EoE, it resolves or goes away once the immunotherapy 
is stopped. 
 
Please note that any treatment required for Eosinophilic Esophagitis (EoE) will 
not be paid for by the research study. If this occurs, you or your insurance 
company will be billed. 
 
 
 
 
 
 


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Protocol Version: 2/12/2020 
     4. BENEFITS 
 
   What are possible benefits of participating in the research? 
 
You may or may not benefit by participating in this research.  Based on currently 
available data, it is possible that patients treated with this novel regimen of boiled peanut 
will demonstrate lower rates of adverse events while obtaining similar immunologic 
markers of peanut desensitization and possible tolerance compared with those treated 
with OIT utilizing a traditional roasted peanut product. 
 
This research will also benefit a society as a whole. It will help people with peanut and 
other food allergies in the future if we can find ways to safely treat patients with oral 
immunotherapy.  
 
5. COSTS 
 
   Are there any costs to you if you participate in this study? 
 
You and your insurance company will be billed the usual and customary charges for all 
items and services except those required specifically and solely for this study. You are 
responsible for paying any deductibles, copayments, or co-insurance that are a normal 
part of your health insurance plan. Because you are participating in this study, the 
following services are considered to be “research only” and will be paid for by the study 
sponsor and will not be billed to you or your health insurance plan. These services 
include: 
All study visits 
Study medication (boiled peanut) 
Blood tests & skin prick testing 
 
 
6. COMPENSATION 
   Are there any payments to you if you participate in this study? 
 
You will receive a parking pass for all study related visit. Beyond this, you will not be 
provided any financial compensation to take part in this research.  
 
7. RESEARCH RELATED INJURY 
    
   What will happen if your child is injured as a result of taking part in the research? 
 
In the event you are injured as a result of participation in this research, medical care is 
available to you. The costs of such medical care will be billed to you or your insurance 
company. There are no plans to provide compensation for lost wages, direct or indirect 
losses. The Cleveland Clinic will not voluntarily provide compensation for research 
related injury. You are not waiving any legal rights by signing this form.  Further 
information about research related injury is available by contacting the Institutional 


Consent Version:  4/06/2020 
 
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Protocol Version: 2/12/2020 
Review Board at (216) 444-2924. Study participants may also contact the Clinical 
Research Unit (CRU) Research Subject Advocate (RSA), at 216-445-7846 with regard to 
questions about study participation and research subject protections.  
 
 
 
8. PRIVACY AND CONFIDENTIALITY 
 
   What will happen to your information that is collected for this research? 
 
Cleveland Clinic has rules and procedures to protect information about you.  Federal and 
State laws also protect your privacy. 
 
The research team working on the study will collect information about you.  This 
includes your health information, data collected for this research study and personal 
identifying information including your name, address, date of birth and other identifying 
information. 
 
Generally, only people on the research team will know your identity and that you are in 
the research study.  However, sometimes other people at Cleveland Clinic may see or 
give out your information.  These include people who review research studies including 
the Institutional Review Board and Research Compliance, their staff, lawyers, or other 
Cleveland Clinic staff. 
 
People outside Cleveland Clinic may need to see your information for this study.  
Examples include government groups (such as the Food and Drug Administration), safety 
monitors, other hospitals in the study and the sponsor of the research and their agents. 
Cleveland Clinic will do our best to ensure your information is kept confidential and that 
only the health information which is minimally required to conduct the study is used or 
disclosed to people outside Cleveland Clinic; however, people outside Cleveland Clinic 
who receive your information may not be covered by this promise. 
 
You do not have to give this permission to use and give out your information; however 
you will not be able to participate in this research study without providing this permission 
by signing this consent form.  The use and disclosure of your information has no 
expiration date.   
 
You may cancel your permission to use and disclose your information at any time by 
notifying the Principal Investigator in writing, Dr. Jaclyn Bjelac, M.D. at The Cleveland 
Clinic, 9500 Euclid Avenue, Mail Code R3, Cleveland, Ohio 44195. If you do cancel 
your permission to use and disclose your information, your participation in this study will 
end and no further information about you will be collected. Your cancellation would not 
affect information already collected in the study.   
 


Consent Version:  4/06/2020 
 
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Protocol Version: 2/12/2020 
By signing this informed consent form, you are authorizing access to your medical 
records. If you choose not to sign this consent form, you will not be permitted to 
participate in this research study. This Authorization does not have an expiration date. 
 
If you have any questions, you can ask the Principal Investigators, Dr. Jaclyn Bjelac 
and/or research staff. You will be given a signed copy of this authorization form for your 
records. By signing this informed consent form, you authorize the use of your identifiable 
information as described in this form. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U. S. law. This Website will not include information that can identify you.  
At most, the Website will include a summary of the results. You can search the Website 
at any time. 
 
9. QUESTIONS 
 
    Who do you call if you have any questions or problems?  
 
If you have any questions, concerns or complaints about the research, or develop a 
 
research-related problem, please contact the study team at any of the phone numbers 
 
below.  
 
 
 
Dr. Jaclyn Bjelac  
Pediatric Allergy and Immunology  
9500 Euclid Ave R3 
Cleveland, OH 44195 
Phone: (216) 445-1449 
Email: bjelacj2@ccf.org 
 
Dr. Kara McNamara 
Pediatric Allergy and Immunology  
9500 Euclid Ave R3 
Cleveland, OH 44195 
Phone: (216) 444-4828 
Email: mcnamak@ccf.org 
Navneet Singh (Research Coordinator) 
 
9500 Euclid Ave, M3 
 
Cleveland, OH 44195 
     Phone: (216) 445-2246 
 
Clinical Research Unit 
9500 Euclid Ave M51 
Cleveland, OH 44195 
Phone: (216) 445-5470 
 
Pediatric Allergy Research Pager# (216) 207-3704 


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Protocol Version: 2/12/2020 
 
 
Study participants may also contact the Clinical Research Unit (CRU) Research Subject 
 
Advocate (RSA), at 216-445-7846 with regard to questions about study participation and 
 
research subject protections. The Institutional Review Board Contact is also available for 
 
any study related questions at 216-444-2924. 
 
 
 
10. VOLUNTARY PARTICIPATION   
      
What are your rights as a research participant? 
Taking part in this study is voluntary.  You will be told of any new, relevant information 
from the research that may affect your health, welfare, or willingness to continue in this 
study.  You may choose not to take part or may leave the study at any time. Withdrawing 
from the study will not result in any penalty or loss of benefits to which you are entitled.  If 
you decide to withdraw from the study you should discuss with your study doctor your 
decision to ensure a safe withdrawal. 
 
The investigator may stop your participation in the study at any time for any of the 
following reasons: 
If it is determined that your continued participation would be harmful for your 
health as shown by a change in your laboratory values or medical condition 
If you do not follow the schedule of visits and treatments for any reason 
If the study objectives are changed or the study is cancelled 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11. SIGNATURES 
Permission of Parent/Legal Guardian (If child less than 18) 
You and your child have had the above research study explained to you and your child in 
language that you and your child can understand, and you give permission for your child’s 
participation. 
 
 
______________________________________________  
___________ 
Parent/Guardian Signature  
 
 
 
 
 
      Date 
 
 
____________________________________ 
 
 
________________ 
Printed name of Parent/Guardian 
 
 
 
            Relationship to child 
 
 
I have had the above research study explained to me in language I understand and I agree to 
participate. 
 
 
__________________________________________________ 
Printed Name of Child 
 
 
 __________________________________________________ 
___________ 
Child Signature 
 
 
 
 
 
 
      Date 
 
Statement of Person Conducting Informed Consent Discussion 
I have discussed the information contained in this document with the participant and it is my 
opinion that the participant understands the risks, benefits, alternatives and procedures involved 
with this research study. 
 
 
_____________________________________________________                     ___________ 
  
Signature of Person Obtaining Consent                                                            Date 
 
 
 
 
 
_____________________________________________________ 
 
Printed Name of Person Obtaining Consent 
 
 


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Schedule of Activities 
* Spirometry will be performed on all patients ages 5+ and/or at the physicians discretion at the initial study visit as 
well as the exit oral food challenge.  Rather than full spirometry, peak flow will be performed at every updosing 
visit on all patients ages 4+ and/or if the physician feels that it is developmentally appropriate 
 
 
 
 
 
 
 
 
Visit 
 
Study Visit 1 
Study Visit 2 
Visit 1 +1-4 weeks  
SV 3  
Visit 2 +2 weeks  
SV 4 
Visit 2 +4 weeks  
SV 5 
Visit 2 +6 weeks  
SV 6 
Visit 2 +8 weeks  
SV 7  
Visit 2 +10 weeks  
SV 8  
Visit 2 +12 weeks  
SV 9 
Visit 2 +14 weeks  
SV 10  
Visit 1 +18 weeks  
Procedures 
Enrollment/Baseline visit 
Oral Food Challenge 
Initial dose escalation  
Dose escalation visit 1 
Dose Escalation Visit 2 
Dose escalation visit 3  
Dose escalation visit 4 
Dose escalation visit 5 
Dose escalation visit 6 
Dose escalation visit 7 
Oral Food Challenge  
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw 
 
 
X 
 
 
 
 
 
 
 
X 
Skin prick test 
 
 
X 
 
 
 
 
 
 
 
X 
Oral food 
challenge 
 
X 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy  
X 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug 
Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmed 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FAQL 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
X 


Assent Version 05/29/2019 
 
Page 1 of 2  
The Cleveland Clinic Foundation 
Assent (ages 7-12) to Participate in a Research Study 
 
Study title: Boiled Peanut Oral Immunotherapy 
Principal Investigator:  Jaclyn Bjelac, MD  
     (216) 445-1449 
 
What is a research study? 
A research study is a way to find out new information about something.  Children do not need to be in a 
research study if they do not want to.  
 
Why are you being asked to be a part of this research study? 
You are being asked to take part in this research study because you have a condition called peanut 
allergy. Peanut allergy is a disease that can cause you to have an allergic reaction if you accidentally eat 
peanut.  
 
Why is the study being done? 
This study is being done to look for a treatment for peanut allergy. People have been studying one 
treatment called oral immunotherapy. It is a good treatment but can cause a lot of side effects. We are 
trying to find a treatment that will cause less side effects. We will use a different kind of oral 
immunotherapy.  
 
What will happen to you as part of the research study?  
You will come to the Cleveland Clinic many times. There will be 2 different days that you will get a 
scratch test on your skin and someone will draw blood from your arm using a needle. The other days 
you come to the Cleveland Clinic you will just eat peanut. Then you will stay in the room for a couple 
hours to see if you have an allergic reaction. You will also check to see how much air you can blow. 
You will come to Cleveland Clinic 10 times for study visits. 
 
Will any part of the study hurt, or will anything bad happen to me?  
• It might hurt a little when you get the blood drawn. We will take blood from a vein in your arm 
using a small needle 2 times during the study.  The poke may hurt for a little while and you could 
have a small bruise after it.  
• You will also have a skin test for peanut 2 times. The scratch test doesn’t really hurt but can 
make you feel itchy.  
• When you eat the peanut, you could have an allergic reaction. This can cause you to have itching 
in your mouth or an upset stomach. Sometimes it can cause more serious symptoms, like 
vomiting, having trouble breathing or feeling dizzy. If you have an allergic reaction, you might 
be given a medicine to help you feel better. 
 
Will this study help me or others? 
This study might help you have a lower chance of having an allergic reaction if you eat peanut. We also 
hope that this study will help us find a better treatment to help other children with food allergies. 
 
Who will see the information collected about you? 


Assent Version 05/29/2019 
 
Page 2 of 2  
Research information is private. The information collected about you during the study will be kept 
safely locked up.  Nobody will know it except the people doing the research.  Your information is coded 
so your name is protected. 
 
What do you get for being in the study? 
You will not be paid for being in the study. 
 
Will it cost anything to be in the study? 
 It will not cost you or your parents extra if you join the study. 
 
Do you have to be in the study? 
You do not have to be in the study if you do not want to be in it.  If you do not want to be in this study, 
you just have to tell us.  It is up to you.  You can also take more time to think about being in the study 
and to talk with your parents and/or regular doctor about the study.  
 
What if I have questions? 
You can ask any questions that you have about the study.  If you have a question later, you may call Dr. 
Jaclyn Bjelac at (216) 445-1449 or Dr. Kara McNamara at (216) 444-4828. You can take as much time 
as you need to think about being in the study.  
 
What choices do you have if you say no to the study? 
The study is extra, so if you choose not to be part of the study then your doctors will still take care of 
you as before. 
 
You may change your mind at any time, and the person in charge will take you off of the study.  
 
 
Signatures: 
 
If you sign this form, it means that you have read this form, you have talked about the study with the 
research team and your parents/guardians. All your questions have been answered, and you want to be in 
the research study.  You will be given a copy of this paper to keep. 
 If you decide to be in the study, write your name below then sign and date it.  
 
_____________________________       __________________________  
__________          
 Printed name of Child                             Signature of Child       
 
                 Date       
 
 
Statement of Person Obtaining Informed Consent Discussion 
I have discussed the information with the above participant using language which is understandable and 
appropriate.  I believe I have fully informed him/her of the nature of the study and their commitment.  I 
believe that the participant understood this explanation and assented to participate in this study.  
 
_______________________________      __________________________           ___________ 
Research Staff Member Name 
            Signature of Research Staff      
      Date 
 
 
 
 
 
 

Prot_000.pdf: 
Boiled Peanut Oral Immunotherapy for the Treatment of Peanut Allergic 
Pediatric Patients 
NCT04090203 
Study Protocol v3 2/12/2020 


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Amendment #3 
 
Boiled Peanut Oral Immunotherapy for the Treatment of 
Peanut Allergic Pediatric Patients (BPOIT) 
 
 
CCF IRB Number: 18-1294 
 
NCT number: 04090203 
 
 IND: 18661  
 
Funded by: Cleveland Clinic RPC 
Mark Lauer Pediatric Research Grant  
 
 
 
Principal Investigator 
Jaclyn Bjelac, MD 
9500 Euclid Avenue A120 
Cleveland, OH 44195 
Bjelacj2@ccf.org 
216.445.1449 office 
216.316.2754 mobile 
 
Co-Investigator/ IND Sponsor 
Alton Melton, MD 
meltona@ccf.org 
216.444.6817  
 
Co-Investigator 
Kara McNamara, MD 
216.444.4828 
mcnamak@ccf.org 
 
Co-Investigator 
Leigh Ann Kerns, MD 
216.444.6340 
Kernsl2@ccf.org 
 
 
 
 
 
 
 
 


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INVESTIGATOR’S SIGNATURE PAGE  
 
 
Protocol Amendment: 
               3 
 
Protocol Date: 
 
 
 12 February 2020 
 
 
Boiled Peanut Oral Immunotherapy for the Treatment of Peanut Allergic Pediatric Patients 
(BPOIT) 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable US federal regulations and ICH guidelines. 
 
The trial will be carried out in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312)  
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Pediatric Research Review Committee (PRRC) and Institutional Review Board (IRB) for 
review and approval.  Approval of both the protocol and the consent form must be obtained before any 
participant is enrolled.  Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study.  In addition, all changes to the consent form will be IRB-
approved; a determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
Sponsor: Alton Melton, M.D. 
 
Signed: 
 
Date: 
 
 
 
 
 
 
Investigator: Jaclyn Bjelac, M.D. 
 
Signed: 
 
Date: 
 
 
 
Name and Address of Institution:  Cleveland Clinic  
 
 
 
             9500 Euclid Avenue 
 
 
 
            Cleveland, Ohio  44195 
 
 
 


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Amendment #3 
 
Table of Contents 
       
 
Investigator Signature Page & Statement of Compliance…………………………………………..  2 
1 
Protocol Summary……………………………………………………………………………………………………. 5 
    1.1 
     Synopsis ………………………………………………………………………………………………………………. 
5 
    1.2 
     Schema ……………………………………………………………………………………………………………….. 
8 
    1.3 
     Schedule of Activities ……………………………………………………………………………………………  9 
2 
Introduction ……………………………………………………………………………………………………………. 
10 
    2.1 
     Study Rationale …………………………………………………………………………………………………… 
10 
    2.2 
     Background …………………………………………………………………………………………………………. 
10 
    2.3 
     Risk Benefit Assessment ………………………………………………………………………………………. 13 
3 
Objectives and Endpoints ……………………………………………………………………………………….. 
15 
4 
Study Design ……………………………………………………………………………………………………………. 17 
    4.1 
     Overall Design ……………………………………………………………………………………………………… 
17 
    4.2 
     Scientific Rationale for Study Design ……………………………………………………………………. 17 
    4.3 
     Justification for Dose …………………………………………………………………………………………… 
17 
    4.4 
     End of Study Definition ………………………………………………………………………………………… 17 
5 
Study Population …………………………………………………………………………………………………… 
18 
    5.1 
     Inclusion Criteria …………………………………………………………………………………………………. 
18 
    5.2 
     Exclusion Criteria …………………………………………………………………………………………………. 18 
    5.3 
     Lifestyle Considerations ………………………………………………………………………………………. 
19 
    5.4 
     Screen Failures ……………………………………………………………………………………………………. 
19 
    5.5 
     Strategies for Recruitment and Retention …………………………………………………………… 
19 
6 
Study Intervention ………………………………………………………………………………………………….. 
20 
    6.1 
     Study Intervention Administration ………………………………………………………………………. 
20 
  6.1.1 
     Study Intervention Description ……………………………………………………………………………. 
20 
  6.1.2 
     Dosing and Administration ………………………………………………………………………………….. 
22 
    6.2 
     Preparation/Handling/Storage/Accountability …………………………………………………….. 27 
    6.3 
     Measures to Minimize Bias ………………………………………………………………………………….. 28 
    6.4 
     Study Intervention Compliance …………………………………………………………………………… 
29 
    6.5 
     Concomitant Therapy ………………………………………………………………………………………….. 
29 
  6.5.1 
     Rescue Medication ………………………………………………………………………………………………. 29 
7 
Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ..  32 
    7.1 
     Discontinuation of Study Intervention …………………………………………………………………. 32 
    7.2 
     Participant Discontinuation/Withdrawal from the Study …………………………………….. 
32 
    7.3 
     Lost to Follow Up ………………………………………………………………………………………………… 
32 
8 
Study Assessments and Procedures ………………………………………………………………………… 34 
    8.1 
     Efficacy Assessments …………………………………………………………………………………………… 
34 
    8.2 
     Safety and Other Assessments …………………………………………………………………………….. 34 
    8.3 
     Adverse Events and Serious Adverse Events ………………………………………………………… 34 
  8.3.1 
     Definition of Adverse Events (AEs) ……………………………………………………………………… 
34 
  8.3.2 
     Definition of Serious Adverse Events (SAEs) ………………………………………………………… 
34 
  8.3.3 
     Classification of an Adverse Event ……………………………………………………………………….. 
35 
  8.3.4 
     Time Period and Frequency for Event Assessment and Follow Up ………………………. 
35 
  8.3.5 
     Adverse Event Reporting ………………………………………………………………………………………   37 
  8.3.6 
     Serious Adverse Event Reporting …………………………………………………………………………. 37 
  8.3.7 
     Reporting Events to Participants …………………………………………………………………………. 
37 


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  8.3.8 
     Events of Special Interest ……………………………………………………………………………………. 
37 
  8.3.9 
     Reporting of Pregnancy ……………………………………………………………………………………….. 38 
    8.4 
     Unanticipated Problems ……………………………………………………………………………………… 
38 
  8.4.1 
     Definition of Unanticipated Problems …………………………………………………………………. 
38 
  8.4.2 
     Unanticipated Problem Reporting ……………………………………………………………………….. 38 
  8.4.3 
     Reporting Unanticipated Problems to Participants ……………………………………………… 
38 
9 
Statistical Considerations ………………………………………………………………………………………… 39 
    9.1 
     Statistical Hypotheses …………………………………………………………………………………………. 
39 
    9.2 
     Sample Size Determination …………………………………………………………………………………. 
39 
    9.3 
     Population for Analyses ………………………………………………………………………………………. 
39 
    9.4 
     Statistical Analysis ……………………………………………………………………………………………….. 39 
10 
Supporting Documentation and Operational Considerations ………………………………… 
40 
   10.1 
     Regulatory, Ethical, and Study Oversight Considerations ……………………………………..  40 
 10.1.1 
     Informed Consent Process …………………………………………………………………………………… 
40 
10.1.1.1 
     Consent/Assent and Other Informational Documents Provided to Participants …… 40 
10.1.1.2 
     Consent Procedures and Documentation …………….…………………………………………  
40 
 10.1.2 
     Study Discontinuation and Closure ……………………………………………………………………… 
40 
 10.1.3 
     Confidentiality and Privacy ………………………………………………………………………………….. 
41 
 10.1.4 
     Future Use of Stored Specimens and Data …………………………………………………………… 
41 
 10.1.5 
     Key Roles and Governance ………………………………………………………………………………….. 
41 
11 
References ………………………………………………………………………………………………………………. 
43 
12 
Supplements …………………………………………………………………………………………………………… 
42 
 12.1 
     Food Allergy Quality of Life Questionnaire for Parents (1-12 years old)……………….. 
42 
 12.2 
     Food Allergy Quality of Life Questionnaire for Parents (13-16 years old)……………… 
43 
 12.3 
13 
     Dosing/Adverse Event Recording Sheet…………………………………………………………........ 
Summary of Changes Table……………………………………………………………………………………… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
44 
45 
 


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1. Protocol Summary 
 
1.1 Study Synopsis 
 
Title: 
Boiled Peanut Oral Immunotherapy 
Study Description:  
Prospective Phase 1 clinical trial providing proof of 
concept data on boiled peanut oral immunotherapy 
(OIT) for the treatment of peanut allergy in children. 
We hypothesize that the proportion of subjects 
successfully desensitized with boiled peanut OIT is 
greater than the theoretical placebo rate of 20%. 
Objectives: 
• 
Determine the effect of boiled peanut 
immunotherapy on the immune response to 
peanut. 
• 
Compare the safety and tolerability of boiled 
peanut oral immunotherapy to published data 
on roasted peanut oral immunotherapy in 
pediatric subjects with confirmed IgE mediated 
peanut allergy. 
Endpoints: 
• 
Primary endpoint:  Response to treatment 
defined as ability to successfully consume a 
single dose of 300 mg or greater of peanut 
protein with no dose limiting symptoms at exit 
double blind placebo controlled food challenge 
(DBPCFC).  
• 
Secondary endpoints: 
• 
Maximum dose achieved with no or minimal 
symptoms at exit DBPCFC. 
• 
Change in the maximum tolerated dose from 
screening to exit DBPCFC. 
• 
The rate of side effects of treatment defined as 
oral itching, rhinorrhea, conjunctivitis, urticaria, 
angioedema, abdominal upset, vomiting, 
diarrhea, cough, wheeze, or anaphylaxis. 
• 
Change in quality of life scores before and after 
treatment utilizing validated , age specific, 
food-related quality-of-life surveys before and 
after peanut oral immunotherapy (Supplement 
1) 
• 
Peanut protein component panel, to determine 
the presence of high levels of sensitivity to 
peanut proteins known to be associated with 
severe systemic reactions (Arah 1,2,3) versus 
mild reactions (Arah8). 


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Melton/Bjelac 
02-12-2020 
Amendment #3 
 
• 
Levels of peanut specific serum IgG4, with 
higher levels associated with increased 
tolerance to peanut protein. 
Study Population:  
Children ages 1-16 with peanut allergy suggested via 
history of reaction and objective evidence of IgE 
mediated hypersensitivity either via skin testing or in 
vitro testing (peanut specific IgE concentration) within 
the last 12 months. 
Inclusion criteria:  
• 
Age 1-16 years 
• 
History of immediate hypersensitivity reaction 
to peanut or a high level of suspicion based on 
testing at the discretion of the investigator 
• 
Evidence of IgE mediated peanut 
hypersensitivity within a 12 month period of 
study enrollment  including:  
• 
Skin prick test with wheal diameter of 
at least 3mm and/or 
• 
Peanut specific IgE >0.35 ku/L  
Exclusion criteria:  
• 
History of life threatening peanut anaphylaxis 
• 
Asthma requiring more than medium dose 
inhaled corticosteroids for age per the National 
Heart, Lung, and Blood Institute Asthma 
Guidelines 
• 
Cardiovascular disease 
• 
Use of beta-blockers (oral), angiotensin 
converting enzyme inhibitors, angiotensin 
receptor blockers, or calcium channel blockers 
• 
Use of steroid medications in the following 
manners: 
• 
Daily oral steroid dosing for greater than 1 
month during the past year OR 
• 
Burst or steroid course in the past 3 months 
before inclusion OR 
• 
Greater than 2 burst oral steroid courses in the 
past year of at least 1 week duration 
• 
Pregnancy or lactation 
• 
Prior participation in food oral immunotherapy 
studies, including OIT, sublingual 
immunotherapy (SLIT), or epicutaenous 
immunotherapy (EPIT) 
• 
Eosinophilic gastrointestinal disease 
• 
Oat allergy, as oat flour is the vehicle with 
which study drug may be mixed for purposes of 
blinding and will be used as placebo for the exit 
DBPCFC 


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Melton/Bjelac 
02-12-2020 
Amendment #3 
 
• 
History of food protein-induced enterocolitis 
syndrome (FPIES) 
• 
History of developmental delay or speech delay 
that precludes age-appropriate 
communication, in the opinion of the 
investigator 
Description of Sites and Facilities Enrolling 
Patients:  
Screening will be performed at the Cleveland Clinic 
main campus and satellite outpatient clinic locations. 
Any patients identified as eligible will be referred to 
main campus for further evaluation and possible 
enrollment.  
Description of Study Intervention:  
Oral Immunotherapy will be administered utilizing a 
powder derived from boiled peanuts. Treatment will 
begin with an initial escalation day in which dosing is 
begun at 0.1 mg peanut protein and escalated to a final 
dose of 6 mg peanut protein. Doses are ingested orally. 
The subjects will continue daily oral ingestion of doses 
at home and return for updosing every 2 weeks to a 
final maintenance dose of 300 mg peanut protein. The 
subjects will continue daily oral ingestion of the peanut 
product for a minimum duration of 28 days before 
undergoing exit DBPCFC. At the conclusion of the study, 
patients will be offered continued maintenance 
therapy off study in line with current specialty 
standards.   
Study Duration: 
18 weeks 
Participant Study Duration:  
18 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2 Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Open food 
challenge 
No signs of allergic 
reaction 
Signs of  
allergic reaction 
Does not 
qualify 
Enrolled in study  
Initial dose escalation day 
Withdrawn 
Continue dose at 
home 
Unacceptable side effect at dose 
≤ 1.5 mg peanut protein 
Ingests dose of ≥ 1.5 mg peanut 
protein without adverse reaction 
Return for dose escalation every 
2 weeks 
Reach maintenance dose of 300 
mg peanut protein 
Continue daily maintenance 
dose 
Return for 1 month exit DBPCFC 


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1.3 Schedule of Activities  
 
 
 
 
 
 
 
Visit 
 
Study Visit 1 
Study Visit 2 
Visit 1 +1-4 weeks  
SV 3  
Visit 2 +2 weeks  
SV 4 
Visit 2 +4 weeks  
SV 5 
Visit 2 +6 weeks  
SV 6 
Visit 2 +8 weeks  
SV 7  
Visit 2 +10 weeks  
SV 8  
Visit 2 +12 weeks  
SV 9 
Visit 2 +14 weeks  
SV 10  
Visit 1 +18 weeks  
Procedures 
Enrollment/Baseline visit 
Oral Food Challenge 
Initial dose escalation  
Dose escalation visit 1 
Dose Escalation Visit 2 
Dose escalation visit 3  
Dose escalation visit 4 
Dose escalation visit 5 
Dose escalation visit 6 
Dose escalation visit 7 
Oral Food Challenge  
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw 
 
 
X 
 
 
 
 
 
 
 
X 
Skin prick test 
 
 
X 
 
 
 
 
 
 
 
X 
Oral food 
challenge 
 
X 
 
 
 
 
 
 
 
 
X 
Urine 
Pregnancy  
X 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug 
Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmed 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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All dose escalation visits have a window of +/- 2 day 
All follow up visits have a window of +/- 7 days 
The enrollment/baseline visit, initial oral food challenge (SV 1), will take place at the Pediatric Allergy 
Clinic at the Cleveland Clinic main campus.  
 
The initial escalation day, dose escalation visits, and final oral food challenge (SV 2-10) will take place in 
the Clinical Research Unit. 
 
* Spirometry will be performed on all patients ages 5+ and/or at the physician’s discretion at the initial 
study visit as well as the exit oral food challenge. Rather than full spirometry, peak flow will be 
performed at every updosing visit on all patients ages 4+ and/or if the physician feels that it is 
developmentally appropriate 
 
2. Introduction  
 
2.1 Study Rationale 
Peanut allergy (PA) is a common and potentially life threatening condition for which the only current 
approved management involves strict dietary avoidance. Oral immunotherapy (OIT) is a promising 
investigational treatment option for this condition, and multiple published studies have demonstrated 
efficacy in achieving successful desensitization to peanut in children with peanut allergy.8-16 However, 
the widespread clinical use of OIT has been limited by numerous factors. These include the high rate of 
adverse events (AEs), including anaphylaxis, which often leads to high subject drop-out rates in 
published studies (Table 1). These studies all used peanut products produced by roasting methods, 
including flour, peanut powder, or peanut butter. Published data have demonstrated that boiling peanut 
results in reduced allergenicity while preserving the immunogenicity necessary to produce tolerance.19 
In this pilot study, we plan to compare the use of boiled peanut OIT to published data on roasted peanut 
OIT in children with peanut allergy. Based on currently available data, we hypothesize that the subjects 
treated with this novel regimen of boiled peanut will demonstrate lower rates of adverse events while 
demonstrating similar immunologic markers of peanut desensitization and possible tolerance compared 
to published data on subjects treated with OIT utilizing a traditional roasted peanut product. 
 
2.2 Background and Significance  
Peanut allergy (PA) has a reported prevalence of 2% in children and 0.7% in adults.1 The prevalence of 
PA also appears to be increasing, and in a registry of fatal food induced anaphylaxis, 63% of the 32 
fatalities were caused by peanut.2 The implications of PA extend beyond the patient and their family. 
This food allergy in particular has impacted the educational system as well as the food industry.3 The 
effect on quality of life can be significant,4,5 often leading to social isolation and even fear of death. 
Currently standard of care for PA consists of allergen avoidance, which is often ineffective, and 
administration of emergency medications on accidental exposure.6 Given the prevalence of PA and its 
associated morbidities, safe and effective therapies are desperately needed. 
 
Immunotherapy relies on the delivery of increasing doses of specific allergens over time with the goal of 
developing desensitization, which increases the dose of protein needed to elicit an allergic response. 
FAQL 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
X 


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Melton/Bjelac 
02-12-2020 
Amendment #3 
 
Over the past century, immunotherapy has been successfully used to treat asthma, allergic rhinitis, and 
insect venom anaphylaxis through subcutaneous or sublingual administration. Although the exact 
mechanisms underlying allergen immunotherapy are still not fully understood, it is known to induce 
allergen-specific regulatory T cells, which suppress TH2 responses that promote IgE production. This 
response is coupled with increases in serum concentrations of allergen-specific IgG4 antibodies which 
compete with IgE on cell surfaces and result in reductions in mast cell and basophil activation and 
mediator release.7 An increased IgG4 to IgE ratio is associated with clinical tolerance to a given food. 
 
Though immunotherapy can be administered in a variety of methods, oral immunotherapy (OIT) has 
shown the most promise in the treatment of food allergy. Several recent trials have utilized the 
technique of oral immunotherapy for treatment of peanut and other food allergies. This therapy 
involves mixing the food allergen into a vehicle of choice and having the subject begin daily consumption 
while gradually increasing the dose. Several endpoints have been defined when evaluating the response 
to immunotherapy. Desensitization results in a higher threshold for an allergic reaction, typically above 
the amount that will be encountered in an accidental exposure. However, this does require ongoing 
dosing. The most desirable outcome of OIT is sustained unresponsiveness, or continued long term 
tolerance of the food without the need for daily maintenance therapy.  
 
Although individual responses vary considerably, OIT will induce significant desensitization in most 
subjects who are able to tolerate the therapy. However, these studies are limited by frequent treatment 
related AEs and high rates of withdrawal due to these AEs. The reported AEs and dropout rates from 
representative studies are outlined in Table 1.8-16  
 
There is a large amount of heterogeneity in the reporting of AEs. More specifically, AEs are at times 
reported in terms of the percent of subjects experiencing an adverse reaction. At other times, adverse 
reactions are reported in terms of the percent of doses that cause an AE. This method is often utilized to 
report AEs during maintenance dosing. This is in part due to the fact that over the course of all phases of 
an individual study and when including mild AEs in addition to more significant reactions, nearly 100% of 
patients have some form of AE during treatment. Thus it may be more meaningful to report the percent 
of doses causing symptoms at times.  
 
Table 1: Prior OIT Trials  
Author 
N 
Age 
Design 
Adverse Events 
Drop 
outs 
Additional Detail on Drop Outs 
Jones et al 
2009 [8] 
39 
1-16 
Open label 
92% of subjects on initial escalation 
day, 46% doses during build up, 3.7% 
doses during maintenance 
10 
(25%) 
4 withdrew  for allergic effects and 
6 for personal reasons 
Hofmann 
et al 
2009 [10] 
28 
1-16 
Open label 
93% of subjects on initial escalation 
day, 46% doses during build up, 3.5% 
of doses during maintenance 
5 
(18%) 
3 withdrew following initial 
escalation, 1 during build up, 1 
during maintenance 
Blumchen 
et al 
2010 [9] 
23 
3-14 
Randomized, 
open label 
7.8% of doses during rush protocol, 
2.9% of doses during maintenance 
8 
(35%) 
1 during rush protocol, 7 during 
long term buildup of which 4 for 
allergic side effects 
Varshney 
et al 
2011 [11] 
19 
1-16 
Double blind, 
placebo 
controlled 
47% subjects with “clinically 
relevant” AEs during initial 
escalation day, 1.2% doses during 
build up 
3 
(16%) 
2 withdrew during initial escalation 
day and 1 after first build up dose 
Anagnostou 
et al 
22 
4-18 
Open label 
86% subjects during build up and 
maintenance 
1 
(5%) 
Withdrew after the first up dose at 
home 


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02-12-2020 
Amendment #3 
 
2011 [12] 
Anagnostou 
et al 
2014 [13] 
99 
7-16 
Randomized, 
placebo 
controlled 
cross over 
6.3 % of all doses 
7 
(7%) 
5 withdrew for allergic reactions or 
persistent symptoms, 1 disliked 
taste, and 1 no specific reason 
Vickery et al 
2014 [14] 
39 
1-16 
Open label 
Previously reported in pilot study 
(Jones et al 2009) 
15 
(38%) 
6 withdrew due to allergic side 
effect and 9 for personal reasons 
Narisety et 
al 
2014 [15] 
21 
7-13 
Randomized, 
double blind, 
placebo 
controlled 
43% doses during blinded phase 
(escalation and maintenance), 36.7% 
doses in OIT group during unblended 
phase 
7 
(33%) 
1 withdrew after initial escalation, 
1 during build up and 3 during 
maintenance. 1 drop out on SLIT 
with placebo OIT 
Vickery et al 
2016 [16] 
37 
9-36 
months 
Randomized, 
double blind, 
low and high 
dose 
95% patients during entire study, 
0.8% doses during study 
5 
(14%) 
2 withdrew for nonadherence, 1 for 
recurrent emesis and 1 for EoE 
Abbreviations: N, number of subjects, AEs, adverse events, SLIT, sublingual immunotherapy, OIT, oral 
immunotherapy, EoE, eosinophilic esophagitis 
 
 
Given the high rate of these treatment related AEs such as oral itching, stomach upset and other GI 
complaints, and occasional serious systemic allergic reactions requiring the use of injectable 
epinephrine, OIT is still considered an experimental treatment. While some major medical centers and a 
number of private practice allergists offer peanut OIT to their patients, it is not yet FDA approved.  
 
A commercially developed product, AR101 (Aimmune Therapeutics), an investigational oral biologic 
drug, was recently trialed in a phase 3 study evaluating efficacy. In the intervention group, 67.2% of 
patients ages 4–17 tolerated at least a 600-mg dose of peanut protein in the exit food challenge, 
compared to 4.0% of placebo patients (p<0.00001). In the trial’s primary analysis group of ages 4-17, 496 
patients from both arms (372 AR101 and 124 placebo) were evaluable for safety. In both arms, the 
incidence of serious adverse events (SAEs) was low. A total of 10 patients experienced SAEs, none of 
which were considered life-threatening: nine of these patients were in the AR101 arm (2.4%) and one 
was in the placebo arm (0.8%). Of the nine AR101 patients who experienced a SAE, five patients 
experienced mild or moderate SAEs. The other four AR101 patients experienced severe SAEs, which, for 
two of these patients, were not related to treatment (a concussion and a viral asthmatic exacerbation). 
Of the two patients who experienced severe SAEs related to treatment, both of whom had elevated 
baseline peanut-specific IgE levels greater than 100 kU/L, one experienced anaphylaxis, and the other 
experienced wheezing on the first day of treatment. Both of these patients discontinued from the study. 
In ages 4–17, 20.4% of AR101 patients and 6.5% of placebo patients discontinued the trial. In the AR101 
arm, 12.4% of patients discontinued due to investigator-reported adverse events, including 6.7% due to 
gastrointestinal adverse events and 2.7% due to systemic allergic hypersensitivity reactions. In the 
placebo arm, 2.4% of patients discontinued due to investigator-reported adverse events (Table 2).28 
 
 
 
 
 
 
 
 


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Table 2: Discontinuations in the AR101 Group28     
 
 
 
  
 
 
AR101 
(n= 372) 
% 
n 
Total discontinuations regardless of causality 
20.4% 
76 
Discontinuations not related to adverse 
events 
8.0% 
30 
Discontinuations related to adverse events 
12.4% 
46 
• 
Gastrointestinal2 
 
6.7% 
25 
• 
Systemic hypersensitivity reactions3 
2.7% 
10 
• 
Respiratory system 
1.1% 
4 
• 
Cutaneous 
0.8% 
3 
• 
Other 
1.1% 
4 
 
 
We seek to identify a means of accomplishing peanut desensitization while decreasing the rate of 
treatment related AEs. It has been shown that standard roasting methods of peanut preparation can 
play a significant role in increasing the undesirable allergenic properties of peanuts.17 It has also been 
demonstrated that peanut antigen stimulation of peripheral blood T lymphocytes is unaffected by 
various heating methods, which is necessary for induction of tolerance.18  An additional study confirms 
the findings of extended boiling resulting in reduction of peanut allergenicity while preserving the effect 
on T cell reactivity.19 A group recently reported a series of 4 subjects with peanut allergy who were 
treated with daily doses of boiled peanut, one of which subsequently transitioned to raw peanut. All 
subjects demonstrated lower IgE reactivity to boiled peanut compared to control suggesting that in vivo 
findings correlate with the prior in vitro data.20 
 
While OIT is a promising therapy, we hypothesize that by treating peanut allergic subjects with a peanut 
product of reduced allergenicity but preserved T cell reactivity, we will be able to desensitize these 
subjects to a target maintenance dose of peanut protein with reduced rates of allergen associated AEs, 
while preserving immunologic effects that will promote tolerance. This will confirm that the 
immunologic changes produced by roasted peanut OIT can be replicated more safely using boiled 
peanut. If successful, such a therapy will decrease the number of subjects that must discontinue this 
treatment due to related AEs, and offer a potentially important therapy for this life threatening 
condition. Improved safety of this intervention may also allow for higher treatment doses to be used, 
may allow inclusion of more severely allergic subjects excluded from previous trials, and possibly 
increase the likelihood for attainment of permanent tolerance with sustained unresponsiveness, rather 
than perpetuating the need for continual daily dosing. This will likely result in the eventual inclusion of 
BPOIT in general Allergy/Immunology practice as a treatment for peanut allergy. We suspect this 
therapy will improve quality of life as measured by validated questionnaires as well as, or better than, 
roasted peanut oral immunotherapy.28 
 


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2.3 Risk/Benefit Assessment  
 
2.3.1 Known potential risks 
There is a significant rate of adverse reactions with peanut oral immunotherapy in clinical trials to date. 
Mild adverse reactions such as oral itching or nausea are reported in up to 10-15% of all doses. Over the 
course of an individual study, this reaches nearly 100% of all subjects. The rate of these adverse events 
are outlined in representative studies in Table 1.  
 
More severe reactions requiring treatment with epinephrine or inhaled beta-agonists are less frequent 
but can occur.  In a large review of multiple centers performing peanut OIT, Wasserman et al noted a 
total of 95 adverse reactions requiring epinephrine in 352 patients that collectively received more than 
240,000 doses of peanut.25 The results of the largest peanut OIT trial to date, a phase 2 clinical trial 
utilizing product AR101 were published in March of 2018.21 In this study, 9 (14%) of 63 subjects received 
a single injection of epinephrine during initial double blind placebo controlled food challenge (DBPCFC) 
at screening: 4 were randomized to AR101, 4 to placebo, and 1 was not enrolled. For the duration of 
maintenance therapy, one treatment subject received a single epinephrine injection for moderate 
anaphylaxis at home. Finally, during the exit DBPCFC, 11 of 26 placebo subjects (42%) were administered 
epinephrine and 2 of 23 AR101 subjects (9%) received a single injection of epinephrine. 
 
Across the various peanut OIT trials, there has been no specific statistical analysis examining adverse 
reaction rate or withdrawal rate at various ages. Presumably this is due to the fact that no specific age 
related pattern has emerged and that anaphylaxis and subject withdrawal has occurred in subjects of all 
ages. 
 
There is also a risk for development of Eosinophilic Esophagitis (EoE). A recent review estimated the 
prevalence across the OIT clinical trials as 3-4% and in the study conducted by Bird et al, EoE occurred in 
only 1 subject ( <5%) from the treatment group.21 Once OIT is discontinued in these patients, the EoE 
typically resolves.  
 
There is also a risk of causing anxiety or stress in the subject or the family. The impact of oral 
immunotherapy on quality of life has been examined with a variety of foods. Quality of life in patients 
with food allergy improves in some but declines in others while undergoing OIT, and in particular tends 
to decline in those rating a higher quality of life prior to initiation of the treatment.26  
 
2.3.1 Known Benefits 
The primary benefit of peanut oral immunotherapy is increasing the threshold of peanut which will 
result in an allergic reaction. This increased threshold is typically above the amount encountered upon 
accidental ingestion. This can reduce the risk of a subject experiencing a severe or life-threatening 
allergic reaction due to an accidental ingestion. Importantly, this can also ease anxiety in both the 
subject and family that is often associated with the diagnosis of a food allergy.  
 
The question of whether oral immunotherapy will induce sustained unresponsiveness, or ongoing 
tolerance of peanut following cessation of the daily maintenance doses, is yet to be fully elucidated. 


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Results have varied among initial clinical trials. If this can be obtained, this would allow full incorporation 
of peanut into the diet of previously allergic subjects. 
 
 
2.3.3 Assessment of the potential risks and benefits 
We believe that given the low rate of serious adverse reactions along with the hypothesis that subjects 
receiving the boiled peanut will experience a lower rate of these adverse reactions, that the potential 
benefit to induce desensitization to peanut outweighs these risks. In addition to personal benefit, this 
study has the potential to further the future treatment options for peanut allergic children.  
 
3. Objectives and Endpoints 
 
Objective 
Endpoints 
Justification 
Primary 
Determine the effect of 
boiled peanut 
immunotherapy on the 
immune response to peanut 
and demonstrate that the 
proportion of subjects 
successfully desensitized with 
boiled peanut OIT is not 
appreciably lower than the 
proportion of subjects 
successfully desensitized with 
roasted peanut OIT in 
published data.  
 
 
 
 
Primary Endpoint: Response to 
treatment defined as ability to 
successfully consume a single dose 
of 300 mg or greater of peanut 
protein with no dose limiting 
symptoms at exit double blind 
placebo controlled food challenge 
(DBPCFC).  
 
The highest dose of roasted 
peanut protein tolerated by the 
subject at exit DBPCFC will also be 
compared to the highest dose 
tolerated at baseline.  
 
The effect of boiled peanut 
immunotherapy on the immune 
response to peanut will be 
evaluated via specific serum 
markers of sensitization and 
tolerance to peanut.  
• 
Levels of serum specific 
peanut IgE, with higher 
levels associated with 
greater likelihood of 
clinical reaction on 
exposure to peanut 
protein. 
• 
Peanut protein component 
panel, to determine the 
presence of high levels of 
sensitivity to peanut 
proteins known to be 
Previous in vitro data has 
demonstrated that boiling 
peanuts can result in reduction 
of peanut allergenicity while 
preserving the effect on T cell 
reactivity.  


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associated with severe 
systemic reactions (Arah 
1,2, 3) versus mild 
reactions (Arah8) 
• 
Levels of peanut specific 
serum IgG4, with higher 
levels associated with 
increased tolerance to 
peanut protein 
• 
These markers will be 
evaluated at baseline and 
the conclusion of the 
study.  
Secondary  
Compare the rate of adverse 
effects of boiled peanut oral 
immunotherapy to published 
data on roasted peanut oral 
immunotherapy. 
The rate of adverse events in the 
subjects receiving boiled peanut 
oral immunotherapy. Possible 
adverse events include: side 
effects of treatment defined as 
oral itching, rhinorrhea, 
conjunctivitis, urticaria, 
angioedema,  abdominal upset, 
vomiting, diarrhea, cough, wheeze, 
or anaphylaxis 
• 
Adverse events will be 
recorded in terms of the 
percentage of subjects 
with adverse events on 
initial escalation day and 
at dose escalation visits by 
CRU staff.  
• 
Adverse events will also be 
recorded in terms of 
overall percentage of 
home doses that result in 
adverse reaction, with 
data compiled from home 
logs (Supplement 2).  
The adverse reactions will be 
graded in severity and the 
treatment required will be 
recorded.   
 
Validated, age-specific, food-
related quality-of-life surveys 
before and after peanut oral 
immunotherapy will be completed 
As described above, the rate of 
adverse events with roasted 
peanut oral immunotherapy is 
high. Thus treatment options 
with less adverse effects are 
highly desirable. In vitro data has 
demonstrated that boiled peanut 
has reduced allergenicity 
compared to roasted peanut and 
similar immunogenicity. As such, 
we anticipate a lower rate of 
adverse reactions in our subjects 
compared to published data on 
roasted peanut OIT. 


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by all patients/families27 
(Supplement 1). 
 
4. Study Design 
 
4.1 Overall Design 
We will perform a phase 1 clinical trial utilizing oral immunotherapy with powder derived from boiled 
peanut. Our hypothesis is that the subjects treated with this novel regimen of boiled peanut will 
demonstrate lower rates of adverse effects while demonstrating similar immunologic markers of peanut 
desensitization and possible tolerance in comparison to published data on subjects treated with OIT 
utilizing roasted peanut product. 
 
4.2 Scientific Rationale  
Oral immunotherapy has not yet been approved by the FDA for the treatment of food allergy. However, 
multiple clinical trials in recent years have shown significant promise in utilizing oral immunotherapy for 
peanut allergy. It is expected that oral immunotherapy will be more widely available in the near future, 
and options with a more favorable side effect profile are highly desirable.  
 
The phases of our clinical trial were modeled after the previous high quality studies utilizing roasted 
peanut OIT and are comparable in methodology and duration.  
 
4.3 Justification for Dose 
The maintenance dose for oral immunotherapy with peanut has varied across previous clinical trials. 
Doses have ranged from 300 mg up to a maximum of 4000 mg.8-16 Only one study has compared the 
efficacy of different maintenance doses. In this study, Vickery et al found that a maintenance dose of 
300 mg was as efficacious as a 3000 mg dose at inducing sustained unresponsiveness. This is also likely 
to be above the dose encountered in an accidental ingestion, as 1 whole peanut contains roughly 250 
mg of peanut protein.22  
 
4.4 End of Study Definition  
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA. 
 
 
5. Study Population 
 
We will recruit 10 children ages 1 to 16 years with peanut allergy suggested via history and objective 
evidence of IgE mediated hypersensitivity to peanut either via skin testing or in vitro testing (peanut 
specific IgE concentration) within the last 12 months. Skin prick testing will be performed with standard 
peanut extract (1:20 w/v, Greer) and peanut specific IgE concentration will be performed using 
ImmunoCap. We will use standard criteria to indicate sensitization.  
 
 
 


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5.1 Inclusion Criteria  
 
Abbreviations: SPT, skin prick test 
 
In addition, the individual’s parent or guardian must provide signed and dated informed consent and the 
individual must provide signed and dated assent when appropriate. The individual and parent or 
guardian must agree to comply with all study procedures and the individual must have the ability to take 
oral medication.  
 
5.2 Exclusion Criteria 
 
Abbreviations: ICS, inhaled corticosteroid, OIT, oral immunotherapy, SLIT, sublingual immunotherapy, EPIT, 
epicutaneous immunotherapy 
 
A history of life-threatening anaphylaxis is defined as a reaction involving respiratory failure, 
hypotension or neurologic compromise. Medium dose ICS is defined by the National Heart, Lung, and 
Blood Institute asthma guidelines. Patients with oat allergy, while rare, are to be excluded as this will 
serve as the placebo for our exit food challenge (SV10). 
Inclusion Criteria 
Age 1-16 years 
History of immediate hypersensitivity reaction to peanut or a high level of suspicion based on 
testing at the discretion of the investigator 
Evidence of IgE mediated peanut hypersensitivity within a 12 month period of study 
enrollment 
           SPT with wheal/flare of at least 3 x 6 mm 
                                and/or 
           Peanut specific IgE >0.35 kU/L 
Exclusion Criteria 
History of life threatening peanut anaphylaxis 
Asthma requiring more than medium dose ICS 
Prior participation in OIT, SLIT or EPIT 
Oat allergy 
Cardiovascular Disease 
Use of beta-blockers (oral), angiotensin converting enzyme inhibitors, angiotensin receptor 
blockers, or calcium channel blockers 
Use of steroid medications in the following manners: 
             Daily oral steroid dosing for greater than 1 month during the past year OR 
             Burst or steroid course in the past 3 month before inclusion OR 
             Greater than 2 bursts oral steroid courses in the past year of at least 1 week duration 
Pregnancy or lactation 
Eosinophilic Gastrointestinal Disease 
History of food protein-induced enterocolitis (FPIES) 
History of developmental delay or speech delay  that precludes age-appropriate communication, 
in the opinion of the investigator 


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5.3 Lifestyle Considerations 
With the exception of the oral immunotherapy treatment, subjects will be instructed to continue strictly 
avoiding peanut in their diet. Prior oral immunotherapy studies have sought to determine predictors of 
adverse reactions to treatment and co-factors are often noted in subjects that do experience adverse 
reactions. This can include illness, exercise, or allergen exposure in subjects with allergic rhinitis.23 
Subjects will be instructed to refrain from exercising for 60 minutes following ingestion of the study 
drug. Subjects and their families will also be instructed to contact the physician investigators if an illness 
or significant rhinitis symptoms occur, as a temporary adjustment to the daily dose may be necessary. 
 
5.4 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because there are 
no objective signs of an IgE mediated reaction during initial food challenge may not be rescreened. 
These individuals are not peanut allergic and thus not candidates for the treatment of peanut allergy.  
 
5.5 Strategies for Recruitment and Retention  
Individuals will be screened for possible study eligibility at the Cleveland Clinic Allergy Clinic locations. 
The recruiting physicians will include the Pediatric Allergy clinic staff as well the Respiratory Institute 
Allergy staff. All Allergy physicians will be made aware of the study and details of recruitment at a 
Quarterly Allergy and Immunology staff meeting which is attended by both Pediatric Institute and 
Respiratory Institute allergy physicians.  
 
Once potential participants are identified, a study investigator will reach out to the parent/guardian of 
the patient via an introductory letters and telephone to inquire about study interest. Should the family 
express a desire to participate, they will be invited to the main campus for Enrollment/Baseline visit. 
This visit will take place with one of the physician investigators and will involve extensive discussion of 
the study including protocol, risks and benefits. If the individual and their parent or guardian opt to 
participate in the study, informed consent, and assent when appropriate, will be obtained at this time 
and the individual will be enrolled. 
 
There has been a significant amount of media and online attention to these evolving treatment options 
for food allergy including OIT. As such, frequent and unsolicited inquiries regarding OIT are made by 
patients/families encountered in the Allergy clinics. This fact accompanied by the prevalence of peanut 
allergy in the pediatric population leads us to believe the accrual rate of participants will be fairly rapid.  
 
6. Study Intervention  
 
6.1 Study Interventions Administration  
 


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6.1.1 Study Intervention Description 
Commercially available whole canned boiled peanuts (Peanut Patch, McCall Farms) will be purchased 
from online retailers. This commercially available product, regulated by the Food and Drug 
Administration, is regularly consumed by humans. 
 
Although additives are typically contained in commercially available products, this is not expected to be 
clinically relevant. The prevalence of allergy to food additives has been reported as high as 0.23% based 
on self-report. However, the reported cases in medical literature are typically either anecdotal or 
diagnosed based on poorly-controlled challenge procedures. Thus expert consensus is that relatively few 
food additives have been convincingly demonstrated to true hypersensitivity reactions.6  
 
Peanut Patch  
Information from the Manufacturer’s Website: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Nutrition Facts 
Serving Size 1/4 cup (about 34g) 
Amount Per Serving 
Calories 100Calories from Fat 70
% Daily Value*
Total Fat 8g 
12%
Saturated Fat 1.5g 
8%
Trans Fat 0g 
Cholesterol 0mg 
0%
Sodium 320mg 
13%
Total Carbohydrate 3g 
1%
Dietary Fiber 2g 
8%
Sugars 0g 
Protein 4g 
Vitamin A 0% 
Vitamin C 0% 
Calcium 0% 
Iron 2% 
* Percent Daily Values are based on a 2,000 calorie diet. Your daily values 
may be higher or lower depending on your calorie needs: 
Calories per gram: 
Fat 9 • Carbohydrate 4 • Protein 4 
 
 
 


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The boiled peanuts will be processed into powder. All processing will take place in the University 
Hospitals Dahms Clinical Research Unit kitchen. The Dahms Clinical Research Unit kitchen is a Class III 
Non-Commercial Food Service establishment and is inspected on a routine basis through the Cleveland 
Health Department.  The peanut processing will be supervised by the CRU Bionutrition director who is 
certified in food protection through the Ohio Department of Health. 
Boiled peanuts will be shelled and placed evenly on individual trays of a food dehydrator purchased for 
use of this process only (Nesco FD-75a Food Dehydrator). The dehydrator was purchased specifically for 
this study and no other food items will come into contact with or be used on this device. Peanuts will be 
dehydrated at a temperature of 105 degrees F (41 degrees C) for 17 hours (1,020 minutes). Immediately 
upon removal, peanuts will be ground to a fine powder in a food processor. 
 
Peanut powder will be placed in Pactiv/Newspring plastic deli containers with lids. These will be sealed, 
labeled, and shipped via courier from the Case Western Clinical Research Unit directly to the 
investigational drug pharmacy for storage in a refrigerator.   
 
We will characterize the processed boiled peanut and determine the concentration of peanut protein. 
This will be necessary to calculate the doses for subjects in the boiled peanut immunotherapy arm. To 
further characterize this product, the specific component proteins including Ara h 1, 2, 3, 8 and 9 will 
also be quantified. These specific proteins are known to be associated with either higher risk for 
anaphylaxis (Ara h 1, 2, and 3) versus more mild reactions (Ara h 8).24 This assay will be performed as an 
ELISA within the Cleveland Clinic Proteomics lab.  
 
A representative sample from each batch of prepared boiled peanut powder will be sent to JLA 
laboratories, a USDA certified lab, in order to test for aflatoxin levels and to quantify a total bacterial 
count and total mold count. This lab is approved by the USDA-AMS for Aflatoxin in Peanuts and ISO 
17025 accredited by ANAB for aflatoxin and microbiological testing. Aflatoxin testing is performed by 
HLPC method in accordance with AOAC 991.31 and AOAC 2005.08. The total bacterial count will be 
obtained using AOAC-RI 051702/MB073.6 and the mold count using AOAC- RI 051702/MB074.03.  
 
The doses will be measured and allotted into individual medicine cups by the Investigational Drug 
Service Department as outlined in Section 6.2. The subjects will mix the powder with a vehicle of the 
subject/family’s choice (applesauce, pudding, or hot cereal) just prior to oral ingestion. 
 
6.1.2 Dosing and Administration 
Oral Food Challenge 
After informed consent is obtained (and assent when relevant), eligible subjects will undergo an open 
roasted peanut graded food challenge to 4000 mg of peanut protein to confirm peanut allergy and to 
determine the amount of peanut protein required to induce an allergic reaction at baseline. An oral food 
challenge is the gold standard for diagnosis of food allergy. PB2 peanut powder (PB2 Foods, Tifton, GA) 
will be used exclusively for this challenge, mixed in a vehicle of the family’s choice (such as applesauce, 
pudding, etc).  
 
Subjects will be instructed to hold medications with strong antihistamine properties for five days prior to 
the challenge (diphenhydramine, loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, 
azelastine). The challenge will not be performed in the setting of acute illness, including febrile illness, 
asthma exacerbations, and significant flares of atopic dermatitis.  
 


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The oral food challenge protocol is outlined in Table 3. The initial oral food challenge will take place 
under the supervision of a trained Allergy/Immunology investigator and trained Allergy/Immunology 
nurse at Cleveland Clinic Children’s main campus Allergy Clinic, where similar food challenges are 
routinely conducted. The physician investigator available will be trained in recognition and treatment of 
IgE mediated food reactions, will be available for immediate evaluation of any signs or symptoms of 
reaction.  
 
Table 3: Oral food challenge to peanut for enrollment (Study Visit 1) 
Time  
Dose 
Clinician Intervention * 
0 
5mg 
Obtain weight, temperature, heart rate, blood pressure, 
respiratory rate, and oxygen saturation level. Peak flow will 
be done on patients 4+ or deemed developmentally 
appropriate. Full physical examination of ears, oropharynx 
and nose, lungs, and skin prior to administration of dose 
+15 minutes  
10mg 
Examination of skin and auscultation of lungs prior to dose 
+30 minutes 
25mg 
Examination of skin and auscultation of lungs prior to dose 
+45 minutes 
50mg 
Examination of skin and auscultation of lungs prior to dose 
+60 minutes 
100mg 
Examination of skin and auscultation of lungs prior to dose 
+75 minutes 
500mg 
Examination of skin and auscultation of lungs prior to dose 
+90 minutes 
1000mg 
Examination of skin and auscultation of lungs prior to dose 
+105 minutes 
4000mg 
Examination of skin and auscultation of lungs prior to dose 
Full physical examination of ears, oropharynx and nose, 
lungs, and skin after completion of final dose.  
*Vital signs including heart rate, blood pressure, respiratory rate and oxygen saturation level to be 
obtained with any change in physical exam or clinical status  
 
If objective signs of an allergic reaction occur, then the challenge will be stopped, and the subject 
treated based on the presenting symptoms and clinical judgment of the supervising investigator (Table 
4). If no objective signs occur within 2 hours after the last dose is consumed, then the child will be 
considered not peanut allergic and will not qualify for the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4: Oral food challenge stopping criteria 
A positive food challenge will be defined by the presence of either of the following:  
• 
One or more major criteria 
• 
Two or more minor criteria 
An indeterminate food challenge will be defined by the presence of one minor criterion. 
A negative food challenge will be defined by the absence of major or minor criteria.  
All symptoms should be of new onset and not due to ongoing disease. Symptoms must occur no later 
than 2 hours after the last dose. 
Major Criteria 
• 
Confluent erythematous pruritic rash 
• 
Respiratory signs (at least one of the following): 
Wheezing 
Inability to speak 
Stridor  
Dysphonia 
Aphonia  
• 
>/= 3 noncontact urticarial lesions lasting for more than 3 minutes  
• 
>/= 1 site of angioedema 
• 
Hypotension for age not associated with vasovagal episode 
• 
Evidence of severe abdominal pain (such as abnormal stillness or doubling over) that persists 
for more than 3 minutes 
Minor Criteria  
• 
Vomiting (persistent symptoms would elevate to major criterion) 
• 
Diarrhea 
• 
Persistent rubbing of nose or eyes that lasts for >/= 3 minutes  
• 
Persistent rhinorrhea that lasts for >/= 3 minutes 
• 
Persistent scratching that lasts for >/= 3 minutes 
 
The subjects with objective signs of an IgE mediated reaction to peanut using standard criteria (Table 4) 
will be eligible for enrollment. 
 
If patient is found to be study eligible, then a urine pregnancy test will be done on females who have 
reached the age of child birthing potential.  
 
Initial Dose Escalation 
 
Upon enrollment, demographic data will be collected including age, sex, race, history of asthma/atopic 
dermatitis/allergic rhinitis. The enrolled subjects will present to the Clinical Research Unit for a one day 
dose escalation. The intent of the initial escalation is to begin and remain at subthreshold levels and 
identify a safe starting dose for home administration. Any subjects unable to tolerate at least 1.5 mg 
peanut protein will be discharged. 
 
Active illness or asthma exacerbation will prompt rescheduling of the initial dose escalation. Patients are 
encouraged to eat foods brought from home before and during dose escalation.  
 
 
 


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Prior to the first dose, patients will receive the following interventions:  
• 
Blood obtained by venipuncture for baseline laboratory evaluation 
o Peanut specific IgE concentration 
o Peanut component testing (peanut specific IgE concentration for Ara h 1, 2, 3, 8 and 9) 
o Peanut specific IgG4 concentration.  
o Serum samples will be sent to the Cleveland Clinic Main Campus laboratory with the 
exception of the peanut IgG4 level which will be sent out to the Mayo Clinic. 
• 
Skin prick test to peanut with extracts routinely used for this purpose in clinical practice 
o Negative control (50% glycerin/50%Cocas) 
o Positive control (Histamine base 6mg/mL) 
o Peanut extract 1:20 (Hollister Stier) 
o Apply one drop of each solution to upper back (infants and young children) or 
forearm (children over the age of 6 able to avoid scratching the extract), and 
prick through with sterile bifurcated needle to disrupt the top layer of the 
epidermis. The location used for the skin prick test will remain consistent for 
each patient throughout the study. 
o The test will be read by the clinician 15 minutes following application. The wheal 
(raised center) and flare (flat erythematous patch) will be measured horizontally 
and vertically with an average of these 2 measurements recorded as the 
diameter.  
 
 
Table 5: Initial dose escalation (Study Visit 2) 
Time  
Dose 
Clinician Intervention * 
0 
0.5 mg peanut 
protein 
Obtain weight, temperature, heart rate, blood pressure, 
respiratory rate, and oxygen saturation level (i.e. vital signs). Peak 
flow will be measure on patient 4+ or deemed developmentally 
appropriate. Full physical examination of ears, oropharynx and 
nose, lungs, and skin prior to administration of dose 
+30 minutes 
1 mg 
Repeat vital signs. Examination of skin and auscultation of lungs 
prior to dose 
+60 minutes 
2 mg 
Repeat vital signs. Examination of skin and auscultation of lungs 
prior to dose 
+90 minutes 
4 mg 
Repeat vital signs. Examination of skin and auscultation of lungs 
prior to dose 
+120 minutes 
6 mg 
Repeat vital signs. Examination of skin and auscultation of lungs 
prior to dose 
*Vital signs including heart rate, blood pressure, respiratory rate and oxygen saturation level to be 
obtained with any change in physical exam or clinical status 
 
Dose escalation will begin with 0.5 mg of peanut protein and increase to a maximum of 6 mg (Table 5). 
The doses will be administered at 30 minute intervals following a set of vital signs and limited physical 
examination. At any objective sign of reaction (Table 4) the escalation will stopped, and the patient will 
be treated based on the presenting symptoms and clinical judgment of the supervising investigator. 
Subjects will be monitored for 2 hours after resolution of any signs of reaction and/or after completion 
of the final dose.  
 


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Subjects will then be instructed to consume the highest tolerated dose of peanut protein daily until their 
return for dose escalation. 
 
 
Build-Up  
For the next phase, participants will undergo incremental dose escalations every two weeks. These dose 
escalations with take place under the supervision of a trained Allergy/Immunology physician investigator 
within the Clinical Research Unit. The subject will be given an increased dose of the peanut and 
observed for at least 2 hours. Subjects will then continue to take daily doses of an identical amount of 
peanut protein at home. We will increase to a target maintenance dose of 300 mg of peanut protein, 
which should be accomplished in approximately 6 dose increases, or 12 weeks’ time. 
 
If a patient is unable to tolerate the maximum dose during the initial dose escalation visit, they will be 
given double the maximum dose tolerated during the dose escalation visits until they are back on the 
dose escalation schedule defined in Table 6. 
 
If a subject does not tolerate a dose increase, then the patient will be administered a dose reduced by 
25%, with increase to the originally intended dose at the subsequent visit. If the patient still does not 
tolerate the dose, then the decision on how to proceed will be determined at the investigator’s 
discretion. This may involve temporarily decreasing the subject’s dose, making a smaller increase, or 
prolonging the duration of a given dose. If any subject is unable to reach the goal maintenance dose, 
then the investigator may decide to continue the subject on a lower maintenance dose for the duration 
of the study. 
 
Table 6: Dose Escalation Schedule 
 
Dose of Peanut Protein 
Week of Protocol 
6 mg 
0 
12 mg 
2 
25 mg 
4 
50 mg 
6 
75 mg 
8 
150 mg 
10 
300 mg 
12 
 
 
Home Dosing 
All subjects will be offered the opportunity to continue once daily consumption of the maintenance dose 
after the end of their study participation. This ongoing maintenance therapy is optional and will not be 
paid for by the study. The subjects will be instructed to otherwise continue a peanut free diet.  
 
 


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Follow Up 
The subject will also undergo a final oral food challenge at the final visit (SV10). This food challenge will 
be double blind and placebo controlled. A double blind placebo controlled food challenge (DBPCFC) is 
the gold standard for diagnosis of food allergy and is the standard utilized for most oral immunotherapy 
trials at exit. 
 
Roasted peanut powder will be utilized for the challenge, with oat flour as placebo. An individual will 
undergo a standard challenge described below (Table 7) with either the roasted peanut or the placebo, 
blinded to both subject and investigators. The same individual will then undergo a second challenge with 
the opposite (either peanut or placebo) either later that day or by returning to clinic the following day. 
Each challenge will be performed by increasing doses up to a final dose of 1000 mg of peanut protein. 
The individual doses will be 25, 100, 200, 300, 600, and 1000 mg of peanut protein. The highest 
tolerated dose will be recorded. If a patient reacted to a dose lower than 25 mg of peanut powder 
during the initial Oral Food Challenge then they will be started at the dose lower than where the 
reaction occurred for the DBOFC. 
 
A urine pregnancy test will be repeated on all females of child bearing potential before the DBOFC. 
 
Table 7: Double blind oral food challenge to peanut or control oat (SV 10) 
Time  
Dose 
Clinician Intervention * 
0 
25 mg peanut 
protein 
Obtain weight, temperature, heart rate, blood pressure, 
respiratory rate, and oxygen saturation level. Peak flow in 
children ages 4+ or as developmentally appropriate. Full 
physical examination of ears, oropharynx and nose, lungs, 
and skin prior to administration of dose 
+15 minutes 
100 mg 
Examination of skin and auscultation of lungs prior to dose 
+30 minutes 
200 mg 
Examination of skin and auscultation of lungs prior to dose 
+45 minutes 
300 mg 
Examination of skin and auscultation of lungs prior to dose 
+60 minutes 
600  mg 
Examination of skin and auscultation of lungs prior to dose 
+75 minutes 
1000 mg 
Examination of skin and auscultation of lungs prior to dose 
Full physical examination of ears, oropharynx and nose, 
lungs, and skin after completion of final dose. 
*Vital signs including heart rate, blood pressure, respiratory rate and oxygen saturation level to be 
obtained with any change in physical exam or clinical status  
 
If objective signs of an allergic reaction occur, then the challenge will be stopped, and the subject 
treated based on the presenting symptoms and clinical judgment of the supervising investigator (Table 
4). If no objective signs occur within 2 hours after the last dose is consumed, then the challenge will be 
considered negative. 
 
Quality of Life Questionnaire 
At enrollment and after completion of the study, patients or caregivers will be asked to complete 
previously validated, age specific food allergy quality of life questionnaires27( Supplement 1) 
 
 


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6.2 Preparation/Handling/Storage/Accountability 
The Investigational Drug Service (IDS) will provide secure storage, temperature monitoring, drug 
accountability, and dispensing of Investigational Product (IP) to comply with the protocol and applicable 
state and federal regulations related to clinical research. 
IP Management 
Upon the receipt of the IP, IDS will electronically document lot numbers, expiration dates, and quantity. 
The supply of roasted peanut powder and boiled peanut powder will be tracked and stored separately.  
 
IP dispensing 
IDS will dispense the IP to eligible subjects upon receipt of a valid prescription. The prescription will be 
scanned to ids@ccf.org or faxed to 216 445-5554, Monday through Friday, 0700-1600. After reviewing 
the prescription, the pharmacist will: 
1. Weigh the prescribed dose 
2. Transfer the prescribed dose into a plastic jar 
3. Dispense the quantity of doses prescribed 
4. Update drug accountability log**  
5. File the prescription in the subjects’ tab in the study binder 
** Associate the dose, quantity, lot of IP dispensed with subject number and date 
IP disposition 
Returned or expired IP will be accounted for and then destroyed per department policy. 
 
6.3 Measures to Minimize Bias 
This study utilizes a prospective trial design in order to minimize recall bias. In addition, the double blind 
placebo controlled exit challenge will help minimize bias.  
 
6.4 Study Intervention Compliance 
The subjects will have periodically scheduled trips to return the empty medicine cups for monitoring of 
adherence. In addition, the subjects or their families will complete a log at home recording 
administration of doses as well as any adverse effects. 
 
6.5 Concomitant Therapy 
Data regarding the subjects’ concomitant medications will be recorded at each study visit to the 
Pediatric Allergy Clinic or the Clinical Research Unit. For this protocol, a prescription medication is 
defined as a medication that can be prescribed only by a properly authorized/licensed clinician. 
Medications to be reported include concomitant prescription medications, over-the-counter 
medications such as oral antihistamines, and supplements. 
 
The concomitant use of antihistamines could directly affect the primary endpoint. The use of 
antihistamines could mask or prevent some symptoms of an allergic reaction such as urticaria or 
pruritus. Upon enrollment, the treating physician investigator will evaluate the specific indication for 
antihistamine use and will make a determination regarding continued use or discontinuation. This will 
be documented within the electronic medical record. 


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6.5.1 Rescue Medication 
All subjects will be prescribed an epinephrine auto-injector to have available for rescue at home. All 
subjects will also be prescribed an oral antihistamine, cetirizine, to have available for rescue at home. It 
will be confirmed that all subjects with an underlying diagnosis of asthma have a prescription for a short 
acting beta-agonist (albuterol or levalbuterol) available for rescue at home. Any subjects with a 
diagnosis of asthma that do not have a short acting beta-agonist will have one prescribed.  
 
The study sites (Pediatric Allergy office and Clinical Research Unit) will have rescue medications available 
at the time of each study visit. The following rescue medications may be used: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal 
 
7.1 Discontinuation of Study Intervention 
Criteria for discontinuing oral immunotherapy in a subject will include: 
• 
Subject nonadherence to OIT, specifically defined by 12 (approximately 10%) nonconsecutive 
missed doses. 
• 
A life-threatening adverse reaction to OIT, specifically a grade 4 reaction as defined by the 
Consortium of Food Allergy Research (CoFAR) criteria. See table in Section 8.3.3.1.  
• 
Symptoms suggestive of Eosinophilic Esophagitis of (EoE) – i.e. difficulty swallowing, chest pain, 
persistent heart burn, upper abdominal pain, and/or no response to gastroesophageal reflux 
disease (GERD) medication 
 
Symptoms suggestive of Eosinophilic Esophagitis (EoE) will prompt discontinuation of oral 
immunotherapy and begin once weekly symptom monitoring phone calls with study staff. If symptoms 
fail to resolve after 1 month off therapy, consultation with Gastroenterology will be considered for 
further evaluation and management.  
 
Discontinuation from oral immunotherapy does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
 


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The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Skin prick test to peanut 
• Peanut sIgE, peanut component panel, and peanut IgG4 
 
 
7.2 Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. Subjects may 
withdraw from the study for the following anticipated reasons 
• 
Adverse events related to OIT 
o Chronic or recurrent GI symptoms 
o Acute hypersensitivity reactions 
o Chronic or recurrent cutaneous symptoms  
• 
Social reasons: time constraints, transport  
• 
Principal Investigator temporarily suspends or prematurely discontinues study participation. The 
date and reason for discontinuation must be documented (e.g. non-compliance). Every effort 
should be made to complete the appropriate assessments. 
• 
Pregnancy during the course of the study for a child-bearing participant 
• 
The investigator considers it, for safety reasons, to be in the best interest of the subject.   
• 
Disease progression 
o Worsening asthma that requires increasing therapy such that exclusion criteria are met  
 
The reason for subject discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are enrolled but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are enrolled 
and receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from 
the study, will not be replaced. 
 
7.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 1 week for 
an updosing visit or within 1 month for a follow up visit and counsel the participant on the 
importance of maintaining the assigned visit schedule and ascertain if the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
 


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8. Study Assessments and Procedures  
 
8.1 Efficacy Assessments  
Procedures  
Skin tests: Skin testing to peanut will be performed at the visits specified in the SoA (section 1.3). Skin 
testing will include skin prick with peanut exact (1:20 w/v, Greer), negative control (saline) and positive 
control (histamine).  
 
Laboratory tests: Blood samples will be collected at the visits specified in the SoA. Blood work will 
include peanut specific IgE concentration, peanut component testing (peanut specific IgE concentration 
for Ara h 1, 2, 3, 8 and 9), and peanut specific IgG4 concentration. The peanut sIgE and peanut 
component panel will be sent to the Cleveland Clinic main laboratory. The peanut specific IgG4 will be 
sent to Mayo Clinic laboratories. The laboratories used will supply a list of reference ranges and units of 
the laboratory parameters.   
Volume of blood to be collected:  
 
Peanut specific IgE concentration 
0.5 mL 
Peanut component panel 
 
0.6 mL 
Peanut IgG4 concentration 
 
0.5 mL 
Total 
 
 
 
 
1.6 mL 
8.2 Safety and Other Assessments 
Screening to ensure all subjects meet the inclusion criteria and do not meet any exclusion criteria will be 
performed within 1 month of the initial oral food challenge visit. At Visit 1, the physician and participant 
will review and update the patient’s Food Allergy & Anaphylaxis Emergency Care Plan. This plan will 
outline the recommended treatment in case of an allergic reaction occurs during their enrollment in the 
study. This plan is signed by a physician, and includes emergency contact information. In addition, each 
study visit will include obtaining a brief interim history to ensure that no potential augmenting factors, 
such as viral illness, are present at the time of study drug or control drug administration. Vital signs, a 
targeted physical exam and conmed review will be performed prior to any study drug administration for 
the same purposes.   
 
Study visit evaluation: 
Brief interim history 
Discussion of any interim AEs 
Vital signs: Temperature, Heart Rate, Respiratory Rate 
Physical Exam: Targeted assessment of General Appearance, HEENT, Cardiac, Respiratory, Abdominal, 
and Skin   
 
8.3 Adverse Events and Serious Adverse Events  
 
8.3.1 Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
The CoFAR (the consortium of Food Allergy research) scale will be referenced to assess SAEs/AEs related 
or possibly related to an allergic reaction. CTCAE (Common Terminology Criteria for Adverse Events) 
version 5.0 will be referenced for SAEs/AEs that are not related to allergic reactions and are therefore 
not listed in the CoFAR scale.  
 


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8.3.2 Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home or hypotension not responsive to 
treatment with epinephrine. 
 
 
8.3.3 Classification of an Adverse Event 
 
8.3.3.1 Severity of an Event  
All adverse events will be graded in severity utilizing criteria specifically developed by the Consortium of 
Food Allergy Research.27 These criteria are widely accepted and applied to OIT clinical trials.  
 
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 
intervention/therapy 
required. These 
symptoms may 
include 
pruritus, swelling or 
rash, abdominal 
discomfort or other 
transient symptoms. 
Symptoms that produce 
mild-to-moderate 
limitation in activity, 
some assistance may be 
needed; no or minimal 
intervention/therapy is 
required.  
Hospitalization is 
possible. These 
symptoms may include 
persistent hives, 
wheezing without 
dyspnea, abdominal 
discomfort/increased 
vomiting or other 
symptoms. 
Marked limitation in 
activity, some 
assistance usually 
required; medical 
intervention/therapy 
required, 
hospitalization is 
possible. Symptoms 
may include 
bronchospasm with 
dyspnea, severe 
abdominal pain, throat 
tightness with 
hoarseness, and 
transient hypotension 
among others. 
Parenteral 
medication(s) are 
usually indicated. 
Extreme limitation in 
activity, significant 
assistance required; 
significant 
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 
Death 
 
 
8.3.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 


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The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician 
 
8.3.3.3 Expectedness  
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study intervention. 
 
8.3.4 Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 


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Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
All reportable events will be recorded with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.  At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events 
will be followed for outcome information until resolution or stabilization. 
 
 
8.3.5 Adverse Event Reporting 
An independent Data Safety Monitoring Board (DSMB) will be utilized during the study. The DSMB will 
consist of 2 Board Certified Allergy/Immunology physicians who are not participating in the study and do 
not have any conflicts of interest as well as 1 pediatric physician of another specialty. The DSMB will 
meet prior to initiation of the study, following the enrollment of the 6th subject, and then quarterly 
during the course of the study. 
 
8.3.6 Serious Adverse Event Reporting 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the study sponsor and should be provided as soon as possible. 
 
The study sponsor is responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting 
 
8.3.7 Reporting Events to Participants  
All anticipated AEs will involve overt symptoms and thus be readily apparent to the subjects and their 
families. When an AE occurs during a study visit, the nature and severity of the AE as well as the 
implications for ongoing treatment will be discussed by a physician investigator with the subject and 
parents/guardians. This discussion will take place after any potential treatment is administered and the 
subject is deemed medically stable but prior to end of the study visit.  
 


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When an AE occurs at home, the nature and severity of the AE as well as the implications for ongoing 
treatment will be discussed by a physician investigator with the subject and parents/guardians via 
phone. If a study visit is deemed appropriate to further manage the AE or for further discussion of the 
AE, then additional discussion will take place at this time.  
 
8.3.8 Events of Special Interest  
This is not applicable to our study.  
 
 
8.3.9 Reporting of Pregnancy 
If a pregnancy were to occur during the course of the study, the subject would be withdrawn from the 
study. The pregnancy would be reported the PRRC and IRB at the Cleveland Clinic. The subject would be 
referred to an appropriate physician (OB/Gyn) for further management.  
 
 
8.4 Unanticipated Problems 
 
8.4.1 Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the lead principal investigator (PI). The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that have serious impact or require a change to the protocol will be reported to the IRB and 
to the study sponsor within 10 days of the investigator becoming aware of the event.  


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• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP). The reporting timeline for UPs that do not have serious 
impact or require a change to the protocol will be the time of continuing renewal with the IRB. 
 
8.4.3 Reporting Unanticipated Problems to Participants  
Should unanticipated problems arise that have serious impact to the protocol or to the safety of 
participants, participants will be notified based on the opinion of the IRB once the UP has been 
reviewed.  
 
 
9. Statistical Considerations 
 
9.1 Statistical Hypothesis 
We will obtain observation data on patients receiving boiled peanut oral immunotherapy which has not 
yet been well described in human trials. We will compare with proportion of patients successfully 
desensitized as defined by meeting the primary endpoint with the expected placebo rate. The null 
hypothesis is that the proportion of patients successfully desensitized by boiled peanut oral 
immunotherapy will not be greater than the expected 20% that has been previously published as the 
proportion of patients successfully meeting the primary endpoint in OIT studies (which aligns with the 
expected 20% that would naturally “outgrow” a peanut allergy). If we reject this null hypothesis, we will 
be able to conclude that the proportion of successfully desensitized by boiled peanut therapy is greater 
than placebo. For the safety aspect of the study we will be comparing the historical SAEs/AEs of patients 
who received OIT with roasted peanuts and compare them with the patients enrolled in this study for 
the rate of occurrence and severity of the SAEs/AEs observed. 
9.2 Sample Size Determination  
The sample of 10 patients will provide >90% power to determine the expected success rate (80%) is 
greater than a theoretical placebo rate (20%). 
9.3 Populations for Analysis  
Both an Intentional-to-Treat (ITT) and per-protocol analysis will be performed.  
 
9.4 Statistical Analysis 
Descriptive statistics will be used to summarize the data.  Categorical variables will be presented as 
number and percentage of total patients.  Continuous variables will be summarized using mean, 
standard deviation, median and [Q1, Q3].  The proportion of patients with successful consumption of 
peanut protein without symptoms (primary endpoint), will be tested to determine whether the 
proportion differs from 0.2 (20%) (the expected success rate in a theoretical placebo group). 
 
10. Supporting Documentation and Operational Considerations 
 
10.1 Regulatory, Ethical and Study Oversight Considerations 
 
10.1.1 Informed Consent Process 


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10.1.1.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with this 
protocol:  
• 
Informed Consent 
• 
Informed Assent 
 
10.1.1.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual and parent/guardian’s agreeing to 
participate in the study and continues throughout the individual’s study participation. Consent forms 
will be Pediatric ResearchReview Committee (PRRC) and Institutional Review Board (IRB)-approved and 
the participant and/or parent/guardian will be asked to read and review the document. The investigator 
will explain the research study to the participant and parent/guardian and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the participant and parent/guardian’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants.  Participants and parents/guardians will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants and parents/guardians 
should have the opportunity to discuss the study with their family or surrogates or think about it prior to 
agreeing to participate. The participant’s parent/guardian will sign the informed consent document prior 
to any procedures being done specifically for the study. Participants and parents/guardians must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participant’s parent/guardian 
for their records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study 
 
10.1.2 Study Discontinuation and Closure  
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to <study participants, investigator, funding agency, 
the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor and regulatory 
authorities>.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, and 
be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 


39 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at within RedCap Cloud. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by CRU research staff will be secured and password protected. At the end of the study, 
all study databases will be de-identified and archived within RedCap Cloud.  
 
10.1.4 Future Use of Stored Specimens and Data 
Data will be maintained on RedCap Cloud per institute policy. Stored specimens will be discarded after 
analysis per Cleveland Clinic Laboratory policy. 
 
10.1.5 Key Roles and Study Governance 
Principal Investigator 
Jaclyn Bjelac, MD 
Staff, Pediatric Allergy and Immunology  
Cleveland Clinic 
9500 Euclid Ave/A120  
Cleveland, OH 44195  
 
 
Medical Monitor 
Clinical Research Unit 
 
 
 


40 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
11. References 
 
1. Bunyavanich et al. Letter to the Editor: Peanut allergy prevalence among school age children in a 
US cohort not selected for any disease. J Allergy Clin Immunol. 2014 Sep;134(3):753-5. 
2. Bock SA, Muñoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J 
Allergy Clin Immunol. 2001 Jan;107(1):191-3.  
3. Sicherer, SH and Sampson, HA. Food allergy: A review and update on epidemiology, 
pathogenesis, diagnosis, prevention, and management. J Allergy Clin Immunol. 2018 
Jan;141(1):41-58.  
4. Primeau MN, Kagan R, Joseph L, et al. The psychological burden of peanut allergy as perceived 
by adults. Clin Exp Allergy. 2000 Aug;30(8):1135-43. 
5. Sicherer SH, Noone SA, Muñoz-Furlong A. The impact of childhood food allergy on quality of life. 
Ann Allergy Asthma Immunol. 2001 Dec;87(6):461-4. 
6. Sampson HA et al. Food allergy: A practice parameter update-2014. J Allergy Clin Immunol. 2014 
Nov;134(5):1016-25. 
7. Wood, RA.  Food allergen immunotherapy: current status and prospects for the future J Allergy 
Clin Immunol. 2016 Apr;137(4):973-982. 
8. Jones, SM, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J 
Allergy Clin Immunol. 2009 Aug;124(2):292-300. 
9. Blumenchen, K et al. Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy 
Clin Immunol. 2010 Jul;126(1):83-91. 
10. Hofmann, AM, et al. Safety of a peanut oral immunotherapy protocol in children with peanut 
allergy. J Allergy Clin Immunol. 2009 Aug;124(2):286-91. 
11. Varshney, P, et al. A randomized controlled study of peanut oral immunotherapy: clinical 
desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011 
Mar;127(3):654-60. 
12. Anagnostou K, et al. Efficacy and safety of high-dose peanut oral immunotherapy with factors 
predicting outcome. Clin Exp Allergy. 2011 Sep;41(9):1273-81. 
13. Anagnostou K, et al. Assessing the efficacy of oral immunotherapy for the desensitisation of 
peanut allergy in children (STOP II): a phase 2 randomised controlled trial. Lancet. 2014 Apr 
12;383(9925):1297-304. 
14. Vickery, VP, et al. Sustained unresponsiveness to peanut in subjects who have completed 
peanut oral immunotherapy. J Allergy Clin Immunol. 2014 Feb;133(2):468-75. 
15. Narisety, SD, et al. A randomized, double-blind, placebo-controlled pilot study of sublingual 
versus oral immunotherapy for the treatment of peanut allergy. J Allergy Clin Immunol. 2015 
May;135(5):1275-82. 
16. Vickery, VP, et al. Early oral immunotherapy in peanut-allergic preschool children is safe and 
highly effective. J Allergy Clin Immunol. 2017 Jan;139(1):173-181. 
17. Maleki SJ, Chung SY, Champagne ET, Raufman JP. The effects of roasting on the allergenic 
properties of peanut proteins. J Allergy Clin Immunol. 2000 Oct;106(4):763-8. 
18. Beyer K, Morrow E, Li XM, et al. Effects of cooking methods on peanut allergenicity. J Allergy Clin 
Immunol. 2001 Jun;107(6):1077-81. 
19. Tao B et al. Extended boiling of peanut progressively reduces IgE allergenicity while retaining T 
cell reactivity. Clin Exp Allergy. 2016 Jul;46(7):1004-14. 
20. Turner PJ, Mehr S, et al. Letter to the Editor: Loss of allergenic proteins during boiling explains 
tolerance to boiled peanut in peanut allergy. J Allergy Clin Immunol. 2014; 134:751-3. 


41 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
21. Bird, JA, et al. Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of 
ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial. J Allergy Clin 
Immunol Pract. 2018 Mar - Apr;6(2):476-485. 
22. United States Department of Agriculture. USDA National Nutrient Database for Standard 
Reference, release 21. 2002. Available at: http://ars.usda.gov/Services/docs.htm?docid=17477. 
23. Virkud YV, et al. Novel baseline predictors of adverse events during oral immunotherapy in 
children with peanut allergy. J Allergy Clin Immunol. 2017 Mar;139(3):882-888 
24. Klemans RJ, et al. Ara h 2 is the best predictor for peanut allergy in adults. J Allergy Clin Immunol 
Pract. 2013 Nov-Dec;1(6):632-8.  
25. Wasserman, RL, et al. Oral Immunotherapy for Peanut Allergy: Multipractice Experience With 
Epinephrine-treated Reactions. J Allergy Clin Immunol Pract. 2014 Jan-Feb;2(1):91-6. 
26. Rigbi, NE, et al. Changes in patient quality of life during oral immunotherapy for food allergy. 
Allergy. 2017 Dec;72(12):1883-1890. 
27. Factor JM et al. Effect of oral immunotherapy to peanut on food-specific quality of life . Ann 
Allergy Asthma Immunol 109 (2012) 348-352. 
28. Burks, AW et al. Oral immunotherapy for treatment of egg allergy in children N Engl J Med. 2012 
Jul 19;367(3):233-43. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


42 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
12. Supplements 
 
12.1 Food Allergy Quality of Life Questionnaire for Parents (1-12 years old) 
 
 
 
 
 
 
 
 


43 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
12.2 Food Allergy Quality of Life Questionnaire for Parents (13-16 years old) 
 
 
 
 
 
 
 
 
 
 
 
 


44 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
12.3 Dosing/Adverse Events Recording Sheet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


45 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
SUMMARY OF CHANGES 
 
Please provide a list of changes from the previous approved version of the protocol starting at IRB 
approval. This table will remain blank until initial IRB approval. The list shall be a brief overview. When 
appropriate, a brief justification for the change should be included. This is a running list for the life of the 
study. 
 
Protocol 
Date 
Section 
Change 
04.02.2019 
Footer and PSP 
Changed Version number and version date to 4.0 
and 4-2-19 respectively 
 
6. Study Intervention 
All references to “UH Lerner Tower Kitchen” were 
replaced with “UH Dahms Clinical Research Unit” 
 
6. Study Intervention 
The onging post study OIT maintenance period 
was changed to being optional for study 
participants and is not paid for by the study. 
 
8.2 
Study 
Assessments 
and 
Procedures 
At Visit 1, the physician and participant will 
review and update the patient’s Food Allergy & 
Anaphylaxis Emergency Care Plan. Conmed 
review also added before each dose escalation 
 
PSP and section 8.3.9 
Changed 
PIRC 
(Pediatric 
Institute 
Review 
Committee) to PRRC (Pediatric Research Review 
Committee) 
 
Inclusion criteria 
Added the additional language “within a 12 
month period of study enrollment” in the 
inclusion criteria requiring Evidence of IgE 
mediated peanut hypersensitivity 
 
1.3 Schedule of activities and section 
6.1 
Added Urine Pregnancy 
 
6.2 IP dispensing 
Remove randomize to treat and place a blinded 
label on jar from. 
 
Section 7.2 
Added additional reasons for discontinuation 
 
1.3 Schedule of activities 
Changed Adverse event review to AE review, 
added Study drug compliance and conmed 
assessment lines 


46 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
Protocol 
Date 
Section 
Change 
 
8.3.1 
The CoFAR and CTCAE are mentioned as the 
scales that will be used to assess SAEs/AEs 
 
8.4.2 and 8.4.3 
Rewording of reporting requirements and 
timelines 
05.28.2019 
PSP and footer 
Updated amendment # and version date 
 
Schedule of events, table #4 and table 
#5 
Added spirometry and peak flow measure to 
study visits 
 
9.1 Statistical Hypothesis 
Added language in regards to safety hypothesis 
10.01.2019 
PSP and footer 
Updated amendment # and version date 
 
Schedule of Events section 1.3 and 
section 6.1 
Added additional urine pregnancy at visit 10  
 
Schedule of Events section 1.3 
Added language on spirometry being done at 
investigators discretion at enrollment as well visit 
10 
 
Section 6.1 
Clarified that the location of the skin prick test 
must be the same throughout the study 
 
Section 6.1 and table 7 
Added a 25 mg dose in DBOFC as well as 
clarification that additional smaller doses may be 
necessary on a patient by patient basis depending 
on the results of the initial OFC 
 
Section 6.1 
In build-up phase a dose double the size of the 
highest tolerated dose in the initial escalation 
may be used before the patient can be entered 
into the build-up phase schedule 
02.12.2020 
Footer 
Updated protocol version date and  amendment 
number 
 
PSP 
Added signature line for sponsor 
 
Inclusion criteria 
Added verbiage to inclusion criteria #2   “or a high 
level of suspicion based on testing at the 
discretion of the investigator.” 


47 
 
Melton/Bjelac 
02-12-2020 
Amendment #3 
 
Protocol 
Date 
Section 
Change 
 
Initial dose escalation (Table 5) 
Removed the first 2 doses in the initial dose 
escalation (0.1 and 0.2 milligrams of peanut 
protein). Added a 4mg dose to be given at +90 
minutes. Adjusted time for 6mg dose to +120 
minutes  
 
 
 
 

SAP_001.pdf: 
Boiled Peanut Oral Immunotherapy for the Treatment of Peanut Allergic 
Pediatric Patients 
NCT04090203 
Statistical Analysis Plan 3/8/2022 


Statistical Analysis Plan 
 BPOIT 
SAP version 1.0: BPOIT 
08MAR2022 
Page 1 of 24 
 
Statistical Analysis Plan 
We would like to acknowledge the Cambridge University Hospitals Clinical Trials Unit for the 
development of the template (version CCTU/TPLV2), which was modified by the Michigan Institute 
for Clinical & Health Research (MICHR). The MICHR template available at 
https://michr.umich.edu/s/SAP-Template_20180821.docx was accessed on November 10, 2021, and 
modified for this Statistical Analysis Plan (SAP). 
 
 
 
TRIAL FULL TITLE
Boiled Peanut Oral Immunotherapy for the Treatment 
of Peanut Allergic Pediatric Patients (BPOIT) 
SAP VERSION
1.0
SAP VERSION DATE
March 8, 2022
TRIAL STATISTICIAN
Sarah Worley, MS
Protocol Version (SAP associated with)
02.12.2020 Amendment 3
TRIAL PRINCIPAL INVESTIGATOR
Jaclyn Bjelac, MD
SAP AUTHOR(s)
Sarah Worley, MS; Wei Lu, MS
 
 
 
 


Statistical Analysis Plan 
 BPOIT 
SAP version 1.0: BPOIT 
08MAR2022 
Page 2 of 24 
 
 
1 SAP Signatures 
I give my approval for the attached SAP entitled BPOIT dated March 8, 2022 
 
Statistician (Author) 
Name:   
Sarah Worley, MS 
 
 
 
Signature: 
 
 
Date: 
 
     08MAR2022                      
 
Statistician Reviewer 
Name:  
Wei Liu, MS 
 
Signature: 
                                                
 
Date: 
 
                                                 
 
Principal Investigator 
Name:  Jaclyn Bjelac, MD 
 
Signature: 
                                                
 
Date: 
 
                                                 
 
 
 
 
 
 
 
 
 
 
 
3/10/22


Statistical Analysis Plan 
 BPOIT 
SAP version 1.0: BPOIT 
08MAR2022 
Page 3 of 24 
 
2 Table of Contents 
1 
SAP Signatures 
2 
2 
Table of Contents 
3 
3 
Abbreviations and Definitions 
5 
4 
Introduction 
6 
4.1 
Preface 
6 
4.2 
Scope of the analyses 
6 
5 
Study Objectives and Endpoints 
6 
5.1 
Study Objectives 
6 
5.2 
Endpoints 
6 
6 
Study Methods 
7 
6.1 
General Study Design and Plan 
7 
6.2 
Inclusion-Exclusion Criteria and General Study Population 
7 
6.3 
Study Assessments 
8 
6.3.1 
Assessment of Primary Efficacy Endpoint 
9 
6.3.2 
Assessment of Secondary Efficacy Endpoints 
10 
6.3.3 
Assessment of Safety Endpoints 
10 
7 
Sample Size 
11 
8 
General Analysis Considerations 
11 
8.1 
Timing of Analyses 
11 
8.2 
Analysis Populations 
11 
8.2.1 
Primary Endpoint Intention to Treat (ITT) Population 
11 
8.2.2 
Efficacy Population 
11 
8.2.2.1 
Modified Efficacy Population for Immune Response 
11 
8.2.2.2 
Modified Efficacy Population for FAQLQ-PF 
11 
8.2.2.3 
Modified Efficacy Population for FAQLQ-TF 
11 
8.2.3 
Safety Population 
11 
8.2.4 
Study Visit Populations 
11 
8.3 
Covariates and Subgroups 
11 
8.4 
Missing Data 
11 
8.5 
Multiple Testing 
12 
9 
Summary of Study Data 
12 
9.1 
Subject Disposition 
12 
9.2 
Derived variables 
12 
9.2.1 Derivation of Primary Efficacy Endpoint 
12 
9.2.2 
Derivation of Secondary Efficacy Endpoints 
13 
9.2.3 
Derivation of Safety Variables 
17 


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9.2.4 
Derivation of Other Variables 
17 
9.3 
Demographic and Baseline Variables 
18 
9.4 
Study Drug Administration 
18 
9.5 
Treatment Compliance 
18 
10 
Efficacy Analyses 
18 
10.1 
Analysis of Primary Efficacy Endpoint 
18 
10.2 
Analysis of Secondary Efficacy Endpoints 
18 
11 
Safety Analyses 
19 
11.1 
Adverse Events 
19 
11.1.1 
Patient- and dose-level summary AE tables 
19 
11.1.2 
Comparative AE table 
20 
11.1.3 
ClinicalTrials.gov ‘Other (Not Including Serious) Adverse Events’ table 
20 
11.2 
Deaths, Serious Adverse Events and other Significant Adverse Events 
20 
11.2.1 
Patient- and dose-level summary AE tables 
20 
11.2.2 
ClinicalTrials.gov ‘Serious Adverse Events’ table 
20 
11.2.3 
ClinicalTrials.gov mortality table 
20 
11.3 
Concomitant Medications 
20 
11.4 
Other Safety Measures 
20 
12 
Reporting Conventions 
21 
13 
Quality Assurance of Statistical Programming 
21 
14 
Listing of Tables 
22 
15 
References 
23 
16 
Appendices 
24 
 
 
 


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 BPOIT 
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3 Abbreviations and Definitions 
 
ASV
Additional Study Visit
AE
Adverse Event
CoFAR
Consortium of Food Allergy Research
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DBPCFC
Double Blind Placebo Controlled Food Challenge
EPIT
Epicutaneous Immunotherapy
FAQL
Food Allergy Quality of Life
FAQLQ
Food Allergy Quality of Life Questionnaire
FAQLQ-PF
Food Allergy Quality of Life Questionnaire – Parent Form
FAQLQ-TF
Food Allergy Quality of Life Questionnaire – Teenager Form
FPIES
Food Protein-Induced Enterocolitis
ICS
Inhaled Corticosteroid
ITT
Intention To Treat
MID 
Minimally Important Difference
OFC
Oral Food Challenge
OIT
Oral Immunotherapy
PA
Peanut Allergy
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SLIT
Sublingual Immunotherapy
SPT
Skin Prick Test
SV
Study Visit
 
 
 


Statistical Analysis Plan 
 BPOIT 
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08MAR2022 
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4 Introduction 
4.1 Preface 
Peanut allergy (PA) is a common and potentially life threatening condition for which the only current 
approved management involves strict dietary avoidance. Oral immunotherapy (OIT) is a promising 
investigational treatment option for this condition, but the widespread clinical use of OIT has been 
limited by factors including the high rate of adverse events (AEs), including anaphylaxis. Published 
studies demonstrating the efficacy of OIT in children with peanut allergy, many of which reported 
high rates of dropout and AEs, have all used peanut products produced by roasting methods, while 
published data have demonstrated that boiling peanut results in reduced allergenicity without 
reduction to immunogenicity. In this pilot study, we plan to compare the use of boiled peanut OIT to 
published data on roasted peanut OIT in children with peanut allergy and hypothesize that the 
subjects treated with a novel regimen of boiled peanut will demonstrate lower rates of adverse 
events while demonstrating similar immunologic markers of peanut desensitization and tolerance. 
4.2 Scope of the analyses 
These analyses will assess the efficacy, safety, and tolerability of boiled peanut immunotherapy on 
the immune response to peanut protein, with comparison to published data on subjects treated 
with OIT utilizing a traditional roasted peanut product and will be included in the study report. 
5 Study Objectives and Endpoints 
5.1 Study Objectives 
Primary objective. Determine the effect of boiled peanut immunotherapy on the immune response 
to peanut and demonstrate that the proportion of subjects successfully desensitized with boiled 
peanut OIT is not appreciably lower than the proportion of subjects successfully desensitized with 
roasted peanut OIT in published data.  
 
Secondary objective. Compare the rate of adverse effects of boiled peanut oral immunotherapy to 
published data on roasted peanut oral immunotherapy. 
5.2 Endpoints 
Primary Endpoints. Response to treatment defined as ability to successfully consume a single dose of 
300 mg or greater of peanut protein with no dose limiting symptoms at exit double blind placebo 
controlled food challenge (DBPCFC).  
 
The highest dose of roasted peanut protein tolerated by the subject at exit DBPCFC will also be 
compared to the highest dose tolerated at baseline.  
 
The effect of boiled peanut immunotherapy on the immune response to peanut will be evaluated via 
specific serum markers of sensitization and tolerance to peanut.  
 
Levels of serum specific peanut IgE, with higher levels associated with greater likelihood of 
clinical reaction on exposure to peanut protein. 


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 
Peanut protein component panel, to determine the presence of high levels of sensitivity to 
peanut proteins known to be associated with severe systemic reactions (Arah 1,2, 3) versus 
mild reactions (Arah8) 
 
Levels of peanut specific serum IgG4, with higher levels associated with increased tolerance 
to peanut protein 
These markers will be evaluated at baseline and the conclusion of the study. 
 
Secondary Endpoints. The rate of adverse events in the subjects receiving boiled peanut oral 
immunotherapy. Possible adverse events include: side effects of treatment defined as oral itching, 
rhinorrhea, conjunctivitis, urticaria, angioedema, abdominal upset, vomiting, diarrhea, cough, 
wheeze, or anaphylaxis 
 
Adverse events will be recorded in terms of the percentage of subjects with adverse events 
on initial escalation day and at dose escalation visits by CRU staff.  
 
Adverse events will also be recorded in terms of overall percentage of home doses that 
result in adverse reaction, with data compiled from home logs. 
The adverse reactions will be graded in severity and the treatment required will be recorded.   
 
Validated, age-specific, food-related quality-of-life surveys before and after peanut oral 
immunotherapy will be completed by all patients/families. 
6 Study Methods 
6.1 General Study Design and Plan 
This study is a prospective single-arm Phase 1 clinical trial providing proof of concept data on boiled 
peanut oral immunotherapy (OIT) for the treatment of peanut allergy in children. There will be no 
randomization or blinding.  
 
The primary endpoint of rate of response to treatment will performed as a one-sample superiority 
test compared to a null hypothesis rate of 20%. Assessments of within-patient changes in maximum 
tolerated dose, cumulative tolerated dose, immune response, and quality of life will be performed 
with two-sided tests. Comparisons of adverse event rates will be made to data in published studies 
of roasted peanut OIT; these comparisons will be descriptive with no hypothesis testing. 
 
For study flow chart, refer to study protocol section 1.2 Study Schema.  
6.2 Inclusion-Exclusion Criteria and General Study Population 
 
Abbreviations: SPT, skin prick test 
Inclusion Criteria
Age 1-16 years
History of immediate hypersensitivity reaction to peanut or a high level of suspicion based on 
testing at the discretion of the investigator 
Evidence of IgE mediated peanut hypersensitivity within a 12 month period of study enrollment
           SPT with wheal/flare of at least 3 x 6 mm 
                                and/or 
           Peanut specific IgE >0.35 kU/L 


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08MAR2022 
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In addition, the individual’s parent or guardian must provide signed and dated informed consent and 
the individual must provide signed and dated assent when appropriate. The individual and parent or 
guardian must agree to comply with all study procedures and the individual must have the ability to 
take oral medication.  
 
 
Abbreviations: ICS, inhaled corticosteroid, OIT, oral immunotherapy, SLIT, sublingual 
immunotherapy, EPIT, epicutaneous immunotherapy 
 
A history of life-threatening anaphylaxis is defined as a reaction involving respiratory failure, 
hypotension or neurologic compromise. Medium dose ICS is defined by the National Heart, Lung, 
and Blood Institute asthma guidelines. Patients with oat allergy, while rare, are to be excluded as 
this will serve as the placebo for our exit food challenge. 
6.3 Study Assessments  
The study Schedule of Activities as provided in section 1.3 of the protocol is as follows. 
Exclusion Criteria
History of life threatening peanut anaphylaxis
Asthma requiring more than medium dose ICS
Prior participation in OIT, SLIT or EPIT
Oat allergy
Cardiovascular Disease
Use of beta-blockers (oral), angiotensin converting enzyme inhibitors, angiotensin receptor 
blockers, or calcium channel blockers 
Use of steroid medications in the following manners:
             Daily oral steroid dosing for greater than 1 month during the past year OR 
             Burst or steroid course in the past 3 month before inclusion OR 
             Greater than 2 bursts oral steroid courses in the past year of at least 1 week duration 
Pregnancy or lactation
Eosinophilic Gastrointestinal Disease
History of food protein-induced enterocolitis (FPIES)
History of developmental delay or speech delay that precludes age-appropriate communication, 
in the opinion of the investigator 
 
 
 
 
 
 
 
Visit 
 
Study Visit 1 
Study Visit 2 
Visit 1 +1-4 weeks  
SV 3  
Visit 2 +2 weeks  
SV 4 
Visit 2 +4 weeks  
SV 5 
Visit 2 +6 weeks  
SV 6 
Visit 2 +8 weeks  
SV 7  
Visit 2 +10 weeks  
SV 8  
Visit 2 +12 weeks  
SV 9 
Visit 2 +14 weeks  
SV 10  
Visit 1 +18 weeks  


Statistical Analysis Plan 
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Due to the difficulties of scheduling study visits during the COVID-19 pandemic, the primary analysis 
will not place any limitations on the timing of study visits. All study visits will be analyzed in order by 
date, and the number of days from initial oral food challenge (OFC) and initial dose escalation visit 
will be reported for each study visit. If more than seven dose escalation visits are required as 
described in the study protocol section 6.1.1 ‘Study Intervention Description’, the additional study 
visits will be named ‘Additional Study Visit 9.1’ through ‘Additional Study Visit 9.x’ for the purposes 
of analysis and reporting. 
6.3.1 
Assessment of Primary Efficacy Endpoint 
The primary efficacy endpoint is ‘response to treatment’ defined as ability to successfully consume a 
single dose of 300 mg or greater of peanut protein with no dose limiting symptoms at the exit 
DBPCFC.  This endpoint will be analyzed as a binary variable (yes response to treatment/no response 
to treatment). 
Procedures 
Enrollment/Baseline visit 
Oral Food Challenge 
Initial dose escalation  
Dose escalation visit 1 
Dose Escalation Visit 2 
Dose escalation visit 3  
Dose escalation visit 4 
Dose escalation visit 5 
Dose escalation visit 6 
Dose escalation visit 7 
Oral Food Challenge  
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographic
s 
X 
 
 
 
 
 
 
 
 
 
 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw 
 
 
X 
 
 
 
 
 
 
 
X 
Skin prick 
test 
 
 
X 
 
 
 
 
 
 
 
X 
Oral food 
challenge 
 
X 
 
 
 
 
 
 
 
 
X 
Urine 
Pregnancy  
X 
 
 
 
 
 
 
 
 
 
X 
Study Drug 
Administratio
n 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug 
Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmed 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FAQL 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
X 


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 BPOIT 
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08MAR2022 
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6.3.2 
Assessment of Secondary Efficacy Endpoints 
Highest tolerated dose and cumulative dose. The highest dose of roasted peanut protein tolerated 
by the subject, cumulative total dose of roasted peanut protein tolerated by the subject, and the 
changes in highest tolerated dose and cumulative tolerated dose from initial OFC to the peanut 
protein arm of the exit DBPCFC will be analyzed as ordinal variables because of the interval nature of 
the dosing schedule (Chinchilli et al., 2005). The dose schedule for initial OFC and exit DBPCFC is 
shown below. 
 
Peanut protein challenge dose schedule at initial (SV 1) and exit (SV 10) oral food challenges. 
Oral food challenge 
Highest tolerated 
dose of peanut 
protein (mg) 
Cumulative  tolerated 
dose of peanut protein 
(mg) at initial OFC 
Cumulative tolerated 
dose of peanut protein 
(mg) at exit DBPCFC 
Initial only
5
5
Initial only
10
15
Initial and Exit
25
40
25
Initial only
50
90
Initial and Exit
100
190
125
Exit only
200
325
Exit only
300
625
Initial only
500
690
Exit only
600
1225
Initial and Exit
1000
1690
2225
Initial only
4000
5690
 
Serum markers of sensitization and tolerance to peanut. Changes in serum markers of sensitization 
and tolerance to peanut from initial dose escalation visit to final study visit will be analyzed as 
continuous variables. 
 
Food Allergy Quality of Life Questionnaires (FAQLQ). The Food Allergy Quality of Life Questionnaire – 
Parent Form (FAQLQ-PF) will be used for patients aged 0-12 years (DunnGalvin et al., 2008). The 
Food Allergy Quality of Life Questionnaire –Teenager Form (FAQLQ-TF) will be used for patients aged 
13-17 year (Flokstra-de Blok et al., 2008). For all FAQLQ surveys, all questions are scored on an 
ordered scale from 1 (“no impairment”) to 7 (“maximal impairment”) for calculations. Subscale and 
summary scores are calculated as item mean scores, on the same scale from 1 to 7. Subscale and 
summary scores, and changes in subscale and summary scores from enrollment/baseline visit to 
final study visit, will be analyzed as continuous variables. The MID (minimally important difference) 
for the FAQLQ is 0.5 (DunnGalvin et al., 2010), and the change in total score will be dichotomized as 
greater than or equal to 0.5 or less than 0.5 and analyzed as a binary variable. Scoring of the FAQLQ 
is detailed in section 9.3.2. 
6.3.3 
Assessment of Safety Endpoints 
AEs, including Serious Adverse Events (SAEs) will be graded according to severity using the 
Consortium of Food Allergy Research (CoFAR) scale, which is 5-point ordered scale from mild (1) to 
death (5). AEs will be categorized by preferred term using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 and for the specific AEs for interest listed in section 5.2, by 
treatment required, and by study phase (dose escalation study visits, home doses, exit DBPCFC, and 
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7 Sample Size  
We will compare with proportion of patients successfully desensitized as defined by meeting the 
primary endpoint with the expected placebo rate. The null hypothesis is that the proportion of 
patients successfully desensitized by boiled peanut oral immunotherapy will not be greater than the 
expected 20% that has been previously published as the proportion of patients successfully meeting 
the primary endpoint in OIT studies (which aligns with the expected 20% that would naturally 
“outgrow” a peanut allergy). If we reject this null hypothesis, we will be able to conclude that the 
proportion of successfully desensitized by boiled peanut therapy is greater than placebo. The sample 
of 10 patients will provide >90% power to determine the expected success rate (80%) is greater than 
a theoretical placebo rate (20%). 
8 General Analysis Considerations 
8.1 Timing of Analyses 
No interim analyses are planned. The final analysis will be performed on data transferred to the 
study statistician, having been documented as meeting the cleaning and approval requirements of 
the study protocol and after the finalization and approval of this SAP document. 
8.2 Analysis Populations 
8.2.1 
Primary Endpoint Intention to Treat (ITT) Population 
 
All patients enrolled in study following the initial OFC. 
8.2.2 
Efficacy Population 
 
All patients who completed both initial OFC and exit DBPCFC. 
8.2.2.1 Modified Efficacy Population for Immune Response 
 
Patients with serum testing for at least one peanut-specific marker of sensitization and 
tolerance at both the initial dose escalation visit and exit DBPCFC. 
8.2.2.2 Modified Efficacy Population for FAQLQ-PF 
 
Patients with at least one subscale or summary score at both enrollment/baseline and exit 
DBPCFC, on the same FAQLQ age-group-specific parent form. 
8.2.2.3 Modified Efficacy Population for FAQLQ-TF 
 
Patients with at least one subscale or summary score on the FAQLQ teenager form at both 
enrollment/baseline and exit DBPCFC. 
8.2.3 
Safety Population 
 
All enrolled patients who took at least one dose of study medication during any dose 
escalation visit or at home, or participated in either arm of the exit DBPCFC.  
8.2.4 
Study Visit Populations 
 
For each SV, all patients with a documented date of visit. 
8.3 
Covariates and Subgroups 
No subgroup analyses are planned. 
8.4 
Missing Data 


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With the exception of the primary endpoint, missing data will not be imputed and analyses will be 
performed on a complete-case basis, due to the small sample size and exploratory nature of the 
study. The expected sample size is smaller than is practical to analyze under multiple imputation, 
with little ability to assess the missing at random assumption. A carry-forward approach is likely to 
be too conservative to provide useful information for future study planning or hypothesis 
generation.  Patients with missing data on particular endpoints will be excluded only for analyses in 
which those variables were used, and the results of the complete-case analyses will be interpreted 
as pertaining to patients with data on the specific analyzed endpoint. Sample sizes will be noted for 
all descriptive statistics and analyses. 
8.5 
Multiple Testing 
As this is a proof-of-concept study with a single primary endpoint, no adjustment for multiple testing 
will be performed. The use of hypothesis testing is limited to primary and secondary efficacy 
endpoints, and within the FAQLQ analysis, to total scores only. Detailed descriptive statistics will be 
presented for secondary endpoints, along with unadjusted p-values, and reports will interpret 
hypothesis testing for secondary endpoints as hypothesis-generating rather than confirmatory. 
9 
 Summary of Study Data 
Continuous variables will be summarized using the following descriptive statistics: n (non-
missing sample size), median, 25th and 75th percentiles, maximum, and minimum (range). 
Categorical variables will be summarized with the frequency and percentages (calculated using 
the non-missing sample size as the denominator) of observed levels.  All summary tables will list 
the total analysis population and missing data for the table, and for individual variables in the 
table where different from the total. Data listings will be sorted by subject and, where 
necessary, by visit number within subject.  
 
Because the secondary efficacy analyses of changes in highest tolerated dose and cumulative dose of 
peanut protein, serum markers of sensitization and tolerance to peanut, and FAQLQ scores will be 
performed on a complete-case basis, the sample sizes of non-missing data for the initial and final 
values may be larger than the sample sizes of non-missing data for the change variables. Therefore 
additional descriptive tables will present univariable summary statistics for all non-missing data for 
the initial and final values of these variables. (Refer to mock Tables 4.3-4.6.) 
9.1 
Subject Disposition 
All subjects in the study database will be considered as assessed for eligibility. Subject disposition 
will be described based on the database fields on the case report forms (CRFs) ‘Inclusion/Exclusion 
BPOIT’, ‘Demographics’ (field indicating date of signed consent), ‘Oral Food Challenge’ (field 
indicating date of participation), ‘Study drug administration’ (any dose of study medication 
administered indicates enrollment in study), ‘Off study/continued therapy’ (field indicating the 
reason the patient came off the study). (Refer to mock Table 1.1.) 
9.2 
Derived variables 
9.2.1 Derivation of Primary Efficacy Endpoint 
The primary efficacy endpoint is ‘response to treatment’ at the exit DBPCFC. A subject will be 
defined to have response to treatment if the question, ‘Was 300mg dose tolerated’ on the CRF 
corresponding to the peanut protein arm of the DBPCFC was marked ‘Yes’.  If this question is marked 
‘No’, or the subject did not complete the DBFCFC for any reason, the subject will be defined as no 
response to treatment.    


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9.2.2 
Derivation of Secondary Efficacy Endpoints 
Highest tolerated dose and cumulative dose. The highest tolerated dose at initial OFC will be the 
largest amount in milligrams to which the question, ‘Was amount dose tolerated’ on the CRF for the 
initial OFC was marked ‘Yes’. The highest tolerated dose at exit DBFCFC will be the largest amount in 
milligrams to which the question, ‘Was amount dose tolerated’ was marked ‘Yes’ on the CRF 
corresponding to the peanut protein arm of the exit DBPCFC.  At both the initial OFC and exit 
DBPCFC, if the lowest dose given was not tolerated, the highest tolerated dose will be zero. The 
change in highest tolerated dose will be calculated as the difference between the final and initial 
highest tolerated doses. 
 
The cumulative tolerated dose at initial OFC will be the sum in milligrams of all doses in which the 
question, ‘Was amount dose tolerated’ on the CRF for the initial OFC was marked ‘Yes’. The 
cumulative tolerated dose at exit DBPCFC will be the sum in milligrams of all doses in which the 
question, ‘Was amount dose tolerated’ was marked ‘Yes’ on the CRF corresponding to the peanut 
protein arm of the DBPCFC.  At both the initial OFC and exit DBFCFC, if the lowest dose given was not 
tolerated, the cumulative tolerated dose will be zero. The change in cumulative tolerated dose will 
be calculated as the difference between the final and initial highest tolerated doses. 
 
Serum markers of sensitization and tolerance to peanut. The change in each serum marker will be 
calculated as the difference between the final and initial values. 
 
FAQLQ.  Questionnaires will be scored according to scoring sheets downloaded from the FAQLQ 
website (faqlq.com, accessed November 1, 2021). The change in the summary score and each 
subscale score from baseline to follow-up FAQLQ will be calculated for each patient. The MID 
(minimally important difference) for the FAQLQ is 0.5 (DunnGalvin et al., 2010); each change score 
will be categorized as greater than or equal to the MID (>= 0.5), or less than the MID (< 0.5).  The 
number and percent of missing items will be assessed for the summary score and each subscale 
score, and scores will not be calculated if the percent of missing items is greater than 20%, as 
recommended on the FAQLQ website (http://faqlq.com/?page_id=15). Item mean scores will be 
calculated as the sum of all non-missing item response values divided by the number of non-missing 
items. 
 
● Subjects ages 0-12 years. The Food Allergy Quality of Life Questionnaire – Parent Form 
(FAQLQ-PF) for ages 0-12 years has different scoring sheets for age group 0-3, 4-6, and 
7-12; there are 3 subscale scores and a summary score for all age groups 
(http://faqlq.com/wp-content/uploads/2011/11/FAQLQ-PF-scoring-sheet-all-age-
groups.pdf). Subscale scores are item mean scores for the specified questions, and the 
summary score is the mean of the three subscale scores. If one or more subscale scores 
cannot be calculated due to missing data, the summary score will not be calculated. 
Figures 9.1-9.3 show the scoring sheets. 
 
● Subjects ages 13-17 years. The Food Allergy Quality of Life Questionnaire –Teenager 
Form (FAQLQ-TF) for ages 13-17 years has 3 subscale scores and a summary score 
(http://faqlq.com/wp-content/uploads/2011/11/FAQLQ-TF-scoring-sheet.pdf).  Subscale 
scores are item mean scores for completed items, and the summary score is the item 
mean score of all questionnaire items for completed items. If one or more subscale 
scores cannot be calculated due to missing data but the overall survey completeness is 
not lower than 80%, the summary score will be calculated. Figure 9.4 shows the scoring 
sheet.  
 


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Figure 9.1. FAQOL-PF scoring sheet for ages 0-3 years. 
 
 


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Figure 9.2. FAQOL-PF scoring sheet for ages 4-6 years. 
 
 
 


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Figure 9.3. FAQOL-PF scoring sheet for ages 7-12 years. 
 
 
 


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Figure 9.4. FAQOL-TF scoring sheet. 
 
 
9.2.3 
Derivation of Safety Variables 
Adverse events (AEs) will be categorized by preferred term using the CTCAE Version 5.0, and by the 
specific AEs of interest listed in section 5.2. The specific AEs of interest with possible alternative 
preferred terms, which will be grouped together, are: oral itching (oral pruritus), rhinorrhea (allergic 
rhinitis or rhinorrhea), conjunctivitis (eye itching), urticaria (hives), angioedema, abdominal upset 
(dyspepsia or nausea), vomiting, diarrhea, cough, wheeze (wheezing), and anaphylaxis.  
 
Mortality. Mortality will be identified by an AE of CoFAR severity grade 5, and/or ‘Death’ indicated as 
a SAE criteria on the CRF for AEs.  
9.2.4 
Derivation of Other Variables 
Age at initial OFC. Age will be calculated using the date of birth (DOB) and the date of the OFC, and 
presented as age at last birthday as an integer.  


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Timing of Study Visits (SVs) and Additional Study Visits (ASVs). The number of days from initial OFC 
and initial dose escalation visit will be calculated for each SV or ASV as the difference in the two 
dates (Date of SV/ASV – Date of OFC/initial dose escalation visit). (Refer to mock Table 1.4) 
9.3 
Demographic and Baseline Variables 
Demographic data presented will be age at OFC, gender, ethnicity, and race. Baseline/enrollment 
variables presented will be height, weight, and known history of asthma, allergic rhinitis, and atopic 
dermatitis. Demographic data will be summarized in separate columns for the Intention to Treat, 
Efficacy, and Safety populations; if any of these represent the same population, the columns will be 
combined. (Refer to mock Table 1.3.) 
9.4 
Study Drug Administration 
For each patient and each dose escalation visit, the maximum dose tolerated (mg) and dose to be 
taken at home (mg), as reported on the CRF for study drug administration, will be listed for the ITT 
population (all enrolled patients) in a single table. (Refer to mock Table 4.1.) 
9.5 
Treatment Compliance 
Treatment compliance will be summarized separately for each SV and ASV using fields from the CRF 
for study drug compliance, including the number of patients with at least one missed dose and 
reasons for missed doses reported by at least one patient. The population for each SV table will be 
all patients in the corresponding Study Visit population. (Refer to mock Tables 4.2.1 -4.2.10.) 
10 
Efficacy Analyses 
10.1 Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is ‘response to treatment’ defined as defined as ability to successfully 
consume a single dose of 300 mg or greater of peanut protein with no dose limiting symptoms at the 
exit DBPCFC. The analysis population will be the Primary Endpoint ITT population. Subjects with 
missing data on the primary endpoint will be considered as non-responders for the primary analysis. 
Due to the small sample size, exact rather than asymptotic statistical methods will be used for the 
analysis of this endpoint. 
 
The proportion of patients who respond to treatment will be assessed using a one-sample 
superiority analysis compared to an expected proportion of 20%. The null hypothesis is that the 
proportion of patients who respond to treatment is less than or equal to 20%, and the alternative 
hypothesis is that the proportion of patients who respond to treatment is greater than 20%.  
As this is a proof-of-concept study, statistical significance in the analysis of primary efficacy endpoint 
will be assessed using a one-sided 0.05 level of significance (or two-sided 0.1) rather than a one-
sided 0.025 level of significance (or two-sided 0.05). The alternative hypothesis of superiority will be 
accepted if the lower bound of the one-sided 95% Clopper-Pearson exact confidence interval 
(equivalent to the lower bound of a two-sided 90% confidence interval) for the primary efficacy 
endpoint is greater than 20%; the p-value for the exact binomial test at a one-sided significance level 
of 0.05 will also be provided. The summary statistics will be reported as described in section 9. 
(Refer to mock Table 2.1.) 
10.2  Analysis of Secondary Efficacy Endpoints  
Secondary efficacy endpoints consist of changes in continuous or ordinal variables from the 


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enrollment/baseline, initial OFC, or initial dose escalation visit to the final study visit. The primary 
analyses of the change endpoints will be performed using Wilcoxon signed rank tests, with null 
hypotheses of no change, versus two-sided alternative hypotheses at a significance criteria of 0.05.  
Missing data will not be imputed, and complete cases only will be analyzed (see section 8.4). Due to 
the small sample size, visual assessments of the symmetry assumptions of the Wilcoxon signed rank 
tests are unlikely to be definitive, and p-values for Sign tests under the same null hypotheses and 
significance criteria will also be presented as sensitivity analyses. The summary statistics will be 
reported as described in section 9. 
 
Highest tolerated dose and cumulative tolerated dose. Changes in highest tolerated dose and 
cumulative tolerated dose from initial OFC to the peanut protein arm of the exit DBPCFC will be 
analyzed as ordinal variables, using nonparametric tests. The analysis population will be the Efficacy 
Population. (Refer to mock Table 2.3.) 
 
Serum markers of sensitization and tolerance to peanut. Changes in serum markers of sensitization 
and tolerance to peanut will be analyzed as continuous variables using nonparametric tests. The 
analysis population will be the Modified Efficacy Population for immune response. (Refer to mock 
Table 2.4.) 
 
FAQLQ.  Changes in FAQLQ subscale and summary scores will be analyzed as continuous variables 
using nonparametric tests. The percent of patients with change in summary score greater than or 
equal to the MID will be reported with 95% Clopper-Pearson exact confidence interval. Hypothesis 
testing will be performed for summary scores only. Parent and Teenager forms will be analyzed 
separately, and the analysis populations will be the Modified Efficacy Populations for FAQLQ-PF and 
FAQLQ-TF. (Refer to mock Tables 2.5 and 2.6.) 
11 
Safety Analyses 
Safety analyses will be performed on the safety population unless otherwise specified. Summary 
statistics will be reported as described in section 9. 
11.1 Adverse Events 
All AEs that affect at least one patient will be reported.  AEs will be categorized as corresponding to a 
study phase (dose escalation study visit, home dose, exit DBPCFC, etc.), and reported within study 
phase and overall. They will be further grouped by preferred term, CoFAR severity grade, or 
treatment given. AEs that meet SAE criteria will also be categorized as corresponding to a study 
phase, and reported within study phase and overall. Adverse events data will be tabulated within 
the categories and groups described above at both the patient and dose level.   
 
Patient-level analysis. The number of patients that experience the AE or SAE at least once will be 
tabulated. Within category and group, each subject will be counted once and any repetitions will be 
ignored.  
 
Dose level analysis. The number and percentage of study medication doses in the category and group 
that are associated with the AE or SAE. The total number of doses of study medication will be 
reported for each category, and the denominator for the calculation of the percentages will be the 
total number of doses given by category.  
11.1.1 Patient- and dose-level summary AE tables 
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DBPCFC, and overall. Specific AEs of interest, which will be included in the patient- and dose-level AE 
tables whether or not any patients experienced them, are listed under Secondary Endpoints in 
section 5.2 and under Derivation of Safety Variables in section 9.2.3. Any additional preferred terms 
recorded for at least one patient or dose will also be reported, listed alphabetically following the 
specific AEs of interest. AEs occurring and doses of study medication administered during both arms 
of the exit DBPBFC will be counted towards the totals. (Refer to mock Tables 3.1 and 3.2.) 
11.1.2 Comparative AE table 
AE data from this study will be compared descriptively to the AE data from three published studies: 
the study medication arms of the Phase 2 and Phase 3 trials of AR101 OIT for peanut allergy (Bird et 
al., 2018; Vickery et al. for PALISADE, 2018), and OIT data from the PACE meta-analysis study of OIT 
for peanut allergy (Chu et al., 2019). No hypothesis testing will be performed. 
 
For this table, study AEs will be categorized into two study phases as best corresponds to the 
comparative data: 1) initial dose escalation study visit, and 2) an increasing dose phase which 
includes all other dose escalation study visits and home doses, but excludes the exit DBPCFC.  AEs 
will be grouped into severity grades, treatments, and preferred terms, where the preferred term list 
will include the specific AEs of interest only (see sections 5.2 and 9.2.3). (Refer to mock Table 3.3 for 
comparative data and source information.) 
11.1.3 ClinicalTrials.gov ‘Other (Not Including Serious) Adverse Events’ table 
The adverse event term list will include all preferred terms recorded for at least one patient, listed 
alphabetically. AEs which meet SAE Criteria will be excluded from the calculations for this table. 
(Refer to mock Table 3.4.) 
11.2 Deaths, Serious Adverse Events and other Significant Adverse Events 
11.2.1 Patient- and dose-level summary AE tables 
SAEs will be included in the patient- and dose-level summary AE tables described in section 11.1.1 as 
a subset of the AEs.  
11.2.2 ClinicalTrials.gov ‘Serious Adverse Events’ table 
The adverse event term list will include all preferred terms recorded for at least one patient and 
meeting SAE criteria, listed alphabetically. (Refer to mock Table 3.5.) 
11.2.3 ClinicalTrials.gov mortality table 
The total number of patients and the number of patients who died due to AEs will be presented. 
(Refer to mock Table 3.6.) 
11.3 Concomitant Medications 
Current medications (listed alphabetically) will be summarized by medication name (as recorded on 
the concomitant medication CRF), the number of patients who reported using each medication at 
least once, and the total number of occurrences of use of the medication. The ITT population (all 
enrolled patients) will used for this analysis. (Refer to mock Table 3.7.) 
11.4 Other Safety Measures 
Vital signs. For each patient, general appearance and vital signs will be listed at each study visit. The 
ITT population (all enrolled patients) will used for this analysis. (Refer to mock Table 3.8.) 
 
Accidental peanut consumption. All reported incidents of accidental peanut consumption will be 


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listed, sorted by patient number and time from initial dose escalation visit. Patients with no 
accidental peanut consumption will not be listed in the table. The ITT population (all enrolled 
patients) will used for this analysis. (Refer to mock Table 3.9.) 
 
Spirometry. Spirometry was performed at the physician’s discretion per protocol. When performed, 
spirometry results at enrollment/baseline, exit DBPCFC, and any other visits will be listed for each 
patient in a single table. The ITT population (all enrolled patients) will used for this analysis. (Refer to 
mock Table 3.10.) 
 
Peak flow. Peak flow was performed at the physician’s discretion per protocol. When performed, 
peak flow results at each visit will be listed for each patient in a single table. The ITT population (all 
enrolled patients) will used for this analysis. (Refer to mock Table 3.11.) 
12 Reporting Conventions 
P-values greater than 0.01 will be reported to 2 decimal places, p-value between 0.01 and 0.001 
inclusive will be reported to 3 decimal places, and p-values less than 0.001 will be reported as 
“<0.001”. Quantiles, such as median, quartiles, minimum, and maximum will use the same number 
of decimal places as the original data. Percentages will be reported to one-tenth of a percent, with 
values less than one-tenth of a percent reported as “<0.1” and zero percent reported as 0. FAQLQ 
subscale and summary scores will be reported to one decimal place. All other statistics will be 
reported to one decimal place greater than the original data. 
13  Quality Assurance of Statistical Programming 
All data, code, and study information will be stored on Cleveland Clinic Lerner Research Institute’s 
password protected servers. Each biostatistician’s final code, log files, output, and derived datasets 
will be saved separately within a shared project directory. At the time of writing, all analyses will be 
performed on SAS 9.4 software via SAS Studio (SAS Institute, Cary, NC) installed on a Linux platform 
on the Lerner Research Institute’s servers. Sarah Worley, MS and Wei Liu, MS, or similarly-qualified 
biostatisticians in the Department of Quantitative Health Sciences at Cleveland Clinic, will 
independently produce the tables listed in the Statistical Analysis Plan and compare the results, and 
the trial statistician will review code and output as necessary.  
 
 


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14 Listing of Tables 
Background and demographic data 
Table 1.1 Disposition of patients. 
Table 1.2 Analysis populations. 
Table 1.3 Demographics and baseline characteristics. 
Table 1.4 Timing of study visits (ITT population). 
 
Efficacy endpoints 
Table 2.1 Primary endpoint: Response to treatment (ITT population). 
Table 2.2 Listing of oral food challenge results by patient (ITT population). 
Table 2.3 Summary of changes in maximum tolerated dose and cumulative tolerated dose, from 
initial OFC to exit DBPCFC (Efficacy population, N=X).  
Table 2.4 Summary of changes in serum markers of sensitization and tolerance to peanut (Modified 
Efficacy population for immune response, N=X).  
Table 2.5 Summary of changes in parent-reported Food Allergy Quality of Life (FAQLQ-PF) scores 
(Modified Efficacy Population for FAQLQ-PF). 
Table 2.6 Summary of changes in child-reported Food Allergy Quality of Life (FAQLQ-TF) scores 
(Modified Efficacy Population for FAQLQ-TF). 
 
Safety endpoints 
Table 3.1 Patient-level summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) (Safety 
Population).   
Table 3.2 Dose-level summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) (Safety 
Population).   
Table 3.3 Comparison of Adverse Events (AEs) and Serious Adverse Events (SAEs) to published data 
(Safety Population). 
Table 3.4 ClinicalTrials.gov reporting requirement ‘Other (Not Including Serious) Adverse Events’ 
(Safety Population). 
Table 3.5 ClinicalTrials.gov reporting requirement ‘Serious Adverse Events’ (Safety Population).  
Table 3.6 ClinicalTrials.gov reporting requirement for mortality (ITT population). 
Table 3.7 Summary of concomitant medications (ITT population). 
Table 3.8 Listing of general appearance and vital signs by patient-visit (ITT population).  
Table 3.9 Listing of episodes of accidental peanut consumption (ITT population).  
Table 3.10 Listing of spirometry results by patient-visit (ITT population). 
Table 3.11 Listing of peak flow results by patient-visit (ITT population). 
 
Additional study data 
Table 4.1 Listing of study drug administration by patient-visit (ITT population). 
Tables 4.2.x Summary of study drug compliance for Study Visit x (Study visit populations). 
Table 4.3 Summary of maximum and cumulative maximum tolerated doses, at initial OFC and exit 
DBPCFC (Study visit populations). 
Table 4.4 Summary of allergen, peanut IgE and skin prick test data, at initial OFC and exit DBPCFC 
(Study visit populations).  
Table 4.5 Summary of FAQLQ-PF summary and subscale scores, at enrollment/baseline and follow-
up visit (Study visit populations).  
Table 4.6 Summary of FAQLQ-TF summary and subscale, at enrollment/baseline and follow-up visit 
(Study visit populations). 
 


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15 References 
Bird JA, Spergel JM, Jones SM, Rachid R, Assa'ad AH, Wang J, Leonard SA, Laubach SS, Kim EH, 
Vickery BP, Davis BP, Heimall J, Cianferoni A, MacGinnitie AJ, Crestani E, Burks AW; ARC001 Study 
Group. Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a 
Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial. J Allergy Clin Immunol Pract. 
2018 Mar-Apr;6(2):476-485.e3. 
 
Chinchilli VM, Fisher L, Craig TJ. Statistical issues in clinical trials that involve the double-blind, 
placebo-controlled food challenge. J Allergy Clin Immunol. 2005 Mar;115(3):592-7.   
 
Chu DK, Wood RA, French S, Fiocchi A, Jordana M, Waserman S, Brożek JL, Schünemann HJ. Oral 
immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and 
safety. Lancet. 2019 Jun 1;393(10187):2222-2232.  
 
DunnGalvin A, de BlokFlokstra BM, Burks AW, Dubois AE, Hourihane JO. Food allergy QoL 
questionnaire for children aged 0-12 years: content, construct, and cross-cultural validity. Clin Exp 
Allergy. 2008 Jun;38(6):977-86.  
 
DunnGalvin A, Cullinane C, Daly DA, Flokstra-de Blok BM, Dubois AE, Hourihane JO. Longitudinal 
validity and responsiveness of the Food Allergy Quality of Life Questionnaire - Parent Form in 
children 0-12 years following positive and negative food challenges. Clin Exp Allergy. 2010 
Mar;40(3):476-85.  
 
FAQLQ. Food Allergy Quality of Life Questionnaire. http://faqlq.com/. Manual: 
http://faqlq.com/?page_id=15. Scoring of FAQLQ-PF: link http://faqlq.com/wp-
content/uploads/2011/11/FAQLQ-PF-scoring-sheet-all-age-groups.pdf. Scoring of FAQLQ-TF: 
http://faqlq.com/wp-content/uploads/2011/11/FAQLQ-TF-scoring-sheet.pdf.  Accessed November 
1, 2021. 
 
Flokstra-de Blok BM, DunnGalvin A, Vlieg-Boerstra BJ, Oude Elberink JN, Duiverman EJ, Hourihane 
JO, Dubois AE. Development and validation of the self-administered Food Allergy Quality of Life 
Questionnaire for adolescents. J Allergy Clin Immunol. 2008 Jul;122(1):139-44, 144.e1-2.  
 
PALISADE Group of Clinical Investigators, Vickery BP, Vereda A, Casale TB, Beyer K, du Toit G, 
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Statistical Analysis Plan 
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16 Appendices 
Appendix I: Mock Tables.