Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations

Abstract

Background: Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure.

Objective: We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school.

Methods: A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations (clincaltrials.gov #NCT01430403). Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined.

Results: Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; 95% CI, 0.25-0.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33-1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02-0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002-0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88). Adverse events were rare and similar among arms.

Conclusions: Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.

Keywords: Asthma; IFN-α; asthma exacerbations; fall season; inhaled corticosteroid; omalizumab; rhinovirus.

FIG 1

CONSORT diagram.

FIG 2

Proportion of participants by treatment arm with at least 1 exacerbation (bar) plus 1 SE (whisker) during the fall outcome period in the placebo and omalizumab arms randomized at steps 2 to 5 (A), in the placebo and omalizumab arms randomized at step 5 (B), and in the placebo, omalizumab, and ICS arms randomized at steps 2 to 4 (C). Values at the top of each panel are ORs (95% CIs). All values are adjusted for site, dosing group, and treatment step. H1, Primary hypothesis 1; H2, primary hypothesis 2.

FIG 3

Proportion of participants by treatment arm with at least 1 exacerbation (bar) plus 1 SE (whisker) during the fall outcome period stratified by exacerbation status during the run-in phase among participants in the placebo and omalizumab arms randomized at steps 2 to 5 (A), in the placebo and omalizumab arms randomized at step 5 (B), and in the placebo, omalizumab, and ICS arms randomized at steps 2 to 4 (C). Values at the top of each panel are ORs (95% CIs). All values are adjusted for site, dosing group, and treatment step. H1, Primary hypothesis 1; H2, primary hypothesis 2. For H1 and H2, there was a significant interaction between subgroups (P < .05).

FIG 4

Enhanced ex vivo IFN-α responses to rhinovirus (RV) in the omalizumab group and relationship to exacerbation rates. PBMCs were incubated ex vivo with rhinovirus in the presence or absence of an IgE cross-linking antibody, and IFN-α levels were measured in culture supernatants. Rhinovirus-induced IFN-α was significantly reduced by IgE cross-linking; the IFN-α response was significantly increased in the omalizumab group during the intervention phase of the study. A, A 3.22-fold increase in omalizumab versus placebo in the postrandomization phase (P = .03). B, Among participants treated with omalizumab, those with the greatest increase in ex vivo IFN-α responses in the presence of IgE cross-linking were less likely to have an asthma exacerbation during the outcome period. Values at the top of each panel are ORs (95% CIs).