OIT and Xolair® (Omalizumab) in Cow's Milk Allergy

Study Overview
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Brief Summary
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Food allergy affects up to 4% of the U.S. population and is most common in young children. Milk allergy is the most common cause of food allergy in infants and young children, and usually develops in the first year of life. There is no treatment for food allergy and the current standard of care for milk-allergic individuals is the avoidance of milk-containing products. Research is underway to identify potential therapeutic strategies to reduce or eliminate the adverse effects experienced by milk-allergic individuals when they consume milk-containing products. Several studies have suggested that milk-allergic children who receive milk protein oral immunotherapy (OIT) may become desensitized to milk, resulting in short term protection against accidental ingestion of milk products. However, these children did not develop tolerance, which is long term protection even after milk immunotherapy is stopped. A potential strategy to induce tolerance to milk uses milk in combination with Xolair® (omalizumab). Xolair consists of anti-IgE molecules that attach to IgE, the major antibody involved in allergic reactions. The goal of this clinical trial is to see whether Xolair® in combination with milk protein OIT is safer and more effective than OIT alone in inducing tolerance to milk and milk products. Participants will be administered a double blind, placebo controlled milk challenge at various time points in the study. If desensitization is achieved participants will be tested for tolerance at a certain time point after stopping treatment.

Official Title
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Oral Immunotherapy Combined With Humanized Monoclonal Anti-IgE Antibody Xolair® (Omalizumab)in the Treatment of Cow's Milk Allergy

Conditions
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Milk Allergy

Intervention / Treatment
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* Biological: Placebo for omalizumab
* Biological: Omalizumab
* Drug: Milk powder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject and/or parent/ legal guardian must be able to understand and provide written informed consent Written or verbal assent from all study subjects less than 18 years (per site Institutional Review Board (IRB) regulations) 7 to 35 years of age; any gender; any racial and ethnic origin No known contraindications to therapy using oral immunotherapy with milk protein or Xolair® (omalizumab) All female subjects of childbearing potential must have a negative pregnancy test upon study entry All treated females of childbearing potential must agree to use FDA approved methods of birth control for the duration of the study Active Treatment Subjects: Cow's milk allergy confirmed by a positive double-blind placebo controlled milk challenge (DBPCMC) to a dose of less than 2 g of milk protein within the past 6 months A skin prick test positive to milk (diameter of wheal >= 3.0 mm) OR detectable serum milk specific Immunoglobulin E (IgE) level within the previous 12 months (UniCAP > = 0.35 kUA/L (allergen-equivalent kilounits per liter)) Control Subjects: • A skin prick test positive to milk (diameter of wheal >= 10.0 mm) OR detectable serum milk specific IgE level within the previous 12 months (UniCAP >= 15 kUA/L) Exclusion Criteria: A history of life-threatening anaphylaxis to milk (involving hypotension or requiring mechanical ventilation) Known allergy to any components of the placebo for Xolair® Chronic disease other than asthma, atopic dermatitis, or allergic rhinitis requiring therapy (e.g., heart disease, diabetes) Use of β-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB), or calcium channel blockers Severe asthma Mild or moderate asthma with any of the following criteria met: Forced expiratory volume in the first second (FEV1) < 80% with or without controller medications Inhaled corticosteroids (ICS) dosing of >500 mcg daily fluticasone (or equivalent inhaled corticosteroids based on NHLBI dosing chart) history of daily oral steroid dosing for >1 month during the past year burst oral steroid course in the past 6 months more than one burst oral steroid course in the past year more than one hospitalization in the past year for asthma, or more than one ER visit in the past 6 months for asthma Baseline spirometry (or peak flow rate (PFR) if unable to perform spirometry) result of FEV1<80% Pregnancy or lactation. All females of child-bearing age will undergo pregnancy testing. All treated females will confirm compliance to appropriate birth control measures throughout the course of the study; Participation in any interventional study for the treatment of food allergy in the past 6 months Subject is on a buildup phase of standard subcutaneous immunotherapy for inhalant allergens (may be enrolled on maintenance dose); Use of Xolair® (omalizumab) or other non-traditional forms of allergen immunotherapy (e.g., oral or sublingual immunotherapy) or immunomodulator therapy (not including corticosteroids) or biologic therapy within the past year Inability to discontinue antihistamines for 5 half-lives prior to routine study tests (DBPCMC or endpoint titration tests) Known sensitivity to Xolair® (omalizumab) or to the class of study drugs Baseline serum total IgE over 1,300 IU/mL or body weight more than 150 kg, or subjects with weight-IgE combination that yields a dose requirement greater than 750 mg (due to limitations of Xolair® (omalizumab) dosing) Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements Inability or unwillingness of a subject to give written informed consent or comply with study protocol Use of investigational drugs within 90 days of participation Other contraindications to milk oral immunotherapy or Xolair® (omalizumab) Recipient of any licensed or investigational live attenuated vaccine(s) within 2 months of enrollment Families who do not speak English Systemic steroids oral, intramuscular (IM), or IV for indications other than asthma for greater than 3 weeks in the past 6 months

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omalizumab/milk OIT<br>Participants receive blinded omalizumab injections every 2 to 4 weeks through Month 16 and unblinded omalizumab injections thereafter until the Month 28 desensitization oral food challenge (OFC). Participants ingest milk powder daily starting at Month 4 with a dose of 0.07 mg milk protein and escalate for 22 to 40 weeks until reaching the maintenance dose of 3.84 g milk protein (minimum required maintenance dose is 520 mg milk protein). At Month 28, participants complete a 10g milk OFC and discontinue omalizumab injections. If they fail the OFC they permanently discontinue ingestion of the milk powder; if they pass the OFC they continue ingestion of the maintenance dose of milk powder through Month 30 and then discontinue it. | Biological: Omalizumab<br>* Omalizumab is injected subcutaneously every 2-4 weeks for 28 months at a dose determined by the participants IgE level and weight.<br>* Other names: Xolair;Drug: Milk powder<br>* Milk powder is ingested orally at a dosage of up to 3.84 grams of of milk protein daily from Month 4 through Month 28 if the Month 28 10 g milk OFC is failed, and through Month 30 if the Month 28 10 g milk OFC is passed.<br>|
| Placebo Comparator: Placebo for omalizumab/milk OIT<br>Participants receive blinded placebo for omalizumab injections every 2 to 4 weeks through Month 16; after unblinding the injections are discontinued. Participants ingest milk powder daily starting at Month 4 with a dose of 0.07 mg milk protein and escalate for 22 to 40 weeks until reaching the maintenance dose of 3.84 g milk protein (minimum required maintenance dose is 520 mg milk protein). At Month 28, participants complete a 10g milk oral food challenge (OFC); if they fail the OFC they permanently discontinue ingestion of the milk powder; if they pass the OFC they continue ingestion of the maintenance dose of milk powder through Month 30 and then discontinue it. | Biological: Placebo for omalizumab<br>* Placebo for omalizumab is injected subcutaneously every 2-4 weeks for 16 months at a volume designed to match that of the verum treatment group (determined by the participant's IgE level and weight).<br>* Other names: Placebo for Xolair;Drug: Milk powder<br>* Milk powder is ingested orally at a dosage of up to 3.84 grams of of milk protein daily from Month 4 through Month 28 if the Month 28 10 g milk OFC is failed, and through Month 30 if the Month 28 10 g milk OFC is passed.<br>|
| No Intervention: Untreated control<br>Participants did not receive any study intervention but provided regular blood draws at specific study time points to allow mechanistic comparisons with the participants in the other two groups who did receive study intervention. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects in the Xolair® (Omalizumab) Group vs. Placebo Group Developing Clinical Tolerance to Milk | Tolerance Assessment: Participants who successfully consumed without dose-limiting symptoms 10,000 mg of milk protein during a double-blind placebo-controlled oral food challenge were then given an open feeding of milk and those who successfully consumed the open feeding were counted as successes. | Month 32 which is 8 weeks following the discontinuation of milk OIT for both groups and 4 months after discontinuation of omalizumab for the omalizumab group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dosing Reactions to Milk OIT During the Escalation Phase | Any reaction to daily milk OIT dosing recorded by the participant during the Escalation Phase. | Baseline to completion of Escalation Phase at 22 to 40 weeks | 
| Incidence of Dosing Reactions to Milk OIT During the Maintenance Phase | Any reaction to daily milk OIT dosing recorded by the participant during the Maintenance Phase. | After completion of Escalation Phase at 22 to 40 weeks, the Maintenance Phase lasted up to Month 30 | 
| Incidence of Severe Hypersensitivity Reactions to Milk OIT | Participants who had a change in mental status or hypotension as a milk OIT dosing symptom were counted as having a severe hypersensitivity reaction. | Through completion of milk OIT dosing (at Month 28 if failed desensitization OFC, at Month 30 if passed desensitization OFC) | 
| Maximum Tolerated Dose of Milk Oral Immunotherapy (OIT) | Maximum tolerated dose of milk OIT is the highest dose of milk powder the participant was able to consume for at least 14 consecutive days. | Baseline to completion of Escalation Phase at 22 to 40 weeks | 
| Percentage of Participants in the Xolair® (Omalizumab) Group vs. Placebo Group Developing Desensitization to Milk | Desensitization Assessment: Participants who successfully consumed without dose-limiting symptoms 10,000 mg of milk protein during a double-blind placebo-controlled oral food challenge were counted as successes. | Month 28 | 
| Time to Maximum Tolerated Dose | Time to reach the maximum tolerated dose (MTD) of milk oral immunotherapy (OIT); MTD is the highest dose of milk powder the participant was able to consume for at least 14 consecutive days. | Baseline to completion of Escalation Phase at 22 to 40 weeks | 
| Change From Baseline to Month 32 in Area Under the Curve for Milk Endpoint Titration Prick Skin Test | A milk endpoint titration is a prick skin test using 5 serial 10-fold dilutions of milk which include 1:20 wt/vol, 1:200 wt/vol, 1:2,000 wt/vol, 1:20,000 wt/vol and 1:200,000 wt/vol. The score for each of these dilutions is calculated by subtracting the diameter of the saline control wheal from the diameter of the milk wheal (in millimeters). The area under the curve is calculated by adding together the scores from all 5 milk dilutions creating a composite score. | Month 32 | 
| Change From Baseline to Month 32 in Antigen-specific Immunoglobulin E (IgE) | The level of milk IgE in plasma as well as the IgE levels of 2 milk proteins, casein and beta-lactoglobulin, were measured. The value for each participant was subtracted from the value for that participant at baseline. Month 32 was the last visit on treatment. | Month 32 | 
| Change From Baseline to Month 32 in Antigen-specific Immunoglobulin G4 (IgG4) | Casein and beta-lactoglobulin milk proteins IgG4 levels were measured in plasma. The value for each participant was subtracted from the value for that participant at baseline. Month 32 was the last visit on treatment. | Month 32 | 
| Change From Baseline to Month 38 in Antigen-specific Immunoglobulin E (IgE) | The level of milk IgE in plasma as well as the IgE levels of 2 milk proteins, casein and beta-lactoglobulin, were measured. The value for each participant was subtracted from the value for that participant at baseline. Month 38 was 6 months after treatment ended at Month 32. | Month 38 | 
| Change From Baseline to Month 38 in Antigen-specific Immunoglobulin G4 (IgG4) | Casein and beta-lactoglobulin milk proteins IgG4 levels were measured in plasma. The value for each participant was subtracted from the value for that participant at baseline. Month 38 was 6 months after treatment ended at Month 32. | Month 38 | 
| Change in Percent of Cells Positive for Cluster of Differentiation 63 (CD63) at Month 32 in Basophils Stimulated by Milk | Basophil cells isolated from blood using flow cytometry were stimulated with 5 different levels of milk and the percent of basophil cells that were CD63 positive was measured. The value for each participant obtained at Month 32 was subtracted from the value for that participant at baseline. The 5 different levels of milk stimulant were: 10 µg/mL, 1 µg/mL , 0.1 µg/mL , 0.01 µg/mL , and 0.001 µg/mL. Month 32 was the last visit on treatment. | Month 32 | 
| Change in Percent of Cells Positive for Cluster of Differentiation 63 (CD63) at Month 38 in Basophils Stimulated by Milk | Basophil cells isolated from blood using flow cytometry were stimulated with 5 different levels of milk and the percent of basophil cells that were CD63 positive was measured. The value for each participant obtained at Month 38 was subtracted from the value for that participant at baseline. The 5 different levels of milk stimulant were: 10 µg/mL, 1 µg/mL , 0.1 µg/mL , 0.01 µg/mL , and 0.001 µg/mL. Month 38 was 6 months after treatment ended at Month 32. | Month 38 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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food allergy