A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy

Robert A Wood, Jennifer S Kim, Robert Lindblad, Kari Nadeau, Alice K Henning, Peter Dawson, Marshall Plaut, Hugh A Sampson, Robert A Wood, Jennifer S Kim, Robert Lindblad, Kari Nadeau, Alice K Henning, Peter Dawson, Marshall Plaut, Hugh A Sampson

Abstract

Background: Although studies of oral immunotherapy (OIT) for food allergy have shown promise, treatment is frequently complicated by adverse reactions and, even when successful, has limited long-term efficacy because benefits usually diminish when treatment is discontinued.

Objective: We sought to examine whether the addition of omalizumab to milk OIT reduces treatment-related reactions, improves outcomes, or both.

Methods: This was a double-blind, placebo-controlled trial with subjects randomized to omalizumab or placebo. Open-label milk OIT was initiated after 4 months of omalizumab/placebo with escalation to maintenance over 22 to 40 weeks, followed by daily maintenance dosing through month 28. At month 28, omalizumab was discontinued, and subjects passing an oral food challenge (OFC) continued OIT for 8 weeks, after which OIT was discontinued with rechallenge at month 32 to assess sustained unresponsiveness (SU).

Results: Fifty-seven subjects (7-32 years) were randomized, with no significant baseline differences in age, milk-specific IgE levels, skin test results, or OFC results. At month 28, 24 (88.9%) omalizumab-treated subjects and 20 (71.4%) placebo-treated subjects passed the 10-g "desensitization" OFC (P = .18). At month 32, SU was demonstrated in 48.1% in the omalizumab group and 35.7% in the placebo group (P = .42). Adverse reactions were markedly reduced during OIT escalation in omalizumab-treated subjects for percentages of doses per subject provoking symptoms (2.1% vs 16.1%, P = .0005), dose-related reactions requiring treatment (0.0% vs 3.8%, P = .0008), and doses required to achieve maintenance (198 vs 225, P = .008).

Conclusions: In this first randomized, double-blind, placebo-controlled trial of omalizumab in combination with food OIT, we found significant improvements in measurements of safety but not in outcomes of efficacy (desensitization and SU).

Trial registration: ClinicalTrials.gov NCT01157117.

Keywords: Milk allergy; desensitization; dose-related adverse reactions; double-blind; omalizumab; oral immunotherapy; placebo-controlled trial; sustained unresponsiveness.

Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Consort Diagram
Figure 1. Consort Diagram
On the first day, dosing was initiated with 0.07mg of milk protein. Subjects were required to tolerate dose #6 (2.1mg) at dosing visit 1 and dose #8 (9mg) by visit 2. Daily home dosing was continued and subjects returned every 2 weeks for dose escalation for a minimum of 22 and a maximum of 40 weeks. Subjects were required to reach a minimum maintenance dose of 520mg milk protein (equivalent to 15mL of liquid milk).
Figure 2
Figure 2
Figures 2a – 2d: Figures 2a&b: Casein and Beta-lactoglobulin IgG4 Levels: Casein and beta-lactoglobulin specific IgG4 levels were measured at baseline and months 4, 16, 22, 28, 30, and 32. Median values are represented by the blue stars. Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001), with no differences seen between the two groups. Figures 2c&d: Casein and Beta-lactoglobulin IgG4/IgE Ratio: The ratio of casein- and β-lactoglobulin IgG4/IgE was calculated after IgG4 levels were converted from mgA/L to ng/mL and IgE level was converted from kUA/L to ng/mL with the formula (IgG4 × 1000) ÷ (IgE × 2.4). Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001). The only significant difference between treatment groups was observed at month 4 with omalizumab subjects exhibiting decreased casein and beta-lactoglobulin IgG4/IgE ratio compared to placebo subjects.
Figure 2
Figure 2
Figures 2a – 2d: Figures 2a&b: Casein and Beta-lactoglobulin IgG4 Levels: Casein and beta-lactoglobulin specific IgG4 levels were measured at baseline and months 4, 16, 22, 28, 30, and 32. Median values are represented by the blue stars. Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001), with no differences seen between the two groups. Figures 2c&d: Casein and Beta-lactoglobulin IgG4/IgE Ratio: The ratio of casein- and β-lactoglobulin IgG4/IgE was calculated after IgG4 levels were converted from mgA/L to ng/mL and IgE level was converted from kUA/L to ng/mL with the formula (IgG4 × 1000) ÷ (IgE × 2.4). Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001). The only significant difference between treatment groups was observed at month 4 with omalizumab subjects exhibiting decreased casein and beta-lactoglobulin IgG4/IgE ratio compared to placebo subjects.
Figure 2
Figure 2
Figures 2a – 2d: Figures 2a&b: Casein and Beta-lactoglobulin IgG4 Levels: Casein and beta-lactoglobulin specific IgG4 levels were measured at baseline and months 4, 16, 22, 28, 30, and 32. Median values are represented by the blue stars. Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001), with no differences seen between the two groups. Figures 2c&d: Casein and Beta-lactoglobulin IgG4/IgE Ratio: The ratio of casein- and β-lactoglobulin IgG4/IgE was calculated after IgG4 levels were converted from mgA/L to ng/mL and IgE level was converted from kUA/L to ng/mL with the formula (IgG4 × 1000) ÷ (IgE × 2.4). Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001). The only significant difference between treatment groups was observed at month 4 with omalizumab subjects exhibiting decreased casein and beta-lactoglobulin IgG4/IgE ratio compared to placebo subjects.
Figure 2
Figure 2
Figures 2a – 2d: Figures 2a&b: Casein and Beta-lactoglobulin IgG4 Levels: Casein and beta-lactoglobulin specific IgG4 levels were measured at baseline and months 4, 16, 22, 28, 30, and 32. Median values are represented by the blue stars. Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001), with no differences seen between the two groups. Figures 2c&d: Casein and Beta-lactoglobulin IgG4/IgE Ratio: The ratio of casein- and β-lactoglobulin IgG4/IgE was calculated after IgG4 levels were converted from mgA/L to ng/mL and IgE level was converted from kUA/L to ng/mL with the formula (IgG4 × 1000) ÷ (IgE × 2.4). Significant increases from baseline were detected within both treatment groups from month 16 onward (all P<0.0001). The only significant difference between treatment groups was observed at month 4 with omalizumab subjects exhibiting decreased casein and beta-lactoglobulin IgG4/IgE ratio compared to placebo subjects.

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