Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Participants

This study is a multi-center, randomized, double-blind, placebo-controlled study in participants 1 to less than 56 years of age who are allergic to peanut and at least two other foods (including milk, egg, wheat, cashew, hazelnut, or walnut). While each participant may be allergic to more than two other foods, the primary endpoint/outcome in this study will only be assessed in peanut and two other foods for each participant. The primary objective of the study is to compare the ability to consume foods without dose-limiting symptoms during a double-blind placebo-controlled food challenge (DBPCFC), after treatment with either omalizumab or placebo for omalizumab.

Food allergy affects about 15 million people in the United States. This includes 6 million children. The current treatment for food allergy is to avoid eating the foods that may cause an allergic reaction and have medications such as epinephrine (adrenaline) in case of a reaction. However, accidental exposures can be extremely difficult to avoid, particularly if you are allergic to multiple foods. The risks of accidental exposures and life-threatening reactions can place a large burden on patients and their families.

Investigators in this study would like to learn if omalizumab injections alone or in combination with multi-allergen oral immunotherapy (OIT) will help people with multiple food allergies eat foods to which they are allergic. Oral means that you will take the food allergen (peanut and 2 other foods to which you are allergic) by mouth. If you are allergic to more than 3 foods, this study will only provide OIT for peanut and 2 other foods.

There are 3 stages to the study:

In Stage 1, investigators would like to learn:

• If omalizumab stops or decreases allergic reactions to peanut and other common food allergens after taking it for a length of time.

Stage 1 will also have an extra part so that 60 participants will receive omalizumab and everyone (the investigators conducting the research and study participants) will know it. This is why it is called the open label extension. This part of the study will assist investigators in learning if receiving omalizumab for a longer time may work better at decreasing allergic reactions.

In Stage 2, investigators would like to learn:

• How a short course of omalizumab combined with Multi-allergen OIT compares with a longer course of omalizumab in decreasing allergic reactions.

In Stage 3, investigators would like to learn:

• If, after participants stop both treatments, will they be able to eat the peanut and the 2 other foods in the form that is normally eaten.

In all stages, investigators would like to learn:

* How safe and effective the treatments are and
* How the OIT affects the immune system.

Participation will last up to 56 months (4 years and 8 months).

Eligibility Criteria:
Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as study participants:

1. Participant and/or parent/legal guardian must be able to understand and provide informed consent and/or assent, as applicable;
2. Peanut allergic: participant must meet all of the following criteria to minimize the chance that the participant will develop natural tolerance to peanut over the course of the study:

   1. Positive skin prick test (SPT) defined as ≥4 mm wheal greater than saline control) to peanut,
   2. Positive peanut immunoglobulin E (IgE), ≥6 kUA/L, at Screening or within three months of Screening, determined by ImmunoCap, and
   3. Positive double-blind placebo-controlled food challenge (DBPCFC), defined as experiencing dose-limiting symptoms at a single dose of ≤100 mg of peanut protein.
3. Allergic to at least two of the six other foods (milk, egg, wheat, cashew, hazelnut, walnut): each participant must meet all of the following criteria for at least two of the six other foods to minimize the chance that the participant will develop natural tolerance to at least two of the six other foods over the course of the study:

   1. Positive SPT (≥4 mm wheal) to food,
   2. Positive food specific IgE (≥6 kUA/L) at Screening or within three months of Screening, determined by ImmunoCap, and
   3. Positive DBPCFC, defined as experiencing dose-limiting symptoms at a single dose of ≤300 mg of food protein.
4. With body weight (as measured at Screening) and total serum IgE level (as measured within three months of Screening) suitable for omalizumab dosing;
5. If female of child-bearing potential, must have a negative urine or serum pregnancy test;
6. For women of childbearing potential, must agree to,during the treatment period and for 60 days after the last dose of study drug:

   * remain abstinent (refrain from heterosexual intercourse), or
   * use acceptable contraceptive methods (barrier methods, or
   * oral, injected, or implanted hormonal methods of contraception, or
   * other forms of hormonal contraception that have comparable efficacy).
7. Plan to remain in the study area of an OUtMATCH clinical research unit (CRU) during the trial; and
8. Be willing to be trained on the proper use of an epinephrine autoinjector for the duration of the study.

Exclusion Criteria:

Individuals who meet any of the following criteria are not eligible for enrollment as study participants:

1. Inability or unwillingness of a participant and/or parent/legal guardian to give written informed consent and/or assent or comply with the study protocol;
2. Clinically significant laboratory abnormalities at Screening;
3. Dose-limiting symptoms to the placebo portion of the Screening DBPCFC;
4. Sensitivity or suspected/known allergy to any ingredients (including excipients) of the

   * active or placebo oral food challenge (OFC) material,
   * multi-allergen oral immunotherapy (OIT), or
   * drugs related to omalizumab (e.g., monoclonal antibodies, polyclonal gamma globulin).

     * Note: Guidance for determination of sensitivity to excipients will be detailed in the study's Manual of Procedures (MOP).
5. Poorly controlled atopic dermatitis (AD) at Screening, per the Principal Investigator's PI's) discretion;
6. Poorly controlled or severe asthma/wheezing at Screening, defined by at least one of the following criteria:

   1. Global Initiative for Asthma (GINA) criteria regarding asthma control latest guidelines,
   2. History of two or more systemic corticosteroid courses within six months of Screening or one course of systemic corticosteroids within three months of Screening to treat asthma/wheezing,
   3. Prior intubation/mechanical ventilation for asthma/wheezing,
   4. One hospitalization or Emergency Department (ED) visit for asthma/wheezing within six months of Screening,
   5. Forced expiratory volume in one second (FEV1) \<80 percent of predicted or FEV1/forced vital capacity (FVC) \<75 percent, with or without controller medications (only for participants who are aged seven years or older and are able to perform spirometry), or
   6. Inhaled corticosteroid (ICS) dosing of \>500 mcg daily fluticasone (or equivalent ICS based on the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) dosing chart).
7. History of severe anaphylaxis to participant-specific foods that will be used in this study, defined as neurological compromise or requiring intubation;
8. Treatment with a burst of oral, intramuscular (IM), or intravenous (IV) steroids of more than two days for an indication other than asthma/wheezing within 30 days of Screening;
9. Currently receiving oral, intramuscular, or intravenous corticosteroids, tricyclic antidepressants, or beta-blockers (oral or topical);
10. Past or current history of eosinophilic gastrointestinal (GI) disease within three years of Screening;
11. Past or current history of cancer, or currently being investigated for possible cancer;
12. Previous adverse reaction to omalizumab;
13. Past or current history of any immunotherapy to any of the foods being treated in this study (e.g., OIT, sublingual immunotherapy \[SLIT\], EPIT) within 6 months of Screening;
14. Treatment with monoclonal antibody therapy, such as omalizumab (Xolair®), dupilumab (Dupixent®), benralizumab (Fasenra™), mepolizumab (Nucala®), reslizumab (Cinqair®), or other immunomodulatory therapy within six months of Screening;
15. Currently on "build-up phase" of inhalant allergen immunotherapy (i.e., has not reached maintenance dosing). Note: Individuals tolerating maintenance allergen immunotherapy can be enrolled;
16. Inability to discontinue antihistamines for the minimum wash-out periods required for SPTs,or OFCs;
17. Current participation in another therapeutic or interventional clinical trial or participation within 90 days of Screening;
18. Use of investigational drugs within 24 weeks of Screening;
19. Pregnant or breastfeeding, or intending to become pregnant during the study or within 60 days after the last dose of omalizumab or placebo for omalizumab;
20. Has a first-degree relative already enrolled in the study; or
21. Past or current medical problems (e.g., severe latex allergy), history of other chronic diseases (other than asthma/wheezing, AD, or rhinitis) requiring therapy (e.g., heart disease, diabetes), findings from physical assessment, or abnormalities in clinical laboratory testing that are not listed above, which, in the opinion of the PI, may:

    * pose additional risks from participation in the study,
    * may interfere with the participant's ability to comply with study requirements, or
    * may impact the quality or interpretation of the data obtained from the study.