Clinical trial NCT03181009
Conditions: Food Allergy
Keywords: Oral Immunotherapy Omalizumab OIT Xolair
Sponsor: Kari Christine Nadeau, MD PhD
Start date: 2017-07-31; Completion date: 2019-01-30
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Few studies have been conducted to optimize safety of multiple food allergen oral immunotherapy (OIT) in conjunction with Omalizumab as well as to identify the immunological mechanism(s) underlying any long-lasting effects of OIT. To address these issues in the field of food allergy research, we have designed this study to test whether: 1) Omalizumab improves the safety of multiple food allergen OIT in subjects with multi food allergies, 2) Omalizumab treatment with multiple food allergen OIT is associated with the ability to use a lower maintenance dose of each food allergens in the OIT regimen, particularly in younger subjects with food allergies.

Detailed description:
This is a phase 2 multisite study that will be conducted at two centers in the U.S. All subjects will receive oral immunotherapy for their specific food allergies (peanut, milk, egg, soy, wheat, cashew, walnut, almond, hazelnut, cod, salmon, sesame, shrimp). All participants will receive three doses of Omalizumab 4 weeks apart over 8 weeks. The subject's allergens will be introduced after receiving the third omalizumab dose. Subjects will return to clinic to escalate the dose of their allergens until 300 mg (group A) vs. 1200 mg (group B) total protein daily dose is reached. There will be equivalent allergen protein portions depending on test allergen per each subject's history. Subjects will be randomized 1:1 to either group A or group B after meeting eligibility criteria. All subjects and study personnel will be blinded to group A vs B.

Food protein and powder will be obtained and prepared as per Investigational New Drug 14831 and will be in compliance with all applicable regulations.

Omalizumab is approved by the European Medicines Agency (European FDA) and by the US FDA. Omalizumab will be dosed according to Genentech Dosing Omalizumab will be provided by the site.

Arms: arm 1: After initial therapy with omalizumab Group A subjects will escalate their food flour allergens to 300 mg in 18 weeks. arm 2: After initial therapy with omalizumab Group B subjects will escalate their food flour allergens to 1200 mg in 18 weeks.
Interventions: intervention 1: Omalizumab intervention 2: Food Flour Allergens
Intervention descriptions: intervention 1: All subjects will receive omalizumab, stored and prepared according to the investigator brochure. Subjects greater or equal to 4 yrs receive 150 mg. Subjects less than 4 yrs receive 75 mg. intervention 2: The subject's allergens will be introduced after receiving the third omalizumab dose.. Subjects will return to clinic to escalate the dose of their allergens until 300 mg (group A) vs. 1200 mg (group B) total protein daily dose is reached. There will be equivalent allergen protein portions depending on test allergen per each subject's history. Subjects will be randomized 1:1 to either group A or group B after meeting eligibility criteria. All subjects and study personnel will be blinded to group A vs B. Research staff will administer food flour to the subject orally in an age-appropriate food vehicle.

Protocol documents:
ICF_002.pdf: 
 
NCT03181009 
 
Full Title: A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
Short Title: Multi Immunotherapy to test Minimum dose using Xolair (MIMiX) 
 
Informed Consent – Approval Date: June 12, 2018 
 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 1 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
 
Please check all that are applicable: 
 
 I am an adult participant in this study. 
 
Print your name here:  
 
______________________________________________________ 
 
 
 I am the parent or guardian granting permission for a child in this study (the 
use of "you" refers to "your child" or “your ward.”) 
  
Print child’s name here:  
 
______________________________________________________ 
 
************* 
 
Are you participating in any other research studies? _____ Yes _____No 
 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study to test the safety and efficacy of 
Oral ImmunoTherapy (OIT) with omalizumab (Xolair, anti-IgE) to help children and 
adults who are allergic to food be able to safely tolerate food allergens. Specifically 
in this protocol, the food allergens will include at least two, maximum of five of the 
following: peanut, almond, cashew, walnut, hazelnut, milk, egg, wheat, soy, sesame 
seed, cod, shrimp, and/or salmon. Omalizumab is considered an investigational drug 
for the treatment of food allergies in children and adults. Investigational means it 
has not been approved by the Food and Drug Administration (FDA) for use in food 
allergies in the U.S.   
 
The purpose of this study is to test whether omalizumab improves the safety of OIT, 
and if omalizumab treatment with multiple food allergen OIT allows the use of a 
lower maintenance dose of each food allergen in the OIT regimen, particularly in 
younger subjects with food allergies. 
 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 2 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
You are being asked to participate in this experimental research study because you 
have a history of multiple food allergies.  
 
If you decide to terminate your participation in this study, you should notify the 
Protocol Director, Dr. Kari Nadeau or the co-Protocol Director Dr. Sayantani Sindher 
at (650) 724-0293.   
 
This research study is looking for 60 participants, between 2 and 25 years of age, 
with multiple food allergies. Enrollment will occur at 2 centers in the United States.  
Sean N Parker Center for Allergy and Asthma Research at Stanford University 
expects to enroll approximately 30 research study participants.  
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to participate 
will not have any negative effect on you or your medical care.  You can decide to 
participate now, but withdraw your consent later and stop being in the study without 
any loss of benefits or medical care to which you are entitled. 
 
DURATION OF STUDY INVOLVEMENT  
 
This research study is expected to take approximately 26 weeks: 
- 
About 1 day for screening 
- 
8 weeks for omalizumab administration  
- 
18 weeks of oral desensitization therapy 
 
PROCEDURES 
 
If you choose to participate, Dr. Kari Nadeau, Dr. Sayantani Sindher and/or the 
research study staff will explain the study to you and ask you to read this consent 
form. The study personnel will answer any questions you may have about the study 
and what is being asked of you. If you decide to participate you will be asked to 
sign this consent form and a copy will be given to you. 
 
While participating in this study, you must be very careful to avoid all allergens 
apart from what is instructed by Dr. Kari Nadeau/Sayantani Sindher and her team 
during the study, as this may potentially cause an allergic reaction. Also, you may 
not change your diet or add new foods during your participation in this study. 
 
There will be at least 9 visits to the clinic throughout the study.  The study 
includes: 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 3 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
• Screening Visit (within 30 days of 1st Omalizumab dose) 
• Omalizumab Administration Visits (3 doses 4 weeks apart) 
• Build Up (start after last Omalizumab dose until 8 weeks post Omalizumab) 
• Maintenance (over 10 weeks) 
• End of Study 
 
All participants will receive omalizumab as a subcutenous (under the skin) injection 
thrice over 8 weeks (at week -8, -4 and week 0) with 4 week intervals between 
injections. Your specific allergens will be introduced in an oral desensitization day at 
week 0, after the last dose of omalizumab. You will be randomly assigned to build 
up your dose of 300mg or 1200mg daily.  There is a 50% chance you will be 
assigned to either group.  Each daily food flour dose will contain about the same 
amount of each allergen protein composed of 2-5 of your allergens.  You will 
increase your allergen dose to reach the goal of a maintenance dose 300mg or 
1200mg every day, depending on which group you are assigned, without having 
an allergic reaction.  The amount of time to reach this will be about 8 weeks.  Oat 
flour may be added to your daily food flour dose in order to ensure that neither you 
nor the study team knows to which arm you are assigned (double blind).  Once the 
goal dose is reached, you will continue to take the same food flour doses daily until 
week 18. 
 
Baseline/Screening Visit  
We will ask you to come first for a screening visit to perform procedures to 
determine if you are eligible for the study, and to review your medical history 
regarding your food allergies, other allergies and general health. We may ask to 
contact your primary provider or allergist to get a copy of any medical records 
pertaining to your food allergies.  
 
At this screening visit, the following procedures will be performed after you sign 
this informed consent form: 
- 
Review of medical history 
- 
Physical examination (including height and weight) 
- 
Vital signs (heart rate, respiratory rate, temperature, and blood pressure) 
- 
Spirometry (a test that uses a hand held instrument connected to a 
computer to measure how deep a breath you can take and how fast you can 
blow air out through your mouth) or Peak Flow Meter (a small tube with a 
mouthpiece that measures how fast you can blow air out through your 
mouth) reading, 
- 
Skin prick test may be done to assess your sensitivity to food allergens.  You 
may be asked to stop taking antihistamines such as Benadryl, Zyrtec, or 
Claritin, before the visit in order to undergo a skin prick test. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 4 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
- 
Review of medications you are currently taking 
- 
Urine pregnancy test for female patients of childbearing potential. Your urine 
samples will be destroyed right after the laboratory tests are completed. 
- 
Blood draw (not more than 50mL or 3-4 tablespoons in volume) for food-
specific Immunoglobulins (IgE and IgG4) and for mechanistic 
studies/immunology markers 
- 
Review of eligibility: you must have food specific IgE>4kU/L in the blood for 
each allergen OR a skin test reactivity to each food allergen greater than or 
equal to 6mm wheal diameter for at least two allergens. 
- 
Training on the following will be done at screening and at each subsequent 
study visit: 
o How to properly store and administer the study dose 
o How to recognize allergic reactions and/or other adverse events 
o What actions you must take should you have an allergic reaction 
o How and when to use the epinephrine-containing autoinjector.  You 
and/or your families will be required to have an epinephrine 
autoinjector with you at all times.  If you do not have the auto 
injector, you will be given a prescription for an epinephrine-containing 
autoinjector (EpiPen Jr. or EpiPen) at the beginning of the study.   
 
The visit will be approximately 2-3 hours long 
 
Omalizumab Administration Visits - Week -8 and Week -4 
At week -8 visit, if you continue to be eligible for the study, you will receive your 
first dose of omalizumab as a subcutaneous (under the skin) injection at this visit.  
Your second dose of Omalizumab will be administered at week-4 visit.  Each time 
omalizumab is administered, you will be closely observed at the clinic for 
approximately 1 ½ hours after the injection. 
A symptom directed physical exam, review of medications and any change in your 
health will be performed at these visits. 
Each visit will be at least 2 hours long. 
 
Oral Immunotherapy - Week 0  
At week 0 visit, you will receive your last omalizumab dose. You will also begin oral 
desensitization with 5mg total protein dose of 2 to 5 foods you are allergic to.  You 
will take your first oral dose 1 hour after the omalizumab injection. 
After the 5 mg dose, you will be observed for a minimum of 2 hours in clinic. 
Physical Exam, serial vital signs, review of medications and any health change, and 
spirometry will be performed at this visit. 
You will also be instructed to keep a daily electronic diary to document that you 
have taken your daily dose and any symptoms that occur at home. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 5 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
If you do not tolerate 5mg total protein of your allergens, you will be asked to leave 
the study. 
If you are able to tolerate the 5 mg dose, you will be given your allergen doses to 
take at home.  You will take your food flour dose every day.  Dosing instructions 
will be provided, including a 24-hour emergency contact information and contact 
information for the research team. 
You will also be instructed to keep a daily electronic diary to document that you 
have taken your daily dose and any symptoms that occur at home. 
The food allergy action plan and epinephrine auto injector use will also be 
reviewed.   
 
Oral Immunotherapy- Week 4 through 16  
You will increase your allergen dose to reach the goal of a maintenance dose 
300mg or 1200mg every day, depending on which group you are assigned.  Once 
the dose is reached, you will remain at the same daily dose until week 18. 
 
At each new dose, you will take the first dose in the clinic followed by an 
observation period of a minimum of 2 hours.  
You will continue to take daily food flour dose at home unless advised otherwise 
by the study doctor or designee.  You will be asked to return to the clinic every 4 
weeks to have the dose increased as appropriate.  The study doctor may ask you 
to come in sooner than 4 weeks in order to assess how you are doing, and 
possibly adjust the allergen dose if necessary. 
At each visit, physical exam, serial vital signs, review of medications and any 
health change, spirometry, and diary review will be performed. 
 
The food allergy action plan and epinephrine auto injector use will also be 
reviewed.   
 
End of Active Phase of Study (Week 18) 
The following will be completed at the end of study visit or if you prematurely 
discontinue from the study: 
- 
Physical examination (including height and weight) 
- 
Vital signs  
- 
Spirometry (a test that uses a hand held instrument connected to a 
computer to measure how deep a breath you can take and how fast you can 
blow air out through your mouth) or Peak Flow Meter (a small tube with a 
mouthpiece that measures how fast you can blow air out through your 
mouth) reading, 
- 
Skin prick testing.  You may be asked to stop taking antihistamines such as 
Benadryl, Zyrtec, or Claritin, before the visit 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 6 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
- 
Review of medications you are currently taking 
- 
Urine pregnancy test for female patients of childbearing potential. Your urine 
samples will be destroyed right after the laboratory tests are completed. 
- 
Blood draw (not more than 50mL or 3-4 tablespoons in volume) for food-
specific Immunoglobulins (IgE and IgG4) and for mechanistic 
studies/immunology markers 
- 
Review of food allergy action plan and epinephrine auto injector use 
 
Throughout the study 
• You will keep electronic diaries during the study to document that you have 
taken your dose and any symptoms that occur at home. 
• You will be asked to continue to follow a food elimination diet of your food 
allergens and will be continually monitored for compliance by thorough 
questioning and review of the electronic diaries at every study clinic visit. 
• If you miss any of your food flour doses, you will be asked to inform the study 
team and ask for guidance on how to proceed with dosing.  
• You will be asked to bring all unused allergen dose(s) at every clinic visit. 
 
 
Women of Childbearing Potential 
If you are pregnant or currently breast feeding, you may not participate in this study 
since the risk of omalizumab to a developing fetus or breastfeeding child is currently 
unknown and could be potentially dangerous.  
 
If you are a woman of childbearing potential, it is expected that you will use an 
effective method of birth control to prevent exposing a fetus to a potentially 
dangerous agent with unknown risk. 
 
To confirm to the extent medically possible that you are not pregnant, you agree to 
have a pregnancy test done at screening and prior to starting omalizumab therapy. 
You must agree to avoid sexual intercourse or use a birth control method judged to 
be effective by the investigator and which will not interfere with the proposed 
investigation. You must accept the risk that pregnancy could still result despite the 
responsible use of reliable method of birth control. You agree to notify the 
investigator as soon as possible of any failure of proper use of your birth control 
method, or if you become pregnant, either of which may result in your being 
withdrawn from the study. 
 
Tissue Sampling for Research  
Research using tissues (blood) is an important way to try to understand human 
disease.  You have been given this information because the investigators want to 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 7 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
include your blood in a research project and because they want to save the 
samples for future research. There are several things you should know before 
allowing your tissues to be studied.  
Your blood sample will be stored for an indefinite period of time under a unique 
numbered identifier in the Nadeau Research lab. Your samples will be sent outside 
of Stanford University for analysis. These research studies are very important to 
understand the changes in the immune system that may occur as you become 
desensitized to your allergens. These results may help us to design better 
treatments in the future for multi food allergic patients.  
You have the right to refuse to allow your tissues to be studied now or saved for 
future study.  You may withdraw from this study at any time.  The investigators 
might retain the identified samples, e.g., as part of your routine clinical care, but 
not for additional research.  
 
The results of the study of your samples will be used for research purposes only 
and you will not be told the results of the tests.  
 
 
_____ I consent to my samples being saved for future research 
 
 
_____ I do not consent to my samples being saved for future research 
 
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include:  
 
• Follow the instructions of the study doctor and study staff. 
• Take the study drug daily as instructed. 
• Call the 24/7 on call number if you missed any doses or have any allergic 
reactions. 
• Keep your study appointments.  If it is necessary to miss an appointment, 
please contact the study doctor or research study staff to reschedule as soon 
as you know you will miss the appointment. 
• Tell the study doctor or research study staff about any side effects, doctor 
visits, or hospitalizations that you may have. 
• Tell the study doctor or research staff if you believe you might be pregnant 
or gotten your partner pregnant. 
• Keep the study drug in a safe place, away from children and for your use 
only. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 8 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
• Keep your electronic diaries as instructed. 
• Ask questions as you think of them. 
• Tell the study doctor or research staff if you change your mind about staying 
in the study. 
 
WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time. Your 
decision will not affect your ability to receive medical care for your disease and you 
will not lose any benefits to which you would otherwise be entitled.  
 
If you decide to withdraw your consent to participate in this study, you should 
notify the Protocol Director Dr. Kari Nadeau or the co-Protocol Director Sayantani 
Sindher at (650) 724-0293. 
If you withdraw from the study, or the study medication is stopped for any reason,  
• You will be asked to return to clinic for an end of study visit  
• You must return all study-related supplies, including unused study 
drug. 
 
The study doctor may also withdraw you from the study and the study medication 
may be stopped, without your consent for one or more of the following reasons: 
• Failure to follow the instructions of the investigator and study staff. 
• The Investigator decides that continuing your participation could be 
harmful to you (including psychological and/or emotional strains). 
• Pregnancy  
• You need treatment not allowed in the study. 
• The study is cancelled.  
• Other administrative reasons. 
• Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research 
study. These deserve careful thought. You should talk with the study investigator if 
you have any questions. 
 
The potential discomforts with the desensitization procedure and OIT may include 
an itchy rash, hives, nausea, abdominal discomfort, vomiting, diarrhea, facial 
swelling, cough, stuffy, runny nose, sneezing, wheezing, and shortness of breath. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 9 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
The major risks involved include severe breathing difficulties and rarely 
anaphylactic shock (severe allergic reaction involving many of the above symptoms 
plus sudden drop in blood pressure and loss of consciousness). A severe allergic 
reaction would require immediate medical treatment and could result in permanent 
disability or death. Medication, personnel, and equipment will be immediately 
available to treat allergic reactions. You will also be provided a prescription for an 
Epinephrine autoinjector to have with you at all times and to use in case of an 
allergic reaction. 
 
The other major concern besides anaphylaxis is eosinophilic esophagitis (EoE). EoE 
is a condition where a type of white blood cell (eosinophil) builds up in the tube 
that connects your mouth to your stomach (esophagus). This can cause 
stomach/chest pain, vomiting, regurgitation, and/or difficulty swallowing.  It is 
possible that EoE may be reversed upon stopping dosing. 
 
The risk involved with skin testing includes discomfort from the needle prick, along 
with itching and swelling at the skin test site in positive responses. Less common 
side effects include severe allergic reactions. You may be given topical steroid 
creams for application to the affected areas if needed. 
 
Risks with blood draws include fainting, local pain, stinging, bleeding, or bruising at 
the site where the needle is inserted into the vein. On rare occasions infection at 
the needle stick site may occur. 
 
Omalizumab Risks 
Omalizumab is approved by the FDA for patients aged 6 years and older with 
moderate to severe asthma. 
The adverse event profile (bad side effects) of omalizumab observed during the 
clinical development program was very similar to placebo with the most commonly 
reported adverse reactions being mild reactions at the place on the skin where the 
omalizumab was injected (injection site reactions). The overall frequency of 
injection site reactions was similar in omalizumab-treated patients and placebo 
patients. Other than injection site reaction, the most frequently reported adverse 
events were nasopharyngitis, upper respiratory tract infection and headache. 
During clinical studies with adult and adolescent patients 12 years of age and older, 
the most commonly reported adverse reactions were injection site reactions, 
including injection site pain, swelling, erythema (redness), pruritus (itching) and 
headaches. In clinical studies with patients 6 to <12 years of age, the most 
commonly reported adverse reactions were headache, pyrexia (fever) and upper 
abdominal pain. Most of the adverse events were mild or moderate in severity. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 10 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
Here is the list of the adverse reactions recorded in clinical studies in the total 
allergic asthma safety population and in patients with chronic 
spontaneous/idiopathic urticaria (CSU/CIU) treated with omalizumab: 
• Very common (≥1/10): pyrexia (fever), headache  
• Common (>1/100; <1/10): headache, upper abdominal pain, injection 
site reactions such as pain, erythema (redness), pruritus (itching), and 
swelling, nasopharyngitis (inflammation of the nose and throat), sinusitis, 
viral upper respiratory tract infection, arthralgia (joint pain) 
• Uncommon (>1/1000; <1/100): pharyngitis (throat swelling), dizziness, 
somnolence (sleepiness), paresthesia (tingling, numbness, or burning), 
syncope (fainting), postural hypotension, flushing, coughing, allergic 
bronchospasm, nausea, diarrhea, dyspeptic signs and symptoms (upset 
stomach), urticaria (hives), rash, pruritus (itching), photosensitivity, 
weight increase, fatigue, swelling arms, influenza-like illness 
• Rare (<1/1000): parasitic infections, anaphylactic reaction and other 
allergic conditions, anti- therapeutic antibody development, 
laryngoedema (throat swelling), angioedema (swelling) 
 
Additional events reported in CSU/CIU studies with incidence ≥1% in any treatment 
group and ≥2% higher in any omalizumab group than placebo: toothache, upper 
respiratory tract infections, urinary tract infection, fungal infection, sinus headache, 
myalgia, pain in extremity, musculoskeletal pain, fever, and injection site reactions 
occurred during the studies in more omalizumab -treated patients than placebo 
patients. 
 
The listing of adverse reactions from post-marketing spontaneous reports (mostly 
from patients with asthma) include:  
• Immune system disorders: Anaphylaxis and anaphylactoid reactions have 
been reported following the first or subsequent administrations, serum 
sickness  
• Skin and subcutaneous disorders: Alopecia (hair loss) 
• Blood and lymphatic system disorders: Idiopathic severe thrombocytopenia 
(decrease of platelets) 
• Arterial thromboembolic events (ATEs) included stroke, transient ischemic 
attack, myocardial infarction, unstable angina, and cardiovascular death 
(including death from unknown cause) 
• Respiratory, thoracic and mediastinal disorders: Allergic granulomatous 
angiitis (i.e. Churg Strauss syndrome, inflammation of the blood vessels)  
• Musculoskeletal and connective tissue disorders: Arthralgia (joint pain), 
myalgia (muscle pain), joint swelling  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 11 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
• Malignant neoplasms (cancer)  
• Antibody formation to omalizumab (not associated with any adverse events) 
 
Of the adverse events of special interest, anaphylactic reactions (presenting as 
wheezing, shortness of breath, cough, chest tightness, or trouble breathing, 
flushing, itching, hives, or feeling warm, swelling of the throat or tongue, throat 
tightness, hoarse voice, or trouble swallowing, low blood pressure, dizziness, 
fainting, rapid or weak heartbeat, anxiety) were observed but were rare and 
typically occurring within 2 hours of the first injection. Anaphylaxis is a life-
threatening condition and can lead to death. There were no reported cases of 
anaphylaxis with a fatal outcome in any of the clinical studies. Fatal cases with 
anaphylaxis have been reported in the post marketing pharmacovigilance reports 
since 2003. None of these fatal cases with anaphylaxis were due to Xolair. 
 
Cases of cancer were observed in some people who received omalizumab. Although 
more cases of malignancy (cancers) were observed in the omalizumab treatment 
group compared with the control group, the short exposure duration is not 
consistent with the biology of cancer pathogenesis; additionally, the diversity in the 
type of cancers observed and the clinical features of the individual cases render a 
causal relationship unlikely. However, study limitations preclude definitively ruling 
out a malignancy risk with omalizumab. 
 
Some people who received omalizumab have had heart and circulation problems 
such as chest pain, heart attack, blood clots in the lungs or legs, or temporary 
symptoms of weakness on one side of the body, slurred speech, or altered vision. It 
is not known whether this is caused by omalizumab. 
 
Inflammation of the blood vessel rarely happened in people with asthma who 
received omalizumab. This usually, but not always, happened in people who also 
take a steroid medicine by mouth that is being stopped or the dose is being 
lowered. It is not known whether this is caused by omalizumab. Tell your study 
doctor right away if you have rash, chest pain, shortness of breath, or a feeling of 
pins and needles or numbness of your arms or legs. 
 
Some people who are at a high risk for parasite (worm) infections, can get a 
parasite infection after receiving omalizumab. In patients at chronic high risk of 
helminth (worm) infection, a placebo-controlled trial showed a slight increase in 
infection rate with omalizumab, although the course, severity, and response to 
treatment of infection were unaltered. The helminth (worm) infection rate in the 
overall clinical program, which was not designed to detect such infections, was less 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 12 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
than 1 in 1,000 patients. However, caution may be warranted in people at high risk 
of helminth infection, in particular when traveling to areas where helminthic 
infections are endemic. 
 
POTENTIAL BENEFITS                              
 
We cannot and do not guarantee or promise that you will receive any benefits from 
this study. You may benefit from a decrease in the sensitivity to your allergens, and 
improve your immune protection to the offending food allergens. The knowledge 
gained from this study may aid in the advancement and understanding of food 
allergy and help in the development of new approaches for its treatment or 
prevention.   
 
ALTERNATIVES 
 
The alternative to participating is to continue food avoidance, which is standard of 
treatment for food allergic individuals. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate. Your questions should be 
answered clearly and to your satisfaction. If you decide not to participate, tell the 
study doctor.  
 
You will be told of any important new information that is learned during the course 
of this research study, which might affect your condition or your willingness to 
continue participation in this study. 
 
ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results.  You can 
search this Web site at any time. 
 
CONFIDENTIALITY 
 
The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals. Your identity and/or your personal 
health information will not be disclosed except as authorized by you or as required 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 13 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
by law. However, there is always some risk that even de-identified information 
might be re-identified.  
 
Patient information may be provided to Federal and other regulatory agencies as 
required. The Food and Drug Administration (FDA), for example, may inspect 
research records and learn your identity if this study falls within its jurisdiction. 
 
The purpose of this research study is to obtain data or information on the safety 
and effectiveness of OIT and omalizumab; the results will be provided to the 
sponsor, the Food and Drug Administration and other federal and regulatory 
agencies as required. 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 14 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
Authorization To Use Your Health Information 
For Research Purposes  
 
Because information about you and your health is personal and private, 
it generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  
The form is intended to inform you about how your health information 
will be used or disclosed in the study.  Your information will only be 
used in accordance with this authorization form and the informed 
consent form and as required or allowed by law.  Please read it 
carefully before signing it.   
 
What is the purpose of this research study and how will my 
health information be utilized in the study? 
The purpose of this study is to see if using omalizumab can help adults 
and children with food allergies be able to tolerate those same foods. 
The study doctor, Dr. Sayantani Sindher and/or Dr. Kari Nadeau, will 
use your personal health information to complete this research. 
Regulatory authorities such as the FDA and the IRB may also review or 
copy your information to make sure that the study is done properly or 
for other purposes required by law. The results of this study may be 
published in a medical journal and shown at medical meetings. You will 
not be identified (by name or any other means) in any of these 
publications.  
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you 
will not be able to participate in this research study, including receiving 
any research-related treatment. 
Signing the form is not a condition for receiving any medical care 
outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 15 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed 
in the study, except to the extent that the law allows us to continue 
using your information (e.g., necessary to maintain integrity of 
research).  If you wish to revoke your authorization for the research 
use or disclosure of your health information in this study, you must 
write to: Dr. Kari Nadeau or Dr. Sayantani Sindher at 269 Campus 
Drive, CCSR Building, Room 3215, Stanford, CA 94305, phone 
number: 650-724-0293 
 
What Personal Information Will Be Obtained, Used or 
Disclosed? 
Your health information related to this study, may be used or disclosed 
in connection with this research study, including, but not limited to, 
your demographic information (including date of birth, gender, 
race/ethnicity, and medical record number), medical history, history of 
allergies, physical examinations, lab test results. 
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
• The Protocol Director, Dr. Kari Nadeau and the co-Protocol 
Director Dr. Sayantani Sindher 
• The Stanford University Administrative Panel on Human Subjects 
in Medical Research and any other unit of Stanford University as 
necessary 
• Research Staff 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 16 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
• The Office for Human Research Protections in the U.S. 
Department of Health and Human Services 
• Data Safety Monitoring Board  
• The National Institutes of Health (NIH) 
• Regeneron/Adelphi Values 
• The Food and Drug Administration 
• Research collaborators outside of Stanford 
 
Your information may be re-disclosed by the recipients described 
above, if they are not required by law to protect the privacy of the 
information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health 
information will end on December 31, 2100 or when the research 
project ends, whichever is earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have 
access to any health information developed as part of this study until it 
is completed.  At that point, you would have access to such health 
information if it was used to make a medical or billing decision about 
you (e.g., if included in your official medical record).  
 
 
________________________________             
  ______________ 
Signature of Adult Participant                                        Date 
 
________________________________             
 
Print Name of Adult Participant                                         
 
 
_______________________________                       ______________ 
Signature of Legally Authorized Representative (LAR)          Date 
(e.g., parent, guardian or conservator) 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 17 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
 
 
________________________________             
 
Print Name of LAR                                    
 
 
________________________________________________________ 
LAR’s Authority to Act for Participant 
(e.g., parent, guardian or conservator)


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 18 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
 
FINANCIAL CONSIDERATIONS 
 
Payment 
You will not be paid to participate in this research study. 
 
 
Costs 
There is no cost to you for participating in this study, other than basic expenses like 
transportation and the personal time it will take to come to all of the study visits. 
 
Sponsor 
This study is being funded by private funding sources, the National Institutes of 
Health (NIH), and by Regeneron/Adelphi Values. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop medical 
complications from participating in this study.  If such complications arise, the 
Protocol Director and the research study staff will assist you in obtaining 
appropriate medical treatment.  In the event that you have an injury or illness that 
is directly caused by your participation in this study, reimbursement for all related 
costs of care first will be sought from your insurer, managed care plan, or other 
benefits program.  You will be responsible for any associated co-payments 
or deductibles as required by your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, managed 
care plan or other benefits program, you may be responsible for these costs.  If you 
are unable to pay for such costs, the Protocol Director will assist you in applying for 
supplemental benefits and explain how to apply for patient financial assistance from 
the hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Questions, Concerns, or Complaints:  If you have any questions, concerns or 
complaints about this research study, its procedures, risks and benefits, or 
alternative courses of treatment, you should ask the Protocol Director, Dr. Kari 
Nadeau or the co-Protocol Director Dr. Sayantani Sindher at (650) 724-0293. You 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 19 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
should also contact her at any time if you feel you have been hurt by being a part 
of this study. 
 
Independent Contact:  If you are not satisfied with how this study is being 
conducted, or if you have any concerns, complaints, or general questions about the 
research or your rights as a participant, please contact the Stanford Institutional 
Review Board (IRB) to speak to someone independent of the research team at 
(650)-723-5244 or toll free at 1-866-680-2906.  You can also write to the Stanford 
IRB, Stanford University, 3000 El Camino Real, Five Palo Alto Square, 4th Floor, 
Palo Alto, CA 94306. 
 
Appointment Contact: If you need to change your appointment, please contact 
snpcenterallergy.scheduler@stanford.edu 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but 
are not limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably to 
be expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices that 
might be advantageous to the subject, their relative risks and benefits; 
• 
be informed of the avenues of medical treatment, if any available to the 
subject after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, 
duress, coercion or undue influence on the subject's decision. 
 
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 20 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
May we contact you about future studies that may be of interest to you?    
____ Yes  ____ No 
 
 
Signing your name means you agree to be in this study and that you will receive a 
copy of this signed and dated consent form.  
 
 
_____________________________________                ____________ 
Signature of Adult Participant 
 
 
 
   
   Date 
 
 
_____________________________________             
Print Name of Adult Participant                                         
 
 
_____________________________________                ____________         
Signature of Legally Authorized Representative (LAR)  
  Date  
(e.g., parent, guardian or conservator)    
 
 
_____________________________________             
Print Name of LAR                                         
                               
 
_____________________________________ 
LAR’s Authority to Act for Participant  
 
 
(e.g., parent, guardian or conservator) 
 
 
_____________________________________                ____________  
(If available) Signature of Other Parent or Guardian               Date       
                       
 
_____________________________________             
Print Name of Other Parent or Guardian                                         
 
 
_____________________________________ 
Authority to Act for Participant  
 


 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director:  
Kari Nadeau, MD PhD   
 
 
Protocol Title:   A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to Test 
Immune Markers after Minimum Maintenance Dose 
 
 
Page 21 of 21 
 
Consent V3 07 May 2018 
IRB Use Only 
Approval Date:   June 12, 2018 
Expiration Date: April 11, 2019 
Participant ID: 
The IRB determined that the permission of two parents is recommended in accordance 
with 21 CFR 50.55 unless one parent is deceased, unknown, incompetent, not 
reasonably available, or only one parent has legal responsibility for the care and custody 
of the child.  Not reasonably available means that the other parent is not present during 
the consenting process, or will not be available prior to the start of research procedures.
 
 
 
 
 
 
 
_____________________________________                ____________  
Signature of Person Obtaining Consent  
 
   
  Date 
 
 
_____________________________________             
Print Name of Person Obtaining Consent 
 

Prot_003.pdf: 
NCT03181009   
Sean N Parker Center for Allergy and 
Asthma Research at Stanford 
CONFIDENTIAL, DO NOT COPY, PROPERTY OF STANFORD UNIVERSITY 
1 
Full Title: A Phase 2 Study of Multi Oral Immunotherapy in Multi Food 
Allergic Patients to Test Immune Markers after Minimum Maintenance Dose 
Short Title: Multi Immunotherapy to test Minimum 
dose using Xolair (MIMiX) 
NCT03181009
 eProtocol 39519 
May 23, 2017 
Amendment 26 


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2 
Key Roles 
PROTOCOL DIRECTOR 
Kari Nadeau, MD 
Stanford University 
269 Campus Drive, CCSR 3215 
Stanford, CA. 94305 
Phone: 650-867-4592 
Email:knadeau@stanford.edu 
SITE INVESTIGATOR-PRINCIPAL 
Maria Lloret-Garcia, MD 
UCLA 
757 Westwood Plaza 
Los Angeles, CA 90095 
Phone: (310) 825-9111 
Email: MiGarcia@mednet.ucla. 
Sayantani Sindher MD 
Stanford University 
2500 Grant Rd 4th Floor Tower C 
El Camino Hospital 
Mountain View, CA 94040 
Phone: 650-724-0293 
Email:tina.sindher@stanford.edu 
NCT03181009   


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3 
PROTOCOL APPROVAL 
Declaration of Sponsor or  Responsible Medical Officer 
Full Title: A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to 
Test Immune Markers after Minimum Maintenance Dose 
I have read this study protocol and approve it.  I agree to meet all obligations of the responsible 
medical officer and sponsor as detailed in all applicable regulations and guidelines.  In addition, I 
will inform the Principal Investigators and all other Investigators of all relevant information that 
becomes available during the conduct of the study.  
___________________________ 
_________________ 
Kari Nadeau, MD PhD    
Date 
Protocol Director 
NCT03181009   


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4 
 PROTOCOL ACKNOWLEDGEMENT 
Full Title: A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic Patients to 
Test Immune Markers after Minimum Maintenance Dose 
I have read this Clinical Study Protocol.  As Principal Investigator, I agree to conduct this 
protocol according to Good Clinical Practice, as delineated in the United States Code of Federal 
Regulations (CFR)-21 CFR Parts 50, 54, and 312 (Subpart D), the international Council of 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for 
Good Clinical Practice, and according to the criteria specified in this protocol.  Furthermore, I 
will conduct this protocol in keeping with local, state and federal requirements. 
___________________________ 
Principal Investigator (Print) 
___________________________ 
_________________ 
Principal Investigator (Signature)       
          Date 


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5 
Table of Contents 
Key Roles ........................................................................................................................................................... 2 
1.
Synopsis .................................................................................................................................................... 9
2. Background Information and Scientific Rationale ........................................................................................ 12
2.1 Background Information ....................................................................................................................... 12 
2.1.1 Description of the Study Agent(s)/Intervention(s) ......................................................................... 14 
2.1.2 Summary of Relevant Clinical Studies and Rationale ...................................................................... 14 
2.2 Potential Risks and Benefits ................................................................................................................... 15 
2.2.1 Potential Risks ................................................................................................................................ 15 
3.0 Study Objectives........................................................................................................................................ 15 
3.1 Primary Objective ................................................................................................................................. 15 
3.2 Secondary Objectives ............................................................................................................................ 16 
4.0 Study Design ............................................................................................................................................. 16 
4.1 Description of Study Design .................................................................................................................. 16 
4.2 Study Endpoints .................................................................................................................................... 16 
4.2.1 Primary Endpoint ........................................................................................................................... 16 
4.2.2 Secondary Endpoints ..................................................................................................................... 16 
5.0 Study Population ....................................................................................................................................... 17 
5.1 Description of Study Population ........................................................................................................... 17 
5.1.1 Subject Inclusion Criteria ............................................................................................................... 17 
5.1.2 Subject Exclusion Criteria ............................................................................................................... 18 
5.2  Study Protocol Stopping Criteria ......................................................................................................... 18 
5.3 Individual Subject Stopping/Termination Criteria ................................................................................ 19 
5.4 Documentation of Termination from Study .......................................................................................... 19 
5.5 Follow Up of Subject who Discontinue Treatment ............................................................................... 19 
5.6 Replacement of Subject who Discontinues Study Treatment ................................................................ 19 
6.0 Study Agent/Interventions ....................................................................................................................... 19 
6.1 Omalizumab .......................................................................................................................................... 19 
6.1.1 Formulation, Packaging and Labeling ............................................................................................ 19 
6.1.1.2 Preparation, Administration, Storage, and Dosage Study Agent(s)/Intervention(s) .................. 19 
6.1.3 Study Agent (Omalizumab) Accountability Procedure .................................................................. 20 
6.2 Food Protein ......................................................................................................................................... 20 
6.2.1 Formulation, Packaging and Labeling ............................................................................................ 20 


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6 
6.2.2 Preparation, Administration, Storage, and Dosage Study Agent(s)/Intervention(s) ..................... 20 
Table 2: Up Dosing Schedule Group A. ........................................................................................................ 20 
Table 3: Up Dosing Schedule Group B. ........................................................................................................ 21 
6.2.3 Study Protein Accountability Procedures ...................................................................................... 21 
6.2 Concomitant Medications and Procedures ............................................................................................ 21 
6.3 Prohibited and Rescue Medications ....................................................................................................... 21 
6.3.1 Prohibited Medications and Procedures ....................................................................................... 22 
6.3.2 Rescue Medications ....................................................................................................................... 22 
6.4 Description of Facility ........................................................................................................................... 22 
7.0 Study Procedures/Evaluations .................................................................................................................. 22 
7.1 Clinical Evaluations ................................................................................................................................ 22 
7.2  General safety precautions for entire study ......................................................................................... 23 
7.3 Laboratory Assessments ........................................................................................................................ 23 
7.3.1 Clinical and Research Laboratory Evaluations and Specimen Collection ......................................... 23 
7.3.2 Specimen Preparation, Handling and Shipping .............................................................................. 24 
7.4 Other Safety Assessments .................................................................................................................... 24 
7.4.1 Physical Examination and Vital Signs ............................................................................................. 24 
7.4.2 Spirometry ..................................................................................................................................... 24 
7.4.3 Skin Prick Test ................................................................................................................................ 24 
7.4.5 Pregnancy Test ............................................................................................................................... 24 
7.5 Data management ................................................................................................................................. 25 
8.0 Study Schedule of Events .......................................................................................................................... 25 
8.1 Screening – Week -36 thru  Day-1 ........................................................................................................ 25 
8.3  Treatment Period ................................................................................................................................. 26 
8.3.1 Week -8 and -4 - Omalizumab Treatment (Dose 1 and 2) ±5 days ................................................ 26 
8.3.2. Week 0 – Last Omalizumab dose (Dose 3) and First dose of food allergen and desensitization . 26 
8.3.3. Weeks 4 through 16 ±5days ......................................................................................................... 27 
8.3.4 Early Discontinuation/End of Study (week 18 ±5 days) ...................................................................... 29 
8.3.5 Unscheduled Visits ......................................................................................................................... 29 
9.0 Assessment of Safety ................................................................................................................................ 29 
9.1 Adverse Event (AE) ................................................................................................................................ 29 
9.2 Unexpected Adverse Event ................................................................................................................... 30 
9.3 Serious Adverse Event (SAE) ................................................................................................................. 31 


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7 
9.4 Grading and Attribution of Adverse Events .......................................................................................... 31 
9.5 Collection and Recording of Adverse Events ........................................................................................ 32 
9.5.1 Collection Period ............................................................................................................................ 32 
9.5.2 Collecting Adverse Events .............................................................................................................. 32 
9.5.3 Recording Adverse Events ............................................................................................................. 32 
9.6 Reporting of Serious Adverse Events and Adverse Events ................................................................... 32 
9.6.1 Reporting of Serious Adverse Events to Sponsor .......................................................................... 32 
9.6.2 Reporting of Unexpected Non-Serious Adverse Events ................................................................ 33 
9.6.3 Reporting to Health Authority ....................................................................................................... 33 
9.7  Pregnancy Reporting ............................................................................................................................ 34 
9.8  Reporting of Other Safety Information ................................................................................................ 35 
9.9 Monitoring and Treatment of Toxicity ................................................................................................. 35 
10 Clinical Monitoring Structure ..................................................................................................................... 35 
10.1 Site Monitoring Plan ........................................................................................................................... 35 
10.2 Study Monitoring Plan ........................................................................................................................ 35 
11.0 Statistical Considerations ....................................................................................................................... 35 
11.1 Description of the Analysis ................................................................................................................. 35 
11.2 Measures to Minimize Bias ................................................................................................................ 35 
11.3 Appropriate Methods and Timing for Analyzing Outcome Measures ................................................ 36 
11.3.1 Primary Endpoint ......................................................................................................................... 36 
4.2.2 Secondary Endpoints ..................................................................................................................... 36 
11.4 Study Hypothesis ................................................................................................................................. 36 
11.5 Sample Size Considerations ................................................................................................................. 36 
11.6 Maintenance of Trial Treatment Randomization Codes ...................................................................... 36 
11.7 Subject Enrollment and Follow-Up ...................................................................................................... 37 
11.8 Planned Interim Analyses (if applicable) ............................................................................................. 37 
11.9 Safety Review ..................................................................................................................................... 37 
11.10 Immunogenicity Review or Efficacy Review ..................................................................................... 37 
12.0 Quality Control and Quality Assurance .................................................................................................. 38 
13.0 Ethics/Protection of Human Subjects ..................................................................................................... 38 
13.1 Institutional Review Board/Ethics Committee .................................................................................... 38 
13.2 Informed Consent................................................................................................................................ 38 
13.2.1 Consent Process .......................................................................................................................... 38 


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8 
13.3 Assent of Informed Consent Process (in Case of Minor) ..................................................................... 39 
13.4 Subject Confidentiality ....................................................................................................................... 39 
13.5 Study Discontinuation ........................................................................................................................ 39 
13.6 Other .................................................................................................................................................. 39 
14 Data Handling Documentation .................................................................................................................. 39 
14.1 Data Capture Methods ....................................................................................................................... 40 
14.2 Types of Data ..................................................................................................................................... 40 
14.3 Source Documents and Access to Source Data/Documents .............................................................. 40 
14.4 Timing/Reports ................................................................................................................................... 40 
14.5 Study Records Retention .................................................................................................................... 40 
17.0 Appendices ............................................................................................................................................. 42 
17.1  Appendix A:  Epinephrine autoinjector Training Form ..................................................................... 42 
17.2 Appendix B: Scoring of Clinical Food Related Reactions that Occur During study ............................. 43 
17.3 Appendix C: GMP and Manufacturing Facility .................................................................................... 46 
17.4 Appendix D: Schedule of Events .......................................................................................................... 49 


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9 
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1. Synopsis
Full Title 
A Phase 2 Study Multi Oral Immunotherapy in Multi 
Food Allergic Patients to test immune markers after 
minimum maintenance dose 
Short Title 
Multi Immunotherapy to test dose 
Clinical Trial Phase 
Phase 2 
IND Sponsor (if applicable) 
Kari C. Nadeau, MD, PhD 
Conducted By 
n/a 
Protocol Director 
Kari C. Nadeau, MD, PhD 
Sample Size 
 60 
Study Population 
We will enroll food allergic subjects (2-25 years of age) 
with proven food allergies.  We anticipate enrolling 60 
subjects with multi food allergies at two sites.  Subjects 
must have food specific IgE>4kU/L for each allergen or 
a skin test reactivity to each food allergen greater than 
or equal to 6mm wheal diameter for at least two 
allergens. 
Accrual Period 
We estimate it will take 15 months to enroll 60 subjects 
into the study. 
Study Design 
This is a phase 2 multisite study that will be conducted 
at two centers in the U.S. All subjects will receive oral 
immunotherapy for their specific food allergies (limited 
to those food allergens in the CMC section of IND 
14831).  All participants will receive three doses of 
Omalizumab 4 weeks apart over 8 weeks (Week-8 to 0). 
The subject’s allergens will be introduced on 
desensitization Day 1 of week 0, after receiving the third 
omalizumab dose.  Subjects will return to clinic to 
escalate the dose of their allergens until 300 mg (group 
A) vs. 1200 mg (group B) total protein daily dose is
reached.  There will be equivalent allergen protein 
portions depending on test allergen per each subject’s 
history. Subjects will be randomized 1:1 to either group 
A or group B after meeting eligibility criteria. All 
subjects and study personnel will be blinded to group 
A vs B.  
NCT03181009   


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10 
CONFIDENTIAL – DO NOT DISTRIBUTE 
Safety is a paramount concern in the study design and 
will be monitored carefully throughout the study. Study 
subjects and their parents/guardians will receive 
extensive education on food allergy reactions and 
medication use. 
Study Duration 
Each subject is planned to be enrolled in the treatment 
phase of the study for 26 weeks. 
Study Agents/Intervention Description 
Food protein and powder will be obtained and prepared 
as per IND 14831 and will be in compliance with all 
applicable regulations. 
Omalizumab is approved by the European Medicines 
Agency (European FDA) and by the US FDA for 
patients with severe asthma >6 years of age. 
Primary Objective 
To determine if the combination of omalizumab and 
multi OIT will increase the IgG4 /IgE ratio of at least 2 
allergens by ≥25% at week 18 from baseline in multi 
food allergic patients.  
Major Secondary Objectives 
To determine  if the combination of omalizumab and multi 
OIT will increase IgG4/IgE ratio of at least of 3 allergens 
by ≥25% at week 18 from baseline in multi food allergic 
patients.   
To determine if the combination of omalizumab and multi 
OIT will increase IgG4/IgE of at least of 4 allergens by 
≥25% at week 18 from baseline. 
To determine if the use of combination of omalizumab and 
multi OIT will increase IgG4/IgE of at least of 5 allergens 
by ≥25% at week 18 from baseline in multi food allergic 
patients. 


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Exploratory Objectives 
We will perform high dimensional and innovative 
immune monitoring during the study. The long term 
objective of this study is to develop a potentially curative 
therapy for patients with multi food allergies.  We 
hypothesize that young and older subjects with multi food 
allergies who receive a combination of Omalizumab and 
multi oral immunotherapy (OIT) can be rapidly 
desensitized and tolerate higher doses of food protein. We 
also hypothesize that 300 mg total protein dose daily, 
when compared to 1200mg total protein dose daily, is 
enough to achieve the primary endpoint in the majority of 
participants. However, we will explore if age, sex, body 
mass index, years with disease, and degree of 
polysensitization affect study outcomes, as well as 
characterize the treatment related adverse events 
throughout the study.    
Endpoints 
Primary Endpoint: The proportion of subjects on a 
combination of omalizumab and multi oral 
immunotherapy who have an increase the IgG4 /IgE ratio 
of at least of 2 allergens by ≥25% from baseline, at week 
18. 
Major Secondary Endpoints: 
The proportion of subjects on a combination of 
omalizumab and multi oral immunotherapy who have an 
an increase the IgG4 /IgE ratio of at least of 3 allergens 
by ≥25% from baseline, at week 18. 
The proportion of subjects on a combination of 
omalizumab and multi oral immunotherapy who have an 
increase the IgG4 /IgE ratio of at least of 4 allergens by 
≥25% from baseline, at week. 
The proportion of subjects on a combination of 
omalizumab and multi oral immunotherapy who have an 
increase the IgG4 /IgE ratio of at least of 5 allergens by 
≥25% from baseline, at week 18. 


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2. Background Information and Scientific Rationale
2.1 Background Information 
The long-term goal of our studies is to develop a better and safer treatment for, and to potentially 
cure patients with multiple food allergies. Many food allergic patients suffer from more than one 
food allergy. One report has published that up to 70% of food allergic patients suffer from another 
food allergy. We recently surveyed the children and adults in our clinics at Stanford Hospital and 
Clinics and many of the children and adults treated at our Allergy Clinics have had a near fatal 
anaphylaxis and have concomitant food allergies to peanut and/or milk and/or egg and/or seed and/or 
tree nut and/or shrimp and/or cod and/or salmon. Currently, subcutaneous immunotherapy to 
environmental allergens employs multiple allergens. Although studies have been performed to 
evaluate the efficacy of oral immunotherapy (OIT) for single food allergens, sufficient studies 
evaluating OIT to multiple food allergens have not yet been performed to address this substantial 
unmet need. 
A pilot study by our group under a separate IND (103080) was the first of its kind to show that 
milk desensitization can occur relatively rapidly when combined with Omalizumab (Xolair) 
treatment in severely milk allergic patients. In this separate IND application, we are applying to 
conduct a Phase 2 study of OIT in patients with multiple food allergies. 
Thus far, few studies have been conducted to optimize safety of OIT in conjunction with 
Omalizumab as well as to identify the immunological mechanism(s) underlying any long-lasting 
effects of OIT. To address these issues in the field of food allergy research, we have designed a 
study to test whether: 1) Omalizumab improves the safety of OIT, 2) Omalizumab treatment with 
multiple food allergen OIT is associated with the ability to tolerate a lower maintenance dose of 
each food allergens used in the OIT regimen, particularly in younger subjects with food allergies. 
Omalizumab is a recombinant DNA-derived humanized IgG1 monoclonal antibody that selectively 
binds to human immunoglobulin E (IgE). The antibody of an approximate molecular weight of 
approximately 149 kilodaltons is produced by a Chinese hamster ovary cell suspension culture. 
Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of 
mast cells and basophils. Reduction in surface bound IgE on FcεRI-bearing cells limits the degree 
of release of mediators of the allergic response. Treatment with omalizumab also reduces the 
number of FcεRI receptors on basophils in atopic patients. 
In previous studies in children with severe asthma (as per product insert and Therapeutic Biologic 
Application (BLA) submitted by Genentech and approved by the FDA in June 2003 with a recent 
approval for use in 6 years and above-2016), anti-IgE treatment was found to be effective in 
preventing and reversing IgE-mediated allergic asthma symptoms . This novel protocol, aims to 
test whether Omalizumab can improve the safety of OIT in subjects with multi food allergies. The 
hypothesis is that the treatment protocol will allow study subjects with multi food allergies to be 
safely and rapidly desensitized to multiple food allergens. The design of this protocol is unique in 
that: 1) Omalizumab is included to improve OIT tolerability, 2) study subjects are desensitized 
more rapidly than in other studies (which do not use Omalizumab), and 3) the use of minimum 
maintenance dose of OIT (300mg versus 1200mg total protein daily). 


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We chose 2 years old as the minimum age due to a previous published study and a study under 
investigation. (J Investig Allergol Clin Immunol. 2015;25(4):303-4 and 'Controlling and Preventing 
Asthma Progression and Severity in Kids (CASK)', sponsored by Dr. Wanda Phipatanakul  at 
Boston Children's, with an age range of 24 to 47 months. NCT02570984. The dosing used was the 
standard 0.016 mg/kg/(IU/mL). 
Our reasons for not requiring a food challenge to diagnose food allergies at screening or to 
prognosticate for clinical outcomes: 
1) Based on our data using IgE and skin test levels with these cutoffs, we will have a very high
likelihood of enrolling children with clinically relevant food allergies (submitted manuscript
by Andorf, et al.). Our criteria are: food specific IgE>4kU/L for each allergen or a skin test
reactivity to each food allergen greater than or equal to 6mm wheal diameter.
2) Food challenges are associated with a higher level of anxiety and stress in clinical trials and
have served as deterrents for many patients/families with food allergies who would likely be
eligible for clinical trials to test food immunotherapy.
3) There are other markers of clinical outcomes that one can use, namely, IgG4/IgE ratios [there
is a large body of evidence (1-8) supporting the use of these immune markers] and the
tolerability of maintenance doses at minimal levels. We feel that this is a pilot study and it
could be that these minimal dosing scenarios (only up to 300 mg total protein, compared to the
1200mg total protein dose, and only 8 weeks of omalizumab) could result in a food challenge
with an allergic reaction; therefore, we prefer only to examine biomarkers at this time to see if
there are trends that would substantiate future randomized controlled studies that incorporate
food challenges. Therefore, we have proposed this study as a pilot study to test concepts that
could be basis for moving forward in larger, phase 2 studies.
We aim to determine whether a minimum maintenance dose for food allergen oral immunotherapy 
(300 mg total protein daily vs. 1200 mg total protein daily) will be sufficient at 18 weeks to increase 
IgG4/IgE ratios by 25% (for each separate food allergen). This dose volumes were chosen because 
300 mg is approximately the dose of one nut’s worth of protein if an accidental ingestion were to 
occur. There is evidence (Byrd, et al 2016, EAACI, Vienna, Austria) that a maintenance of 300 mg 
food allergen protein a day will protect approximately 70% of participants up to 1000 mg or more 
of food allergen protein at 40 weeks into therapy. At Stanford, our phase 1 and long term studies 
have confirmed these findings (Monahar, et al, submitted); however, with the combination of 
omalizumab, our data demonstrate that it could be possible to have a total protein dose of 300 mg 
(for example, if a subject had been enrolled for 5 food allergies, then their mixture would contain 
60 mg of food allergen protein each). A total of 300 mg of food allergen protein can be achieved 
much more rapidly with omalizumab, leading to decreased dropout rates and potentially longer 
lasting effects of immunotherapy. Finally, instead of accomplishing a degree of immune protection 
for some (70%) and instead of waiting for 40 weeks (which is associated with a dropout rate of 20% 
or more), we are proposing in this protocol to test outcomes at 18 weeks, and expect higher rates of 
immune protection due to combination dosing of omalizumab and multi food allergen 
immunotherapy, the latter customized based on the food allergies documented for the subject).  We 
will compare with a group receiving 1200 mg of total protein since 1200 mg is approximately the 
amount involved in an accidental ingestion (for example, if one bites into a nut bar or nut-containing 
cookie). It is possible that 1200 mg total vs 300 mg total will have an enhanced effect on IgG4 and 


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14 
IgE. This is a pilot phase 2a study and our sample size is likely not large enough to detect a difference 
between 1200 mg vs 300 mg for the primary endpoint; therefore, we will only examine trends. 
This protocol is designed to try to maximize safety (with Xolair dosing used concomitantly with 
OIT therapy), to try to maximize customization of therapy (i.e. multiple food allergic patients will 
receive the food allergens they are allergic to), and to try to test practical applications of OIT in 
clinical management scenarios (i.e. use minimal amount of maintenance dose and minimal amount 
of Omalizumab and minimal time periods).  
Lastly, we will examine biomarkers that could predict a patient’s eventual outcome for 
desensitization. High dimensional and innovative immune monitoring will occur on the same 
participants in the clinical trial. We believe it will be important to test for trends of differences 
between age groups, specifically, to examine the immune repertoire of the very young (prethymic 
involution) vs older (postthymic involution). It may be possible that intervening with omalizumab 
and multifood oral immunotherapy in the very young (i.e. around 2 yr of age) has a more permanent 
beneficial effect to desensitize the child to their food allergies.  
Outside of the conductance of this particular study, we will ask the PIs and staff at each site to 
consider a long term follow up study to ensure the longitudinal follow up of the participants after 
they finish the active phase of the study. In this long term follow up study, food challenges will be 
offered to participants once skin tests become negative for a particular food under a separate IRB-
approved study.  
2.1.1 Description of the Study Agent(s)/Intervention(s) 
Study Agents: Omalizumab is approved by the European Commission and US FDA for patients 
with severe asthma >6 years of age. Therefore the risk of Omalizumab is relatively low. In an 
expanded access protocol at Stanford (PI, Nadeau) under this IND (14831) and in a study run by Dr. 
Wanda Phipatanakul at Children’s Boston, young children are receiving Omalizumab with no adverse 
effects. 
Food flours will be obtained from commercial manufacturers. CMC documents are available and 
written according to GCP/CFR guidelines and are cross referenced for their INDs (milk, egg, 
almond, cashew, hazelnut, walnut, peanut, sesame seed, soy, wheat, shrimp, cod and salmon). 
2.1.2 Summary of Relevant Clinical Studies and Rationale 
We have incorporated procedures of peanut OIT as conducted and published by others- Section 16 
(1-3). In addition, we have conducted studies with Omalizumab for food allergy subjects over the 
past 8 years at Stanford (4-6). 
We recently published phase 2 studies using Omalizumab and food allergen immunotherapy (Wood, 
et al. 2016, and MacGinnitie, et al. 2016). In addition, we have submitted two manuscripts which 
further justify our dosing, eligibility criteria, and our immune markers chosen for this study (Andorf 
et al. accepted in JACI In Practice and Monahar, et al.).  
Preliminary results of some patients in the phase 1 study results have been published (8). 


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We have recently used Omalizumab  pretreatment to rapidly and successfully desensitize children 
with severe milk allergy, suggesting that such an approach might be useful for inducing tolerance in 
patients with multiple food allergies. Oral desensitization for food allergy is currently being studied 
by many investigators (without Omalizumab), but because of significant side effects, it cannot be 
recommended for routine use. 
2.2 Potential Risks and Benefits 
2.2.1 Potential Risks 
Omalizumab is approved by the European Commission and US  FDA  for patients with severe asthma 
>6 years of age. Therefore the risk of Omalizumab is relatively low (please refer to investigator’s 
brochure and cross-reference of IND 103080). 
The overall risks of participation range from mild to moderate to severe due to the OIT (oral 
immunotherapy). These could be as mild as transient pruritus to as severe as anaphylaxis. We are 
employing procedures that have been used with many children and adults in other studies and have 
been found to be acceptable around the world. Relative to the information to be gained, these risks 
are acceptable. 
Protection Against Risk: Each research center keeps injectable epinephrine in case of an anaphylactic 
reaction, and all staff are trained in their use and how to obtain emergency help, if needed. After 
skin testing, subjects may be given topical l ow t o m i d pot e nc y s t e r oi d c r e a m s u c h a s 
triamcinolone or hydrocortisone for application to affected areas if the patient complains of itching. 
All patients will sign a current IRB approved consent and assent if applicable, and will be 
given written instructions about home dosing and epinephrine use.  
2.2.2 Potential Benefits 
The only direct and major benefit to the subjects is for those subjects are able to tolerate the OIT and 
improve their immune protection to the offending food allergens. There is a theoretical benefit of 
multiple allergen therapy to enable the immune system to develop long-term tolerance with multiple 
allergen therapy. We will make any of the medically relevant data [skin test results, blood tests (IgE 
levels)] available to the medical provider upon written request of the parent/guardian. 
Importance of the knowledge to be gained:  There is considerable discrepancy on which subjects 
benefit from immunotherapy for their food allergy health outcome and there is a need to determine 
the success of immunotherapy used in conjunction with Omalizumab; this study will contribute to 
developing criteria for optimizing this therapy. 
3.0 Study Objectives 
3.1 Primary Objective   
To determine if the use of combination of omalizumab and multi OIT will increase the IgG4 /IgE 
ratio of at least 2 allergens by ≥25% at week 18 from baseline in multi food allergic patients. . 


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3.2 Secondary Objectives 
To determine if the use of combination of omalizumab and multi OIT will increase IgG4/IgE ratio 
of at least of 3 allergens by ≥25% at week 18 from baseline in multi food allergic patients.   
To determine if the use of combination of omalizumab and multi OIT will increase IgG4/IgE of at 
least of 4 allergens by ≥25% at week 18 from baseline. 
To determine if the use of combination of omalizumab and multi OIT will increase IgG4/IgE of at 
least of 5 allergens by ≥25% at week 18 from baseline in multi food allergic patients. 
Other objectives include monitoring treatment related adverse events according to CTCAE v4.03 
criteria. Allergic reactions will be monitored separately as allergic adverse events. 
We will also explore immune monitoring studies and we will perform high dimensional and 
innovative immune monitoring during the study. The long term objective of this study is to develop 
a potentially curative therapy for patients with multi food allergies. We hypothesize that young and 
older subjects with multi food allergies who receive a combination of Omalizumab and multi oral 
immunotherapy (OIT) can be rapidly desensitized and tolerate higher doses of food protein. We also 
hypothesize that 300 mg daily total protein dose will be adequate and similar to 1200 mg daily total 
protein dose to achieve the primary endpoint in the majority of participants. However, we will 
explore if age, sex, body mass index, years with disease, and degree if polysensitization affect 
outcomes, as well as characterize the treatment related adverse events throughout the study. 
4.0 Study Design 
4.1 Description of Study Design 
This is a phase 2 multisite study which will be conducted at two centers in the U.S. All subjects 
will receive oral immunotherapy for their specific food allergies (limited to those food allergens in 
the CMC section of IND 14831). All participants will receive three doses of omalizumab over 8 
weeks. The subject’s allergens will be introduced on desensitization day 1 at week 0, after receiving 
the third omalizumab dose.   Subjects will return to clinic to escalate the dose of their allergens 
until 300 mg or 1200 mg daily total protein, depending on randomization assignment, is reached. 
Clinical and laboratory based assessments will be performed at certain visits throughout the study as 
per the schedule of events (Appendix D) and as needed per the investigator’s discretion. 
4.2 Study Endpoints 
4.2.1 Primary Endpoint 
The proportion of subjects on a combination of omalizumab and multi oral immunotherapy who 
have increase in the IgG4 /IgE ratio of at least of 2 allergens by ≥25% from baseline at wk18.  
4.2.2 Secondary Endpoints 
The proportion of subjects on a combination of omalizumab and multi oral immunotherapy who 
have an increase the IgG4 /IgE ratio of at least of 3 allergens by ≥25% from baseline, at week 18. 


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The proportion of subjects on a combination of omalizumab and multi oral immunotherapy who 
have an increase the IgG4 /IgE ratio of at least of 4 allergens by ≥25% from baseline, at week. 
The proportion of subjects on a combination of omalizumab and multi oral immunotherapy who 
have an increase the IgG4 /IgE ratio of at least of 5 allergens by ≥25% from baseline, at week 18. 
Other endpoints include monitoring treatment related adverse events according to CTCAE v4.03 
criteria. Allergic reactions will be monitored separately as allergic adverse events. 
We will also explore immune monitoring studies and we will perform high dimensional and innovate 
immune monitoring during the study. The long term objective of this study is to develop a potentially 
curative therapy for patients with multi food allergies. We hypothesize that young and older subjects 
with multi food allergies who receive a combination of Omalizumab and multi oral immunotherapy 
(OIT) can be rapidly desensitized and tolerate higher doses of food protein. We also hypothesize 
that 300 mg total protein dose will be adequate to achieve the primary endpoint in the majority of 
participants. However, we will explore if age, sex, body mass index, years with disease, and degree 
if polysensitization affect outcomes, as well as characterize the treatment related adverse events 
throughout the study. 
5.0 Study Population 
5.1 Description of Study Population 
We will enroll food allergic subjects (2-25 years of age) with proven food allergies. We anticipate 
enrolling 60 subjects with multi food allergies at two sites.  
5.1.1 Subject Inclusion Criteria 
Subjects who meet all of the following criteria are eligible: 
1.
Subjects aged 2 to 25 years, inclusive, with clinical history of allergy to at least two of the following:

milk

egg

peanut

almond

wheat

cashew

sesame seed

soy

walnut

hazelnut

shrimp

cod

salmon
2. Sensitivity to food allergens documented by a positive skin prick test result ≥6mm wheal
diameter to each allergen at screening or ImmunoCAP IgE level >4kU/L for each allergen at
screening.
3. If female of child bearing potential, a negative urine pregnancy test at screening, and
week 0 visit if visit is more than 7 days from screening.
4. Female subjects who are of child-bearing potential must agree to comply with using
medically-approved method of contraception (please see Section 7.4.5 Pregnancy Test) for the
duration of the study.
5. Agrees to comply with study protocol visits, procedure requirements, and to remain in the
area of the research center during the trial.


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6. Able to follow anaphylaxis action plan including administration of epinephrine and is trained
on the proper use of the Epinephrine autoinjector as indicated by signing the epinephrine
autoinjector training form. (see appendix A).
7. Able to eliminate other known food allergens from subject’s diet so as not to confound
the safety and efficacy data from the study
8.
Willing to avoid open or blinded food challenges to food allergens, other than study designated
allergens, for the duration of the study.
5.1.2 Subject Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible: 
1. Previous anaphylactic reaction to Omalizumab.
2. Allergy to oat.
3. A history of severe anaphylaxis to food allergens that will be desensitized in this study
requiring intubation or admission to an ICU, frequent allergic or non-allergic urticaria, or
history consistent with poorly controlled persistent asthma.
4. Unstable angina, significant arrhythmia, uncontrolled hypertension, chronic sinusitis, or other
chronic or immunological diseases that, in the judgment of the investigator, might interfere
with the evaluation or administration of the test drug or pose additional risk to the subject
(e.g., gastrointestinal or gastroesophageal disease, chronic infections, scleroderma, hepatic
and gallbladder disease, chronic non-allergic pulmonary disease).
5. An average FEV1 or PEF less than 80% predicted (moderate persistent asthma) with or
without controller medication (if able to perform the maneuver) at screening, or at up
dosing visits.
6. Current users of oral, intramuscular, or intravenous corticosteroids, tricyclic antidepressants,
or are taking a beta-blocker (oral or topical).
7. Routinely using medication that, in the investigator’s judgement, could induce adverse
gastrointestinal reactions during the study.
8. Pregnant or breast feeding women.
9. Use of omalizumab or any other monoclonal antibody therapy, or use of
immunomodulatory therapy, besides aeroallergen or venom immunotherapy, within 6
months of screening.
10. Diagnosis of eosinophilic esophagitis, eosinophilic colitis, or eosinophilic gastritis.
5.2  Study Protocol Stopping Criteria 
During the course of the study, if the investigator or DSMB discover conditions that indicate that 
the study should be discontinued, an appropriate procedure for terminating the study will be 
instituted, including notification of the FDA and IRB or EC (ethics committee). 
Stopping rules for the study: 
•
Any death related to dosing
•
More than one participant has systemic allergic symptoms associated with hypotension in
response to oral immunotherapy
•
More than 3 participants require more than 2 injections of epinephrine during dosing of
the food products
•
More than 3 of the following events:
o
Severe adverse event, other than anaphylaxis, related to investigational product
o
Eosinophil Esophagitis


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5.3 Individual Subject Stopping/Termination Criteria 
A subject may be prematurely terminated from the study for the following reasons: 
• The investigator feels that it is not safe for the subject to continue receiving treatment.
• Examples include significant side effects from the study drug (any Bock’s criteria grade
3 reaction that is associated with hypoxia (less than 92% oxygen saturation) or blood
pressure changes (greater than 20 mm Hg drop in systolic or diastolic blood pressure)
•
Any serious or unexpected adverse event
•
Serious intercurrent illness
•
Progression of disease that requires alternative treatment
•
The subject desires to discontinue participation in this study.
•
The subject is unwilling or unable to comply with the protocol.
•
The subject becomes pregnant.
•
The subject misses more than 5 consecutive study visits.
•
The subject does not tolerate 5mg total dose at desensitization (week 0).
•
The subject misses 7 consecutive days or more days of OIT dosing due to non compliance.
5.4 Documentation of Termination from Study 
The reasons for termination of a subject from the study must be documented clearly on the 
termination page of the subject’s CRF, and must be completed for any subject who has received any 
amount of test drug. If the reason for termination is an adverse event, the specific event or test result 
must also be recorded on the subject’s AE CRF page. 
5.5 Follow Up of Subject who Discontinue Treatment 
A subject can voluntarily withdraw from the study at any point in the study. If the subject withdraws 
consent to participate in the study, and/or subjects who prematurely discontinue treatment at any other 
time during the study, will return for an Early Discontinuation visit that consists of the same procedures 
as the end of study visit.   Early discontinuation visit must occur within 14 days after the last dose of 
subject’s allergen. 
5.6 Replacement of Subject who Discontinues Study Treatment 
Terminations due to safety or issues that are not treatment-related, such as relocation, will be 
included in the analyses up and through the last valid visit prior to withdrawal. Subjects who 
withdraw/are terminated may not be replaced. 
6.0 Study Agent/Interventions 
6.1 Omalizumab 
6.1.1 Formulation, Packaging and Labeling 
Omalizumab is a sterile, white, preservative-free, lyophilized powder contained in a single-
use vial that is reconstituted with Sterile Water for Injection (SWFI), USP, and administered 
as a subcutaneous (SC) injection.   
6.1.1.2 Preparation, Administration, Storage, and Dosage Study Agent(s)/Intervention(s) 
Omalizumab will be stored and prepared according to the investigator brochure and the 
MOP. The omalizumab will should be stored in a secure location and kept refrigerated 


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between 2-8°C.  Sites will maintain temperature logs for all refrigerators storing 
study drug for the duration of the study. 
Dosing for Omalizumab will be 150 mg via subcutaneous injection monthly for three 
doses for participants ≥4 years of age, and 75 mg via subcutaneous injection monthly for 
three doses for participants <4 years of age.   
6.1.3 Study Agent (Omalizumab) Accountability Procedure 
Omalizumab will be ordered and shipped directly to the site according to the site’s institutional 
policies. Documentation of omalizumab receipt will include date of receipt, lot number and 
expiration date. Dispensation of omalizumab will include date of dispensation, participant ID 
and lot number. 
The site investigator will agree to administer study drug only to subjects in the research clinic 
who have signed the informed consent. The investigator will not supply study drug to any 
person not authorized to receive it. 
Following study drug administration, the research staff will retain all empty or partially used 
vials and return to investigational pharmacist until appropriately accounted for during a 
monitoring visit. All vials may be then be disposed of per hospital destruction policies. 
6.2 Food Protein 
6.2.1 Formulation, Packaging and Labeling 
Food flours will be obtained from commercial manufacturers. CMC documents are available and 
written according to GCP/CFR guidelines and are cross referenced for their INDs (milk, egg, 
almond, cashew, hazelnut, walnut, peanut, sesame seed, soy, wheat, shrimp, cod and salmon) (see 
Error! Reference source not found.).   
6.2.2 Preparation, Administration, Storage, and Dosage Study Agent(s)/Intervention(s) 
All food flours will be obtained from the same manufacturer (Stanford) per the CMC; a certificate 
of analysis will be prepared by Stanford according to FDA requirements and the CMC. All food 
flour doses will be packaged, inventoried, and labeled at Stanford GMP facility.  The doses will be 
shipped to the site pharmacy for distribution to subject/subject’s parents by site study personnel.  
The food flours will be stored at the sites per the CMC and SOPs to maximize stability. Research 
staff will administer food flour to the subject orally in an age-appropriate food vehicle. Each food 
flour dose containing equivalent portions of test allergen protein will be prepared into a separate 
container by the Stanford GMP staff and labelled with the subject identifier. Dosage for OIT will be 
prepared in accordance by Stanford GMP with each subject’s allergen history and will be sent to the 
site in advance of subjects clinic visit.  Food flour doses may also contain oat flour so that the volume 
of group A and group B doses are the same size in order to maintain the blind. 
Table 2: Up Dosing Schedule Group A. 
Dosing Interval 
Total Protein Dose (mg) 
Week 0 
5 
Week 4 
60 
Week 8 
300 


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Week 12 
300 
Week 16 
300 
Table 3: Up Dosing Schedule Group B. 
Dosing Interval 
Total protein Dose (mg) 
Week 0 
5 
Week 4 
240 
Week 8 
1200 
Week 12 
1200 
Week 16 
1200 
6.2.3 Study Protein Accountability Procedures 
The Investigational Pharmacist will maintain adequate records of the receipt of all food flours 
shipped to the site. Records will include dates, quantities received, quantities dispensed, and the 
identification code number of the subject who received the study drug. 
The investigator will agree to administer test drug only to subjects under his or her personal 
supervision. The investigator will not supply test drug to any person not authorized to receive it. 
Following administration of food flours, the site personnel will destroy used containers and 
document on the product accountability log. 
6.2 Concomitant Medications and Procedures 
During the study, subjects will be allowed to use medications for allergic rhinitis, asthma, and 
atopic dermatitis, including intranasal glucocorticoids, inhaled corticosteroids, inhaled beta 2 
antagonist, antihistamines, and leukotriene inhibitors.  Daily concomitant medication use will be 
documented in the subject’s chart. Subjects may use an antihistamine such as diphenhydramine or 
cetirizine for pruritis and other allergy symptoms. More specifically the following are permitted 
medications: 
•
Oral antihistamines (must abstain before skin prick testing)
•
Oral and inhaled corticosteroids (duration should be limited and ideally stopped upon AE
resolution).
•
Topical steroids to treat any local cutaneous AE
•
Intramuscular injectable epinephrine
•
Treatment prescribed in case of any AE
•
Treatment with Cromolyn sodium, and leukotriene inhibitors
6.3 Prohibited and Rescue Medications  


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22 
Refer to the most recent package insert or investigator’s brochure to access additional current 
information on prohibited and precautionary medications for Omalizumab (cross-reference IND 
103080). 
6.3.1 Prohibited Medications and Procedures 
At any time during study participation, subjects may not receive any of the following treatments: 
•
Another investigational drug or approved therapy for investigational use
•
Systemic steroids (intravenous, intramuscular or oral dosing) for more than 5
consecutive days or 15 days total in the study period
Prior to skin prick-testing subjects will be asked to restrict the use of antihistamines (short-acting, 
72 hours: long-acting, 7 days). 
6.3.2 Rescue Medications 
Rescue medications for any clinically significant reaction will include Epinephrine, including 
autoinjectors (dosed according to product insert), antihistamine class of medications (dosed 
according to weight of subject and according to package guidelines), and inhaler medications (short-
acting beta agonist class of medications). The investigators will use their clinical judgment to apply 
these medications in an event of a reaction. In addition, all rescue medications are available within 
immediate reach in each room of the research clinic while dosing occurs. Rescue medications can 
be given IV, IO, IM, by inhalation, and/or by oral route as dictated by the research clinician.  
For home 
dosing, the same class 
of medications 
will 
be 
available and 
all the 
subjects/parents/guardians will receive detailed instructions and education on the use of these 
reaction medications.  Subjects must have their own epinephrine auto injector supply for use per 
the food allergy action plan.  A prescription for epinephrine auto injector may be provided to 
subjects, as appropriate. 
6.4 Description of Facility 
The study visits will be conducted in a research center at each study site location. Beds or chairs 
are dedicated to clinical research and will be used for the conduct of food allergy OIT studies. A 
code team w ill b e available to the food allergy research center and clinical staff should have 
immediate access to a code cart and emergency personnel. Each site should have a documented 
code plan for emergency use. In addition, the research center will have vital sign monitors, oxygen 
tanks, and reaction medications. 
Emergency trained health care professionals are located within 25 feet of the rooms in which oral 
immunotherapy is being performed. 
7.0 Study Procedures/Evaluations 
7.1 Clinical Evaluations 
Subjects will keep electronic  diaries during the study to document daily dosing and any symptoms 
during the oral immunotherapy perios. Please refer to the Study Schedule of Events (appendix D), 
for full details. 
Missed OIT Doses 
• If the subject misses up to three consecutive days of the daily dose for any reason then
he/she may resume with same dose at home or in to the research center.


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23 
• If the subject misses >3 but <6 consecutive days of the daily dose for any reason then
he/she may be asked to return to the research center for the next daily dose for observe dosing,
if deemed appropriate by the investigator.
If the subject misses more than six days of the daily dose for any reason he or she will return to
the research center for the next daily dose possibly for dose reduction or discontinue OIT
updosing ( may be deemed a desensitization failure based on PI discretion), as deemed
appropriate by the investigator.
• If the subject misses 14 or more days of the daily dose for any reason, subject will be terminated
from the study.
7.2  General safety precautions for entire study 
1. If the subject develops a mild objective reaction, the next dose may be kept the same until
no reaction for at least 2 weeks occurs before continuing dose escalation.
2. If a significant acute viral infection (i.e. gastroenterological, upper airway) is diagnosed, the
dosing will be decreased or stopped up to 4 days at any time during OIT dosing per Investigator’s
discretion.
3. If any subject has a serious adverse reaction (serious as defined by CFR/GCP [Code of Federal
Regulation/ Good Clinical Practice] Guidelines, 
http://www.fda.gov/Safety/Med Watch/
HowTo Report/uc m0530 87.ht m), the principal investigator will report to the FDA and DSMB
and ask the subject to discontinue OIT.
4. The subject will be told to eat the OIT dose within an hour of eating a meal and to drink at
least 4 ounces of c ol d water or suck on ice cubes after the ingestion to try to prevent local
reactions in the mouth and throat.
5. If, at any point in the study, the subject complains of new onset vomiting, dysphagia, chronic
abdominal pain, and difficulty swallowing for more than 6 weeks, the patient will be referred
to a gastroenterologist for assessment of possible gastroenterological disorders associated with
food allergy (i.e., eosinophilic esophagitis).
6. If there is abdominal pain or vomiting within or outside of a 2 hr window from eating the food
allergen mixture for more than 4 days in a row - without the presence of a gastroenterological
virus, we suggest a decrease in the dose by 25%, encourage participant to start an antacid or
protein pump inhibitor, take 5-10 mg of cetirizine one hour ahead of food allergen mixture
dosing, and drinking water or sucking on ice cubes after ingestion of the food allergens. If within
about 5 days, symptoms have not subsided, decrease dose again by 25% and continue other
above procedures. When there is two weeks with no abdominal pain or vomiting symptoms then
consider dose escalation.
7. If there is a medical necessity to take oral prednisone (i.e., any oral steroid class of agents),
the daily dose of prednisone must be limited to 5 c o n s ecu t i v e days or 15 total days during
the study. If additional daily doses are needed, the patient will be terminated from the study.
8. All precautions as suggested by Varshey, P. et al. (2009)(1) and by Hofmann, et al. (2009)(2)
will be implemented.
9. Daily doses of 5-10 mg of cetirizine (as per product label) are strongly encouraged throughout
the study unless otherwise specified. 
10. If there are other concomitant allergic medical issues (i.e. allergic rhinitis, allergic
conjunctivitis, eczema) that the PI is concerned about, the subject may be asked to decrease 
their dose per investigator discretion. 
7.3 Laboratory Assessments 
7.3.1 Clinical and Research Laboratory Evaluations and Specimen Collection 
The laboratory assessments for each subject includes ImmunoCap (Phadia, Sweden) to food allergen 
IgEs and IgG4s, total IgE, and other translational and mechanistic laboratory tests. Baseline labs 
will include ImmunoCap to food allergens and will be documented to confirm inclusion criteria.  


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24 
Plasma and cells will be banked for future translational research if patient agrees per the informed 
consent. 
Blood sample collection and shipment to the Nadeau laboratory are required procedures in the 
protocol (please see Study Schedule of Events-Appendix D). 
7.3.2 Specimen Preparation, Handling and Shipping 
Quality Assurance: All samples will be coded, processed, and stored. Whole blood will be 
collected. Each laboratory that stores specimens has a 24-hour, 7-days a week monitoring of the 
storage units, and has a back-up generator in case of power outage. Sites sending specimens to 
Stanford should send specimens the same day per the MOP. 
Standard Operating Procedures (SOPs) are in place for:  1) sample handling (aliquoting, transfer of 
samples); 2) record keeping (chain of custody forms, shipping inventory, data entry to laboratory 
databases); 3) storage and shipping conditions (temperature requirements, back- up power systems, 
overnight delivery); and 4) problem resolution (discrepancy reports, etc). 
Every aliquot is labeled that uniquely identifies it according to participant ID, visit, sample type, 
and aliquot number. Samples will be sent to the Nadeau lab per the MOP. Samples received at the 
Nadeau lab will be barcoded to enter the sample ID into the database to a location unique to that 
aliquot. The Nadeau laboratory biorepository has developed a customized database to track and 
locate all bar-coded samples. The database information does not contain any personal identifiers 
and is backed up nightly on a secured Stanford server with up-to-date network protection. 
7.4 Other Safety Assessments 
7.4.1 Physical Examination and Vital Signs 
Physical examination will be conducted at visits indicated in the Schedule of Event (AppendixD).  
Height and weight will also be recorded.  Vitals signs will also be assessed to include resting blood 
pressure, heart rate, respiratory rate, body temperature, and oxygen saturations. 
7.4.2 Spirometry 
Spirometry to determine FEV1 (3 attempts are to be performed). For subject <6 or who are unable 
to do spirometry may complete Peak expiratory flow rate (PEFR) assessment.  Subjects who are 
unable to complete either should be assessed by an investigator by physical examination. If 
possible, airflow assessment should be measured at each visit. 
7.4.3 Skin Prick Test 
Skin testing will be performed per standard techniques.  Subject have to be off antihistamine for 
an appropriate length of time (5 half lives of the antihistamine that is being used) prior to 
testing. 
7.4.5 Pregnancy Test 
All females of child-bearing potential will undergo a urine Human Chorionic Gonadotropin (HCG) 
test at screening, prior to initial administration of Omalizumab at week 0 visit, if more than 7 days 
from screening, and  when deemed necessary by the investigator. 
All women of child-bearing potential must agree to practice preventive measures regarding 
pregnancy with the prevention measures of their choosing. If they choose oral contraceptives, a 


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25 
prescription will be provided to them or they will be referred to an OB/GYN physician. They will be 
required to disclose their method of pregnancy prevention at the initial screening visit and at the 
initiation of Omalizumab dosing.  
If a participant becomes pregnant during the course of the study, she will be required to cease all 
study-related treatments immediately. She will continue to be followed until study completion and 
monitored until the conclusion of the pregnancy. 
7.5 Data management 
All research data that is required at each study time point will be documented using Stanford Allergy 
Center templates. If there are outside records from healthcare providers or clinics, these will be kept as 
source documents. These may include lab results, progress notes, etc. during screening or any visits that 
do not occur at the study site following randomization. Electronic Data Capture will be via Redcap. 
8.0 Study Schedule of Events 
See 17.0.4 Appendix D: 
8.1 Screening – Week -36 thru  Day-1 
Written informed consent will be obtained prior to any study related procedures by the principal 
investigator or their designee according to ICH/GCP guidelines. 
Screening Procedures will be completed within 36 weeks prior to Week -8 visit and will include the 
following: 

Obtain informed consent, and assent if applicable

Review of inclusion/exclusion criteria

Medical, allergy, and dietary history

Concomitant medication review

Physical exam

Vital signs including resting blood pressure, heart rate, respiratory rate, body temperature,
height, and weight

Spirometry

Skin prick testing, if applicable per investigator discretion

Urine pregnancy test for women of child bearing potential

Blood draw to collect sample for:
o
Allergen specific IgE, total IgE
o
Allergen specific IgG4
o
Mechanistic labs
o
The amount of blood to be taken for the above assays will not exceed a total volume
of 50mL or 3ml/kg, whichever is lesser, within an 8 week period in children, and
lesser of 300mL or 5ml/kg within a 12 week period in adults.

Training on Epinephrine autoinjector use and food allergy action plan.
If the subject meets initial eligibility based on skin testing, allergen-specific IgE, spirometry, 
total IgE, they may undergo further screening to determine eligibility (e.g assess commitment 
to compliance). 


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26 
Subjects will be monitored for adverse events (categorized as allergic vs. non allergic adverse 
events) and any changes in concomitant medications at every study visit after Screening. 
Eligible subjects will be enrolled and randomized in the study, then initiate  Omalizumab therapy . 
8.3  Treatment Period 
8.3.1 Week -8 and -4 - Omalizumab Treatment (Dose 1 and 2) ±5 days 
Once deemed eligible, subjects will be randomized 1:1 to either group A (300mg) or Group B 
(1200mg).  All subjects will be treated with three doses of Omalizumab  over 8 weeks (Week -8, 
Week-4 and Week 0 prior to starting oral allergen immunotherapy) to allow food-specific IgE on 
mast cells and basophils to equilibrate with anti-IgE mAb. Omalizumab will be dosed as 0.016 mg 
omalizumab/kg/total IgE U/mL per product brochure guidelines.(see Error! Reference source n
ot found.) 
The following procedures will be completed at Week -8 and -4 visits: 

Symptom directed physical exam

Review of adverse events and concomitant medication

Administration of omalizumab.  Subjects will stay for post dose observation at the research
center for at least 90 minutes after injection or longer as deemed necessary by the
investigator.
8.3.2. Week 0 – Last Omalizumab dose (Dose 3) and First dose of food allergen and desensitization 
After the last dose of omalizumab administration, subjects will undergo an oral desensitization to up 
to five offending food allergens.  The allergen mix will be prepared by the Stanford GMP Facility 
and include the total number of allergens (1:1 in mg protein) for an initial dose of 5 mg total protein 
dose. Food vehicles may include applesauce, chocolate pudding or vanilla pudding or other age 
appropriate food vehicles.  Heating or cooking of food flour will not be allowed.  
The following procedures will be completed at Week 0 visit 
•
Complete physical examination

Predose vital sign measurement (heart rate, respiratory rate, blood pressure and pulse
oximetry)

Spirometry
o
If spirometry FEV1 and/or peak flow is less than 80% of predictive values,
clinician must document clear breath sounds before dose escalation.

Administration of Omalizumab subcutaneous injection.

Oral administration of food flour 5mg total protein dose at least 60 minutes after last
Omalizumab injection.

Post dose vital signs measurements (heart rate, respiratory rate, blood pressure and pulse
oximetry) within15 minutes post dose then every 15 minutes for the duration of the
minimum 2 hour post dose observation period or longer as per investigator discretion.
•
Treatment for objective symptoms should occur via treatment recommendations as per
institutional 
and 
NIAID 
published 
guidelines 
for 
anaphylaxis.
(https://www.niaid.nih.gov/topics/foodAllergy/clinical/Documents/FAguidelinesPatient.
pdf)
•
AEs will be monitored, including allergic symptoms
•
When dosing with the allergen/s elicits an acute reaction, the investigator will assess if the


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27 
dose was tolerated or not. 

Subjects who tolerates 5 mg of total protein with no grade >1 objective allergic reaction
(as per Bock’s criteria in Section Error! Reference source not found.) during dosing a
nd until 2 hour post dose observation period will be dispensed 4 week supply of 5 mg
total protein allergen doses.  They will be instructed to continue daily oral dosing at home,
starting the following day (day 2), and to continue daily home dosing at that dose level
for 4 weeks until the next escalation.
•
Subjects who do not tolerate 5mg total protein, deemed to have dose limiting symptoms
such as grade 3 reaction by Bock’s criteria or who receive intensive therapy for allergic
reaction, will be classified as desensitization failures.  There will be no further dosing of
study product and subject will  return to the research unit about 14 days after last allergen
dose for an early discontinuation visit.
•
Subjects will be given home dosing instructions, which will include a 24-hour emergency
contact information, and contact information for the research team for questions or
concerns with home dosing.
•
Subjects will be instructed to keep an electronic diary of food allergy symptoms.
•
Subjects will be reminded to continue allergen avoidant diet for the duration of the study.
A starting dose of 5mg total dose of the food allergens was chosen since this is the starting dose 
given in most single food allergen oral immunotherapy regimens. Since all participants are 
receiving 3 doses of Omalizumab prior to initiation of oral immunotherapy (OIT), we expect 
participants to tolerate at least 625 mg or more of total food allergen protein (Nadeau et al. JACI 
2011). 
The oral immunotherapy treatment period will last approximately 18 weeks and comprise of  up dosing 
visits every 4 weeks until reaching a the assigned maintenance dose, with the potential for unscheduled 
visits for assessments of dose tolerability, dose reduction, dose re escalation, or assessment and 
management of AEs.   
8.3.2.1 Discharge criteria for any subjects upon completion of procedures: 
Subjects will only be discharged from the research center all allergic symptoms have resolved or 
significantly improved for at least 60 consecutive minutes. 
8.3.2.2 Criteria that would require further observation and/or hospital admission. 
1. Any allergic symptom that are mild or moderate (Bock’s criteria 1 or 2, reference 7) will be
observed for at least 60 minutes per the NIAID food allergy guidelines or per PI or their designee 
discretion. 
2. Any allergic symptom that is severe (Bock’s criteria 3, reference 7) or that is deemed medically
worrisome by the medical staff and principal investigator, will be considered for a possible hospital 
admission or observation. 
8.3.3. Weeks 4 through 16 ±5days 
Subjects will return to clinic every 4 weeks for dose escalation to a maximum daily total protein dose 
of 300 for group A and 1200mg for group B participants.   
The first dose of each new dose level will be administered in the research unit under direct 
observation and medical supervision.  Subjects should withhold their daily home dose on in clinic 
dosing days. 


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28 
At week 4 visit, total protein daily dose will be increased to 30 mg (group A) or 240 mg (group 
B) of their food allergens.  (see Table 2: Up Dosing Schedule Group A. and Table 3: Up Dosing Schedule
Group B.)  
The following procedures will be completed at each up dosing visit: 

Adverse event and concomitant medication review

Diet (food allergen exposure) history review

Return unused allergen doses to clinic, and assess compliance

Diary review with subject

Symptom directed physical exam

Predose vital signs measurement (BP, HR, RR, body temperature, oxygen saturation)

Spirometry

Oral allergen dose administration under observation in clinic

Post dose vital signs measurements (heart rate, respiratory rate, blood pressure and pulse
oximetry) within 15 minutes post dose then every 15 minutes for a minimum of 2 hours
post dose observation period or longer as per investigator discretion.

Remind subject to keep an electronic diary of food allergy symptoms.

Remind subject to continue allergen avoidant diet for the duration of the study.

Review of food allergy action plan and epinephrine autoinjector use
Subjects must be free from active wheezing, a flare of atopic dermatitis, or suspected inter-current 
illness prior to any dose escalation. 
If increased dose was tolerated with no dose limiting symptoms detected during the post dose 
observation period, the subject may be sent home with increased tolerated dose for daily home 
dosing. 

If subject has mild reactions to the increased dose in the research center, subject will
continue with the previous dose at home.  No increase in the dose will occur for that visit.
A dose escalation will be attempted in 2-4 weeks until the maximum daily total protein dose
is reached per subject treatment assignment.  Dose must be tolerated for at least 2 weeks
prior to any dose escalation.

If subject has moderate reactions to the increased dose in the research center, dose
escalation will not occur.  Subject will continue with the previous dose at home.  A dose
escalation will be attempted in 2 weeks to approximately half of the dose eliciting the
moderate allergic reaction.  Another dose escalation may be scheduled every 2-4weeks until
the maximum daily total protein dose is reached per subject treatment assignment.  Subject
requiring partial dosing will have to maintain and tolerate the new dose level for a 2 week
period prior to attempting to re-escalate.

If subject has severe reactions to the increased dose in the research center that included
hypoxia, hypotension, or change in mental status, or who receives intensive therapy such as
IV epinephrine or intubation or admission as assessed by an investigator, subject will be
terminated from the study.  There will be no further dosing of study product and subject will
return to the research unit about 14 days after last allergen dose for an early discontinuation
visit.
It is possible that allergic cell (i.e. mast cell, basophil, eosinophil) activity will be present. 
Therefore, subjects will be observed closely (every 15 min vital signs in a facility with trained personnel 


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29 
and access to reaction medications) for the development of symptoms, including hives, worsening of 
eczema or wheezing during this time period, and will be reminded to keep a diary of food allergy 
symptoms. It is expected that patients will remain tolerant to this dose of cumulative offending food 
allergen(s) even when Omalizumab is discontinued at week 0 since the half life is approximately 26 
days, and should remain effective at 3 months.   Omalizumab  is deemed to continue to have some effects 
up to week 12 of the study, as was observed in the milk desensitization study (5) and phase 1 study 
results of this IND (8). (Section 16.0). 
8.3.4 Early Discontinuation/ End of Study (week 18 ±5 days) 
Subjects who tolerate their oral allergen doses to the maximum total protein dose per treatment assignment 
will have an End of Study visit at week 18. 
Subjects who fail dose escalation, or who prematurely discontinue treatment at any other time during 
the study, will return for an Early Discontinuation visit that consists of the same procedures as the end 
of study visit.   Early discontinuation visit must occur within 14 days after the last dose of subject’s 
allergen. 
The following procedures will be performed at the End of Study/Early Discontinuation Visit: 

Adverse event and concomitant medication review

Diet (food allergen exposure) history review

Return unused allergen doses to clinic, and assess compliance

Diary review with subject

Complete physical exam

Vital signs measurement (BP, HR, RR, body temperature, oxygen saturation)

Spirometry

Skin Prick Testing

Blood draw to collect sample for:
o
Allergen specific IgE, total IgE
o
Allergen specific IgG4
o
Mechanistic labs

The amount of blood to be taken for the above assays will not exceed a total volume of
50mL or 3ml/kg, whichever is lesser, within an 8 week period in children, and lesser of
450mL or 5ml/kg within a 12 week period in adults.

Training on Epinephrine autoinjector use and food allergy action plan.
8.3.5Unscheduled Visits 
The procedures performed at unscheduled visits may include any or all of those performed at Visit 1.  
Unscheduled visits will take place for an unexpected pregnancy or any complication or AE/SAE that 
requires an extra visit. These visits will be documented in the source document and the unscheduled 
visit elect roni c case report form. 
9.0 Assessment of Safety 
9.1 Adverse Event (AE) 
An adverse event is defined as any untoward or unfavorable medical occurrence associated with 
the subject’s participation in the research, whether or not considered related to the subject’s 


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participation in the research (modified from the definition of adverse events in the 1996 
International Conference on Harmonization E-6 Guidelines for Good Clinical Practice) (from 
OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to 
Subjects or Others and Adverse Events (1/15/07) 
http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2). 
For this study, an adverse event will include any untoward or unfavorable medical occurrence 
associated with: 
• Study therapy regimen:
Home OIT Dosing 
•
Food allergy episodes in response to home dosing that are Grade 1 or 2 by
Modified Bock’s Criteria (Appendix B) will be recorded on the AE CRFs.
•
Food allergy episodes in response to home dosing that are Grade 3 by Modified
Bock’s Criteria (Appendix B) or that are classified as SAEs defined in Section
12.2.3 below will be recorded on the AE/SAE CRF, as appropriate.
• Study mandated procedures:
For the procedures below, clinical situations are listed that are considered to be 
outside the normal range of outcomes and will be recorded as Adverse Events. 
These situations do not limit an investigator from recording and reporting any 
other events, associated or not with these procedures as AEs. 
Allergen Skin Testing 
•
Prolonged (>24 hours) itching at test site
•
Swelling (> 10 cm) at site of test lasting more than 24 hours
•
Nasal allergic symptoms within 30 minutes from the procedure
•
Fainting /Vasovagal event within 30 minutes from the procedure
Phlebotomy 
•
Bruising at phlebotomy site >5 cm with onset within 24 hours of procedure
•
Erythema at phlebotomy site >5 cm with onset within 24 hours of procedure
•
Infection at phlebotomy site
•
Fainting /Vasovagal event within 30 minutes from the procedure
Suspected Adverse Reaction (SAR) 
Any adverse event for which there is a reasonable possibility that the investigational 
drug [or investigational study therapy regimen] caused the adverse event. For the 
purposes of safety reporting, ‘reasonable possibility’ means there is evidence to 
suggest a causal relationship between the drug and the adverse event. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug (21 CFR 312.32(a)).  
9.2 Unexpected Adverse Event 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the Investigator Brochure or package insert or is not listed at the specificity, severity 
or rate of occurrence that has been observed; or, if an Investigator Brochure is not required 
or available, is not consistent with the risk information described in the general 


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31 
investigational plan or elsewhere in the IND or protocol. 
The Principal Investigator will review all adverse events related to skin prick testing, 
spirometry, food challenge, or other study procedures to determine if they are unexpected. 
9.3 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if it results in any 
of the following outcomes (21 CFR 312.32(a)): 
1. Death.
2. A life-threatening event: An AE or SAR is considered “life-threatening” if its occurrence
places the subject at immediate risk of death. It does not include an AE or SAR that, had
it occurred in a more severe form, might have caused death.
3. Inpatient hospitalization or prolongation of existing hospitalization.
4. Persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions.
5. Congenital anomaly or birth defect.
6. Important medical events that may not result in death, be life threatening, or require
hospitalization may be considered serious when, based upon appropriate medical
judgment, they may jeopardize the subject and may require medical or surgical
intervention to prevent one of the outcomes listed above.
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol 
mandated procedures are not to be reported as an SAE unless hospitalization is prolonged 
due to complications. 
9.4 Grading and Attribution of Adverse Events 
Grading Criteria 
The study investigator will grade the severity of adverse events experienced by the study 
subjects according to the criteria set forth in the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0. This document (referred to herein 
as the NCI-CTCAE manual) provides a common language to describe levels of severity, to 
analyze and interpret data, and to articulate the clinical significance of all adverse events. 
The NCI-CTCAE has been reviewed by the Principal Investigator and has been deemed 
appropriate for the subject population to be studied in this protocol. 
Adverse events will be graded on a scale from 1 to 5 according to the following standards 
in the NCI-CTCAE manual: 
Grade 1 = mild adverse event. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
Events Grade 1 or higher will be recorded on the appropriate AE case report form for 
this study. 
Anaphylaxis will be defined when there is: 1) Symptomatic bronchospasm, with or 


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32 
without urticaria, with parenteral intervention indicated for edema and hypotension; or 
2) Life-threatening consequences with urgent intervention indicated.
Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study 
procedure(s) will initially be determined by the site investigator/study physician and 
recorded on the appropriate AE/SAE paper case report form and according to SUSAR 
guidelines (http://www.fda.gov/downloads/Drugs/.../Guidances/UCM227351.pdf). Final 
determination of attribution of SAE for safety reporting will be determined by PD. 
For additional information and a printable version of the NCI-CTCAE manual, consult the 
NCI-CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html. 
9.5 Collection and Recording of Adverse Events 
9.5.1 Collection Period 
Adverse events will be collected from the time of consent  until a subject completes study 
participation or until 30 days after last OIT dose. 
AEs related to allergic reactions will be collected separately. Allergy reactions are expected 
during this study. Reactions due to allergy are within the first 2 hours after dosing with the 
food allergen mix. 
9.5.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
•
Observing the subject.
•
Interviewing the subject [e.g., using a checklist, structured questioning, diary, etc].
•
Receiving an unsolicited complaint from the subject.

Review of medical records/

Review of home dosing symptom log in subject diary (symptoms between visits)
9.5.3 Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse 
events as described previously in this section  on the appropriate AE/SAE source document 
regardless of the relationship to study therapy regimen or study procedure. Once recorded, 
an AE/SAE will be followed until it resolves with or without sequelae, or until 30 days after 
the subject prematurely withdraws (without withdrawing consent)/or is withdrawn from the 
study, whichever occurs first. 
Allergic reactions will be recorded separately as allergic adverse events. 
9.6 Reporting of Serious Adverse Events and Adverse Events 
9.6.1 Reporting of Serious Adverse Events to Sponsor 
This section describes the responsibilities of the site investigator to report serious adverse 
events to the sponsor. Timely reporting of adverse events is required by 21 CFR and ICH 


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33 
E6 guidelines. 
The site investigator will report to the Protocol Director/Sponsor all serious adverse events 
within 24 hours of becoming aware of the event, regardless of relationship or expectedness. 
For serious adverse events, all requested information on the AE/SAE source document will 
be provided. However, unavailable details of the event will not delay submission of the 
known information. As additional details become available, the AE/SAE source document 
will be updated and submitted. 
9.6.2 Reporting of Unexpected Non-Serious Adverse Events 
An unexpected, non-serious adverse event that is of Grade 2 severity or higher and study 
related will be recorded and reported to the Protocol Director/Sponsor under the serious 
adverse event reporting procedure above (i.e. within 24 hours). 
9.6.3 Reporting to Health Authority 
Dr. Nadeau will be the sponsor of the IND and has the responsibility of reporting all AEs 
and SAEs to the FDA within the reporting time limits set forth by the FDA. 
Standard Reporting (IND Annual Report) 
This option applies if the AE is classified as one of the following: 
o
Serious, expected, suspected adverse reactions (see Section Suspected Adverse
Reaction, and Section  Unexpected Adverse Event). 
o
Serious and not a suspected adverse reaction (see Section  Suspected Adverse
Reaction).
o
Pregnancies
Note that all adverse events (not just those requiring 24-hour reporting) will be reported 
in the Annual IND Report. 
Expedited Safety Reporting 
• Expedited reporting is required.
This option applies if the AE is classified as one of the following: 
Serious and unexpected suspected adverse reaction [SUSAR] (see Section 
Suspected Adverse Reaction and Section  Unexpected Adverse 
Event and 21 CFR 312.32(c)(1)i 
o
The IND sponsor, Dr. Nadeau, must report any suspected adverse reaction that is both
serious and unexpected. The IND sponsor must report an adverse event as a 
suspected adverse reaction only if there is evidence to suggest a causal relationship 
between the study drug and the adverse event, such as: 
A single occurrence of an event that is uncommon and known to be strongly
associated with drug exposure.
One or more occurrences of an event that is not commonly associated with drug
exposure, but is otherwise uncommon in the population exposed to the drug
o
Aggregate analysis of specific serious adverse events observed in a clinical trial (such
as known consequences of the underlying disease or condition under investigation 
or other events that commonly occur in the study population independent of drug 
therapy) that indicates those events occur more frequently in the drug treatment 


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34 
group than in a concurrent or historical control group. 
o
Any findings from clinical or epidemiological studies, analysis of data pooled across
multiple studies, published or unpublished scientific papers, or from animal or in 
vitro testing that would result in a safety-related change in the protocol, informed 
consent, General Investigational Plan section of the IND or other aspects of the 
overall conduct of the trial. 
SUSARs must be reported to the FDA within 15 calendar days; fatal or life threatening 
events must be reported to the FDA as soon as possible, but no later than 7 calendar 
days.  
To report a SUSAR, a finalized, initial SAE case report form and a MedWatch 3500A form 
will be generated by the site Principal Investigator 
Any findings from studies that suggests a significant human risk 
The IND sponsor, Dr. Nadeau,  shall report any findings from other epidemiological studies, 
analyses of adverse events within the current study or pooled analysis across clinical studies 
or animal or in vitro testing (e.g. mutagenicity, teratogenicity, carcinogenicity) that suggest 
a significant risk in humans exposed to the drug that would result in a safety-related change 
in the protocol, informed consent, investigator brochure or package insert or other aspects 
of the overall conduct of the study. 
Reporting of Adverse Events to IRBs/IECs 
The site investigator shall report adverse events, including expedited reports, in a 
timely fashion to their respective IRBs/IECs in accordance with applicable regulations 
and guidelines. All Safety Reports to the FDA shall be distributed by Dr. Lloret-Garcia 
and Dr. Nadeau. 
9.7  Pregnancy Reporting 
The investigator shall be informed immediately of any pregnancy in a study subject who 
has initiated study treatment. A pregnant subject shall be instructed to stop taking study 
medication. The investigator shall counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. Monitoring of the pregnant subject 
shall continue until the conclusion of the pregnancy. 
The investigator and sites shall report to the sponsor all pregnancies within 1 business day 
of becoming aware of the event. All pregnancies identified during the study shall be 
followed to conclusion and the outcome of each must be reported. 
Information requested about the delivery shall include:  
O  Gestational age at delivery 
o
Birth weight, length, and head circumference
o
Gender
o
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5
minutes, and 24 hours after birth, if available
o
Any abnormalities.
Any complication to pregnancy such as a congenital abnormality or birth defect shall be 
submitted as an SAE to the sponsor using the SAE reporting procedures described above 


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35 
and to the FDA. 
9.8  Reporting of Other Safety Information 
The site investigator shall promptly notify the site IRB when an “unanticipated problem 
involving risks to subjects or others” is identified, which is not otherwise reportable as an 
adverse event. 
Specification of Safety Parameters 
Research staff will report any clinical adverse event (AE), whether it is observed by the 
investigator or the subject (see Adverse Events, below, for further details regarding the 
definition, management, and reporting of AEs). 
9.9 Monitoring and Treatment of Toxicity 
The investigator, sub-investigator, or designated health professional must be present during initial test 
drug administration and for increases in dose for the evaluation and treatment of any AEs. 
10 Clinical Monitoring Structure 
10.1 Site Monitoring Plan 
Every effort will be made to maintain the anonymity and confidentiality of subjects during this clinical 
study. However, because of the experimental nature of this treatment, the investigator agrees to allow 
representatives of the DSMB, and authorized employees of the appropriate regulatory agencies and 
the sponsor (i.e. Stanford University) to inspect the facilities used in this study and to inspect, for 
purposes of verification, the hospital or clinic records of all subjects enrolled into this study. 
10.2 Study Monitoring Plan 
The investigators will work with the independent Data and Safety Monitoring Board (DSMB). 
11.0 Statistical Considerations 
The design of this study is a multi-site, trial assessing desensitization following treatment with 
Omalizumab+food OIT. Ability to tolerate offending food for subjects will be evaluated by immune 
biomarkers (IgG4/IgE ratio) and monitoring of adverse events. 
11.1 Description of the Analysis 
Primary efficacy analyses will be conducted using an Intention to Treat (ITT) population and will 
include all subjects. Subjects who withdraw/are terminated will be considered treatment failures for 
subsequent efficacy outcomes. There will be no adjustment made for multiple testing done within this 
study. 
11.2 Measures to Minimize Bias 
Participants will be seen by trained personnel.  Subjects and assessing study personnel will also 
blinded to the maintenance dose assignment. 


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36 
11.3 Appropriate Methods and Timing for Analyzing Outcome Measures  
11.3.1 Primary Endpoint   
To proportion of subjects on a combination of omalizumab and multi oral immunotherapy who have 
increase in the IgG4 /IgE ratio of at least of 2 allergens by ≥25% from baseline at wk18.  
4.2.2 Secondary Endpoints 
The proportion of subjects on a combination of omalizumab and multi oral immunotherapy who 
have an an increase the IgG4 /IgE ratio of at least of 3 allergens by ≥25% from baseline, at week 
18. 
The proportion of subjects on a combination of omalizumab and multi oral immunotherapy who 
have an increase the IgG4 /IgE ratio of at least of 4 allergens by ≥25% from baseline, at week. 
The proportion of subjects on a combination of omalizumab and multi oral immunotherapy who 
have an increase the IgG4 /IgE ratio of at least of 5 allergens by ≥25% from baseline, at week 18 
Other endpoints include monitoring safety outcomes according to CTCAE v4.03 criteria. Allergic 
reactions will be monitored separately as allergic adverse events. 
We will also explore immune monitoring studies and we will perform high dimensional and 
innovative immune monitoring during the study. The long term objective of this study is to develop 
a potentially curative therapy for patients with multi food allergies. We hypothesize that young and 
older subjects with multi food allergies who receive a combination of Omalizumab and multi oral 
immunotherapy (OIT) can be rapidly desensitized and tolerate higher doses of food protein. We also 
hypothesize that 300 mg total protein dose vs 1200 mg total protein dose will be adequate to achieve 
the primary endpoint in the majority of participants. However, we will explore if age, sex, body 
mass index, years with disease, and degree of polysensitization affect outcomes; as well as  
characterize the treatment related adverse events throughout the study.   . 
11.4 Study Hypothesis 
To address the primary objective of this trial of assessing the ability of a combination of omalizumab 
and multi food  allergen oral immunotherapy to increase IgG4/IgE to at least 2 food allergens by 
equal or greater to 25% at week 18 in patients who have multi food allergy, we will test the 
following null hypotheses: 
1. There is less than a 25% increase in IgG4/IgE among multi
11.5 Sample Size Considerations 
To address the primary objective of this trial and test the primary study hypotheses as stated in 
section 11.5, we are planning to enroll total of 60 subjects. Assuming 15% drop out from the trial, 
we expect to have primary endpoint observation on 50 subjects in each treatment group. Based on 
our phase 1 study of Omalizumab and multiple OIT (Begin, et al. AACI 2014) and the paper by 
Andorf, et al (accepted, attached), we expect that 70% of subjects will reach the primary endpoint. 
11.6 Maintenance of Trial Treatment Randomization Codes 
Subjects will be randomized 1:1 into one of two study groups: 


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37 
 Group A- 300 mg total food allergen protein, 
 Group B- 1200 mg total food allergen protein,  
A randomized block design will be used.  A Master Randomization Assignment List will be kept by 
the designated unblinded personnel in a secure limited access location in order to ensure that the list 
is available only to unblinded study personnel.   
Once a patient is eligible for enrollment to the treatment phase of the study, blinded site personnel 
will complete and submit a request for randomization form to the unblinded sponsor personnel in 
order to randomize the participant. This request will include date of request, subject initials and 
screening number, allergens to be included in their OIT, and an acknowledgement that the participant 
has met all eligibility criteria for randomization. Treatment will be assigned by the unblinded sponsor 
personnel based on a Randomization Master List. The designated unblinded personnel will ensure 
that the assigned randomization number is in fact the next unused treatment assignment on the master 
list.  He/she will then complete the Randomization Allocation form with the treatment assignment 
and randomization information including, randomization number/participant ID, randomization date, 
and treatment assignment. A copy of the completed randomization allocation form will be provided 
to GMP and site unblinded personnel in a manner that maintains the blind.  GMP will prepare and 
distribute the appropriate daily dose kits to the unblinded personnel at each site.  Dosing kits will be 
labelled in a blinded manner, but will include an unblinded tear-off label that includes unbinded 
treatment identity and expiration date. This unblinded label will be removed by the unblinded site 
personnel prior to dispensing and placed on the appropriate subject accountability log. Strict 
compliance with documentation of randomization procedures is essential to ensure there is a reliable, 
verifiable link between the study subject’s study ID and the treatment assignment.  At the end of the 
study, the Master Randomization List with all randomization numbers and corresponding treatment 
assignments will be provided as an Excel file to the biostatistician as a further check on the 
randomization process. 
11.7 Subject Enrollment and Follow-Up 
We will maximize study subject compliance with the maintenance protocol with frequent contact 
with subjects and by reviewing the home diary. Our sites have extensive experience in clinical trials, 
and in enrolling and retaining subjects. 
11.8 Planned Interim Analyses (if applicable) 
Formal interim analyses of efficacy endpoints are not planned. Interim analyses will be descriptive 
analyses of safety data.  
11.9 Safety Review 
Please refer to individual and study stopping rules. 
11.10 Immunogenicity Review or Efficacy Review 
Information on immunogenicity of Omalizumab can be provided in the investigator’s brochure. 
The primary investigator is aware of possible human anti human antibodies that could be generated 
against Omalizumab. We will be monitoring for any side effects related to immunogenicity of 
Omalizumab by monitoring clinical reactions associated with the administration of the 


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38 
Omalizumab. 
12.0 Quality Control and Quality Assurance 
Following written standard operating procedures, the monitor will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements. 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
Stanford will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
13.0 Ethics/Protection of Human Subjects 
13.1 Institutional Review Board/Ethics Committee 
The investigator will ensure that this study is conducted in full conformity with the current revision 
of the Declaration of Helsinki, or with the International Conference for Harmonization Good Clinical 
Practice (ICH-GCP) regulations and guidelines, whichever affords the greater protection to the 
subject. 
13.2 Informed Consent 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continuing throughout the individual’s study participation. Extensive discussion of risks 
and possible benefits of this therapy will be provided to the subjects and their families. Consent 
forms describing in detail the study procedures, Omalizumab dosing, and allergen protein dosing 
procedures and risks are given to the subject and written documentation of informed consent is 
required prior to starting study agent/intervention. Consent forms will be IRB approved and the subject 
will be asked to read and review the document. Upon reviewing the document, the investigator will 
explain the research study to the subject and answer any questions that may arise. The subjects will 
sign the informed consent document prior to any procedures being done specifically for the study. 
The subjects should have sufficient opportunity to discuss the study and process the information in 
the consent process prior to agreeing to participate. The subject may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
subject for their records. The rights and welfare of the subjects 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.  
13.2.1 Consent Process 
The consent process will provide information about the study to a prospective participant and will 
allow adequate time for review and discussion prior to his/her decision. The principal investigator 
or study staff will review the consent and answer questions with the potential participant and must 


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39 
sign the consent form with the participant and document the informed consent process. For minors 
participating in this study, informed consent will be obtained from their parent(s) or legal 
guardian(s). Minors participating in this study will provide assent if they are capable. The 
prospective participant will be told that being in the trial is voluntary and that he or she may 
withdraw from the study at any time, for any reason. All participants (or their legally acceptable 
representative) will read, sign, and date a consent form before undergoing any study procedures. 
Consent materials will be presented in participants’ primary language. A copy of the signed consent 
form will be given to the participant. 
The consent process will be ongoing. The consent form will be revised when important new 
safety information is available, the protocol is amended, and/or new information becomes 
available that may affect participation in the study. 
13.3 Assent of Informed Consent Process (in Case of Minor) 
A separate IRB-approved assent form, describing (in simplified terms) the details of the study, 
Omalizumab dosing, and food protein dosing procedures and risks will be used. Assent forms will 
not substitute for the consent form signed by the subject’s legally authorized representative. 
13.4 Subject Confidentiality 
By conducting this study, the investigator affirms that all study results and information furnished 
will be maintained in strict confidence. Such information will be communicated to the investigator’s 
review committee under an appropriate understanding of confidentiality. 
A published summary of the results of this study is not inconsistent with the preceding affirmation 
of confidentiality. Any formal publication of data collected as a result of this study will be considered 
a joint publication by the investigator and the appropriate personnel. 
13.5 Study Discontinuation 
In the event that the study is discontinued, we will not continue therapy. 
13.6 Other 
Subjects may withdraw with or without medical advice, or if it is determined that the subject is non- 
compliant. Withdrawal of the subject will not impact upon future care of any subjects at the Stanford 
University Hospital or clinics. 
14 Data Handling Documentation 
Study center personnel will complete individual s ou r c e do c um e nt s in black or blue ink. All 
corrections to entered data will be made by drawing a single line through the information to correct.  
All corrections must be initialed and dated. Personnel will not use “white-out” or obscuring 
correction fluid/tape. Electronic case report forms are required for every subject who signs consent 
for participation in the study. 
The investigator will retain a copy of all files pertaining to this study for 2 years following the date 
of marketing approval in an International Conference on Harmonization (ICH) region and until there 
are no contemplated marketing applications in an ICH region. If an application is not filed or not 
approved for the indication under study, all study-related files will be retained for at least 2 years 
following the date of discontinuance of the clinical development program. 


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14.1 Data Capture Methods 
All data will be captured using source document and then entered into the electronic case 
report forms. The study personnel will enter the data into the electronic case report forms, 
the study investigator will review data for accuracy, completeness and accurate 
documentation. 
14.2 Types of Data 
The data collected include demographics, physical exam information, vital signs, food challenge 
results, total and specific IgE and IgG4, adverse events, concomitant medications, dose escalations 
home diary reviews and adverse events. The EDC should be completed within 10 days of each visit. 
14.3 Source Documents and Access to Source Data/Documents 
Each site will maintain medical and research records for this trial including source documents and 
CRFs, in compliance with ICH-GCP, local and national regulatory requirements for the protection 
of confidentiality of subjects. Source data will include information including original records of 
clinical finds, observations or other activities relevant to the clinical trial. These can include, but not 
limited to hospital records, clinical and office charts, laboratory notes, subjects’ diaries, recorded data 
from automated instruments, x-rays, pharmacy records, laboratory records. 
Approved study staff will have access to subject records. Further, as required by law or other 
regulations, the IRB, and FDA will have access to the study records. 
14.4 Timing/Reports 
Annual reports will be generated for the FDA and IRB. The DSMB will meet every 6-12 months 
or earlier if needed. 
14.5 Study Records Retention 
The investigator will hold research records for a minimum of two years. Permission is required 
from Dr. Nadeau prior to destruction of records. All Omalizumab dispensing logs will be kept and 
destroyed only with permission by Dr. Nadeau. 
14.6 Protocol Deviations 
Dr. Kari Nadeau will consider any deviations from the protocol on a case-by-case basis. The 
investigator or other health professional in attendance must contact Dr. Nadeau as soon as possible 
to discuss the associated circumstances. The principal investigator (with the DSMB panel if needed) 
will then decide whether the subject should continue to participate in the study. All protocol 
deviations and the reasons for such deviations must be noted on the appropriate page of the subject’s 
CRF and recorded on a protocol deviation logs. 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements. The noncompliance may be either on the part of the 
subject, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
These practices are consistent with Good Clinical Practice (GCP ICH E6) Sections: 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
Quality Assurance and Quality Control, section 5.1.1 


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Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
according to the guidelines of the IND sponsor. Protocol deviations will be sent to each local 
IRB/IEC per their guidelines and policies. The site PI/study staff is responsible for understanding 
and adhering to their central IRB reporting requirements. 
15.0 Publication Policy 
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal. The International Committee of Medical Journal Editors (ICMJE) member journals 
have adopted a trials-registration policy as a condition for publication. This policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored 
by the National Library of Medicine. 
16.0 Scientific References 
1. VARSHNEY P, STEELE PH, VICKERY BP, et al. Adverse reactions during peanut oral
immunotherapy home dosing. J Allergy Clin Immunol 2009: 124: 1351-1352.
2.
HOFMANN AM, SCURLOCK AM, JONES SM, et al. Safety of a peanut oral
immunotherapy protocol in children with peanut allergy. J Allergy Clin Immunol 2009: 124:
286-291, 291 e281-286.
3. VARSHNEY P, JONES SM, SCURLOCK AM, et al. A randomized controlled study of
peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.
J  Allergy Clin Immunol: 127: 654-660.
4.
GERNEZ Y, TIROUVANZIAM R, YU G, et al. Basophil CD203c levels are increased at
baseline and can be used to monitor omalizumab treatment in subjects with nut allergy. Int
Arch Allergy Immunol: 154: 318-327.
5.
NADEAU KC, SCHNEIDER LC, HOYTE L, BORRAS I, UMETSU DT. Rapid oral
desensitization in combination with omalizumab therapy in Participants with cow's milk 
allergy. J Allergy Clin  Immunol: 127: 1622-1624. 
6. YU GP TK, HAMILTON RG, NADEAU KC.  Omalizumab in Peanut-allergic Participants
Reduces Free IgE to Peanut and Skin Prick Tests to Peanut. Journal of Allergy and Clinical
Immunology 2010: 125: AB22.
7.
BOCK SA, SAMPSON HA, ATKINS FM, et al. Double-blind, placebo-controlled food
challenge (DBPCFC) as an office procedure: a manual. J Allergy Clin Immunol 1988: 82:
986-997.
8. BEGIN P, DOMINGUEZ T, MEHROTRA A, O’RIORDAN G, and NADEAU KC. Phase
1 study results of Rush multi oral immunotherapy with omalizumab in a single center.
Allergy, Asthma, and Clinical Immunology. (February 2014).


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17.0 Appendices 
17.1  Appendix A:  Epinephrine autoinjector Training Form 
Trainin,g Form 
By signing the  training form, I acknowledge being appropriately trained and demonstrate understanding 
in the use and proper storage ofepinephrine auto injectors and have read the accompanying directions for 
use (instruct ions). 
Signature of Adult Participant  
        Date 
Signature of LAR (Parent, Guardian  or Conservator) 
         Date 
Authority  to act for participant 
Current wt: ____________kg 
  Dose: 
 EpiPen 0.3mg or equivalent       
 EpiPen  Junior 0.15mg or equivalent 
ANAPHYLAXIS INFORMATION (All boxes must be checked) 
 Subject and/or family given verbal and written instructions on anaphylaxis. 
 Subject and/or  family given Food Allergy Action Plan with a verbal review to 
ensure understanding 
 Subject and/or  family given information on how to purchase medical 
identification jewelry tag (e.g. MedicAlert bracelet. 
Signature of trainer 
Date 
Printed Name of Trainer 


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17.2 Appendix B: Scoring of Clinical Food Related Reactions that Occur During study 
Note: Grade 1=mild, Grade 2=moderate, Grade 3=severe reaction 
Category 
Grade and Symptom(s) 
Skin 
 Nasal 
Rash 
Grade 0: 
Sign or symptom not observed 
Grade 1: 
Few areas of faint erythema 
Grade 2: 
Areas of erythema, macular and raised rash 
Grade 3: 
Generalized marked erythema (>50%); extensive 
raised lesion (>25%); vesiculation and/or 
piloerections 
Pruritus 
Grade 0: 
Sign or symptom not observed 
Grade 1: 
Occasional scratching 
Grade 2: 
Scratching continuously for >2 minutes at a time 
Grade 3: 
Hard continuous scratching leading to excoriations 
Urticaria 
Grade 0: 
Sign or symptom not observed 
Grade 1: 
<3 Hives 
Grade 2: 
3 to <10 Hives 
Grade 3: 
Generalized involvement 
Angioedema 
Grade 0: 
Sign or symptom not observed 
Grade 1: 
One site of angioedema 
Grade 2: 
Two or more sites of angioedema 
Grade 3: 
Generalized involvement, including airway 
involvement 
Sneezing 
Grade 0: 
Sign or symptom not observed 
Grade 1: 
Rare bursts of sneezing 
Grade 2: 
<10 bursts of sneezing 
Grade 3: 
Continuous rubbing of nose and/or eyes; periocular 
swelling &/or long bursts of sneezing 


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


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


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17.3 Appendix C: GMP and Manufacturing Facility 
We follow all phase 2 guidelines for CMC and for drug preparation as per FDA 
(http://www.fda.gov/ohrms/dockets/98fr/990674gd.pdf). In addition, we have a Manufacturing 
facility approved by the Stanford IRB that we have used for the phase 1 study for the same flours 
and powders listed in the IND 14831 (please see separate CMC and Investigational Brochures 
for each food/powder The facility is located in the same hospital in a double locked area to meet 
specifications for a GMP facility as per the FDA guidelines. 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u 
cm070273.pdf.) 
Stanford Food Allergy Center Manufacturing Facility 
2500 Grant Rd, 1st Floor, El Camino Hospital 
Mountain View, CA 94043 
Tel. 650-724-0293  
Email:knadeau@stanford.edu 
Monitoring: Our facility will be independently monitored per the Data Safety Monitoring Plan 
approved by the Stanford IRB for Stanford food allergy clinical trials. The same monitor as 
University of North Carolina Chapel Hill GMP facility will monitor the Stanford University 
Manufacturing facility. The monitor will use the same procedures to monitor as used at University 
of North Carolina. 
Shipment of Study Drug to participating Sites: After preparation of doses per the CMC and SOPs, 
each lot will have a Certificate of Analysis (see below) which will list the release criteria.  Batch 
records will document preparation of all doses for all subjects. The study drug will be put into 
individual soufflé cups, wrapped with paraffin, labelled and shipped to the designated pharmacy 
at the site. A chain of custody form will be completed at Stanford and upon receipt at the site 
pharmacy, the form will be faxed back to Stanford. Shipment will be with a courier that will 
have tracking systems in place to ensure quality shipment and compliance of study drug. 


CONFIDENTIAL, DO NOT COPY, PROPERTY OF STANFORD UNIVERSITY 
47 
CONFIDENTIAL – DO NOT DISTRIBUTE 
Certificate of Analysis Example: 
Protocol # 
IND 14831 
Lot Number 
(to be filled in for each lot) 
Product 
(to be filled in for each product) 
Date Processed 
(to be filled in) 
Microbiological 
- 
Test done at Deibel Laboratories, S. 
San Francisco, CA 
E. Coli 
Negative or positive 
Salmonella 
Negative or positive 
Total Mold Count 
---- cfu/g 
Total Yeast Count 
---- cfu/g 
Acceptable Results for E. Coli and 
Salmonella 
negative 
Acceptable Results for TAMC and TYMC 
< 140 cfu/g 
Analysis of Flour 
- testing done at the laboratory of Dr. Kari 
Nadeau, S303, Grant Building, 300 Pasteur 
Drive, Stanford, CA. 94305. 
Was the completion of Gel and Densitometry 
run? Date of Gel was run? 
Yes or No, Date 
% variation from Reference Standard 
(to be filled in) 
% variation from previous lot # 
(to be filled in) 
Previous Lot #: 
(to be filled in) 
Acceptable answer to: Was Gel and 
Densitometry Results completed ? 
Yes 
Acceptable Results for % variance 
<30% 


CONFIDENTIAL, DO NOT COPY, PROPERTY OF STANFORD UNIVERSITY 
48 
CONFIDENTIAL – DO NOT DISTRIBUTE 
Stanford Food Allergy Center Manufacturing Facility 
2500 Grant Rd, 1st Floor, El Camino Hospital 
Mountain View, CA 94043 
Tel. 650-724-0293 
knadeau@stanford.edu 
Appearance 
- testing done at GMP facility at Stanford 
Food Allergy Center 
Color 
(to be filled in) 
Odor 
(to be filled in) 
Acceptable Result for Color 
(to be filled in) 
Acceptable Result for Odor 
(to be filled in) 
Deviations: (to be filled in if appropriate) 
In line with the USP proposed criteria, the recorded mold count in this product is within the 
acceptable limits. Therefore, the product is being released as acceptable for use in this clinical 
trial. 
Reviewer Batch Record 
Signature: 
Date: 
Name: 
Title: 


CONFIDENTIAL – DO NOT DISTRIBUTE 
CONFIDENTIAL, DO NOT COPY, PROPERTY OF STANFORD UNIVERSITY 
49 
17.4 Appendix D: Schedule of Events 
Screening/
Baseline 
Omalizumab3 + OIT 
End of 
study/Early 
Discontinuation 
Week (+5 days) 
-36 
-8 
-4 
0 
4 through 16 
18 
Omalizumab 
Administration 
X 
X 
X 
Oral 
Immunotherapy 
X4 
X 
X5 
Medical History 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
Con Meds 
X 
X 
X 
X 
X 
X 
Food IgE/IgG4 
X 
X 
Mechanistic 
labs1 
X 
X 
Skin Testing8 
X 
X 
Spirometry- 
full/peak flow2 
X 
X 
X 
Epinephrine 
autoinjector 
Training 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Diary 
X 
X 
Urine 
Pregnancy Test 
X 
X 
1 Samples for translational research collected at screening and early discontinuation/end of study 
visit 
2 Full spirometry is preferred, however if subject is unable, peak flow may be performed instead. 
For those unable to perform peak flow, they will be examined by physical exam. 
3 Dosing for Omalizumab will be 150 mg via subcutaneous injection monthly for three doses for 
participants ≥4 years of age, and 75 mg via subcutaneous injection monthly for three doses for 
participants <4 years of age.   
4 If 5mg total is not tolerated at week 0, subject will be a desensitization failure. 
5 If subject has not tolerated 300mg or 1200 mg total of all allergens by week 16, subject 
may be updosed at week 18 to 300 mg or 1200 mg total. 
6 Baseline/Screening results may be obtained within no more than 9 month prior to week -8 
7 Repeat urine pregnancy test if visit is ≥7 days of Screening visit. 
8 Skin prick test at screening, if applicable per investigator’s discretion. 

SAP_001.pdf: 
 
 
 
Full Title: A Phase 2 Study of Multi Oral Immunotherapy in Multi Food Allergic 
Patients to Test Immune Markers after Minimum Maintenance Dose  
Short Title: Multi Immunotherapy to test Minimum dose using Xolair (MIMiX) 
 
 
Statistical Analysis Plan 
NCT03181009 
 July 23, 2019 


NCT03181009
 Version 1.0
Statistical Analysis Plan 
MIMIX 
Collaborator(s): Tina Sindher, Sharon Chinthrajah, Divya Kumar, Andres Alvarez Pinzon, Kari Nadeau 
Statistician(s): Natasha Purington 
Objective: To determine if the combination of omalizumab and multi OIT will increase the 
IgG4:IgE ratio of at least 2 allergens by ≥ 25% at week 18 from baseline in multi food allergic 
patients. 
Study Design: This phase 2 multisite study was conducted at two centers in the U.S. All 
participants received oral immunotherapy for their specific food allergies. Further, all participants 
received three doses of Omalizumab over 8 weeks. The subject’s allergens were introduced on 
desensitization Day 1 of week 0, after receiving the third omalizumab dose. Participants 
returned to clinic to escalate the dose of their allergens until 300 mg (group A) or 1200 mg 
(group B) total protein daily dose was reached. Subjects were randomized 1:1 to either group A 
or group B after meeting eligibility criteria. 
Primary endpoint: Indicator for whether or not a participant had an IgG4:IgE increase of at least 
25% for at least 2 allergens from baseline to week 18. 
Exposure: Treatment group – 300 mg (group A) vs 1200 mg (group B) 
Methods: 
Baseline characteristics will be summarized overall and by treatment group using medians and 
ranges, and counts and percentages. Categorical and continuous variables will be tested across 
treatment arms using Fisher’s exact test and the Wilcoxon rank sum test, respectively. 
To evaluate the primary endpoint of the overall proportion of participants who had an IgG4:IgE 
increase of at least 25% for at least 2 allergens from baseline to week 18, a one-sided exact 
binomial test will be used, with a null hypothesis that the probability of success (i.e. meeting the 
primary endpoint) is no better than chance (i.e. H0: p = 0.50 vs H1: p > 0.50). The probability of 
success and 95% confidence interval will be reported. Fisher’s exact test will be used to 
determine whether the probability of success differs by treatment group. The odds ratio of group 
A vs group B and 95% confidence interval will be reported. Similar methods will be used to 
evaluate secondary endpoints of a ratio increase of at least 25% for 3, 4, and 5 allergens.  
The continuous change in the IgG4:IgE ratio from baseline for each allergen will also be reported 
descriptively overall and by treatment group. 
Logistic regression models will be used to determine whether any baseline characteristics 
predict success of the primary endpoint, adjusting for treatment arm.  
The proportion of doses in which an adverse event occurred will be summarized by treatment 
arm. To determine whether adverse event rates are different by treatment group and across 
home doses, a mixed effect Poisson regression model will be fit to the number of AEs as a 


Version 1.0  
function of group and home dose amount, with an offset for log(number of home doses) and a 
random subject effect. 
A Cox proportional hazards model will be used to determine whether time-to-OIT-maintenance 
differed between groups A and B. Participants who do not reach maintenance will be censored 
at their end of study visit. The p-value from the log-rank test will be reported.