Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either Omalizumab or an Inhaled Corticosteroid boost to prevent fall asthma exacerbations. J. Allergy Clin Imm. 2015; 136: 1476-85.
Asthma affects about 5% of children worldwide, with upwards of 13% of children in the United States acquiring a diagnosis of asthma in their lifetime. Despite continued efforts towards symptom control and avoidance of triggers, exacerbations are a large contributor to childhood morbidity and mortality. Stepwise treatment (6 total steps) recommended by the National Heart, Lung, and Blood Institute is initially based on asthma severity and progresses systematically based on asthma control. Exacerbations, though they can occur anytime, are more likely to occur in the fall in the US, particularly in children with recent exacerbations and more severe disease. Consequences of exacerbations include higher health care costs, school absenteeism, and possible disease progression. The significant burdens asthma exacerbations place on patients and society has stimulated the evaluation of prophylactic augmentation of guideline-based care prior to the start of the school year to prevent asthma exacerbations in children.
The “Preventive Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE)” randomized controlled trial compared omalizumab to placebo or inhaled corticosteroid (ICS) boost administered 4-6 weeks before the start of school in 513 US urban children aged 6-17 years. Racial characteristics were reported as 58.4% African-American, 33.7% Hispanic, and 7.9% white, mixed or other. All had persistent asthma with 1 or more exacerbations, and were randomized to receive 1 of 3 treatments: omalizumab 75-375 mg subcutaneously (dosed every 2 or 4 weeks based on weight, dosing frequency, and baseline IgE level) plus inhaled placebo twice daily; placebo injection plus boost inhaled corticosteroid (ICS) (fluticasone 100 mcg or 250 mcg) twice daily; or placebo injection plus inhaled placebo. Total daily dose of ICS did not exceed 1,000 mcg of fluticasone because this has shown no additional benefit and increased side effects. Children at treatment Step 5 were excluded from the ICS boost group.
All participants had four visits during a 4-6 month run-in phase to ensure adequate control followed by randomization to either control or treatment group. Children receiving asthma treatment at steps 1 (intermittent short-acting beta agonist alone) and step 6 (oral corticosteroids) were excluded. The primary outcome was an asthma exacerbation requiring systemic corticosteroids or hospitalization in the first 90 days of the school year. At randomization, 62% of participants were in steps 2-4 of treatment (low dose ICS, medium dose ICS, and medium dose ICS plus long-acting beta-agonist or montelukast, respectively) and 38% were at treatment step 5 (high dose ICS and long-acting beta agonist or montelukast). Thirty-five percent of children had at least 1 asthma exacerbation during the run-in phase. Results were analyzed using a modified intention-to-treat method.
The overall rate of exacerbation at 90 days was significantly lower in the omalizumab group compared to placebo, 11.3% vs 21% (odds ratio [OR] 0.48, 95% CI 0.25-0.92, NNT 11). The effect can be primarily attributed to the severe asthma group (treatment step 5), whose rates of exacerbation in the omalizumab group were 15.1% compared to 32.6% in the placebo group (OR 0.37; CI 0.17-0.81, NNT 6). There was no significant difference comparing omalizumab and ICS boost when evaluating asthma exacerbations in children at treatment steps 2-4. Omalizumab also demonstrated a significant reduction in asthma exacerbations in children who had at least one exacerbation in the run-in phase compared to both ICS (OR 0.05, 95% CI 0.002-0.98, NNT 4) and placebo (OR 0.12, 95% CI 0.02-0.64, NNT 4). There was no difference in adverse effects between treatment groups, although the overall rates were more than 50% for both groups. Serious adverse events during the intervention period were rare and included a case of seventh nerve palsy in the placebo group and a case of anaphylaxis in the ICS boost group.
The PROSE study demonstrated that omalizumab may reduce asthma exacerbations in urban children in the US with severe asthma during the time of year when rates of asthma exacerbations are highest. The modified intention to treat analysis resulted in 7% of patients being excluded which limited the validity of the results. Despite a narrow patient population and a short outcome phase of only 90 days after the start of school, these data point to a possible targeted benefit of omalizumab in children with severe asthma in whom the ICS dose is already maximized. However, for the majority of children with less severe asthma (treatment stages 2-4), the possible adverse effects of omalizumab or ICS boost may do more harm than good.
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