Adding the drug omalizumab to ongoing guidelines-based asthma therapy for a targeted four-month period beginning just before the start of school reduced the number of autumn asthma attacks, or exacerbations, in inner-city children, according to results from a clinical trial sponsored by the National Institutes of Health (NIH). Asthma exacerbations—worsenings of asthma symptoms—disrupt quality of life and may contribute to chronic lung disease.
The study findings, reported online on Oct. 27 in the Journal of Allergy and Clinical Immunology, also show that short-term treatment with omalizumab was most effective at preventing additional exacerbations in children who had experienced an exacerbation earlier that year.
The trial was conducted by the Inner-City Asthma Consortium (ICAC), an asthma research program supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. Asthma is a leading cause of childhood hospitalizations and missed school days in the United States, and disease severity is disproportionately high among children living in inner-city communities.
Asthma exacerbations typically spike in the fall, with several factors contributing to this seasonal trend, including infections with cold-causing viruses and exposure to respiratory allergens. A previous ICAC study found that adding year-round treatment with omalizumab (brand name Xolair) to guidelines-based asthma care decreased seasonal exacerbations, with the most striking effects observed during the fall. Based on these results, ICAC investigators sought to determine whether short-term treatment with omalizumab during the late summer and fall would have a similar effect. The drug currently is approved in the United States for patients ages 12 and older with moderate-to-severe persistent allergic asthma.
“Although treatment based on NIH guidelines is generally effective for asthma management, many children still experience seasonal exacerbations requiring treatment with oral steroids or even hospitalization,” said NIAID Director Anthony S. Fauci, M.D. “The results of this study show that a short-term, targeted treatment initiated shortly before the greatest risk for asthma exacerbations can potentially prevent these events, improving children’s health.”
In the current study, researchers enrolled children 6 to 17 years of age with asthma in eight U.S. cities prior to the fall seasons of 2012 and 2013. All of the children first received four to nine months of guidelines-based care to achieve asthma control. Guidelines-based care focuses on measures to assess and monitor asthma, patient education, medications and control of environmental factors and other conditions that can worsen asthma.
Participants with the most difficult-to-control asthma were then randomly assigned to receive omalizumab or placebo. Participants with easier-to-control asthma were randomly assigned to receive omalizumab, placebo or an inhaled corticosteroid boost (in which their normal dose was doubled). These treatments began four to six weeks before the start of school and ended 90 days after school started. Participants continued to receive guidelines-based asthma care throughout the study. Complications and side effects were rare and did not differ between the study groups.
Based on analysis of data from 478 study participants, the researchers found that, overall, children treated with omalizumab were about half as likely to experience an asthma exacerbation during the first 90 days of the school year as those who did not receive the drug.
Further analysis revealed that children who had experienced an exacerbation in the four-to-nine-month period before omalizumab treatment started benefited most from the drug. Within this group, omalizumab reduced the risk of an exacerbation by more than 80 percent—36.3 percent of children who received placebo had at least one fall exacerbation, compared to only 6.4 percent of children who received omalizumab. Children who did not experience an exacerbation in the months before school were not helped by addition of the drug to their asthma regimens. In children with easier-to-control asthma, the inhaled corticosteroid boost did not help prevent exacerbations, regardless of their history of exacerbations in the previous months.
“Identifying those children who are at greatest risk for fall asthma exacerbations and who are most likely to benefit from short-term addition of omalizumab to guidelines-based care is an important step toward delivering personalized asthma treatments,” said Daniel Rotrosen, M.D., director of the NIAID Division of Allergy, Immunology and Transplantation, which oversees the ICAC program.
Compared to their peers, participants who experienced an exacerbation in the months before school had evidence of higher levels of allergic inflammation. Specifically, they had high numbers of immune cells called eosinophils in the blood and increased levels of nitric oxide in the breath, two measurable markers of asthma-associated inflammation.
“This study’s most exciting result demonstrates how clinicians can individualize care for young patients with certain high-risk clinical profiles. This is an important step forward in advancing asthma care, with large benefits for some of the most at-risk, underserved children,” said Stephen J. Teach, M.D., M.P.H., of Children’s National Health System, the lead author of the study.
The researchers also are working to understand the mechanism underlying the protective effects of omalizumab. Respiratory viruses were common in samples of nasal mucus taken from participants around the time they experienced an asthma exacerbation. By analyzing blood samples from a subset of trial participants, the scientists found that the beneficial effects of omalizumab may be partly explained by an increased release of an antiviral substance called interferon-alpha from certain immune cells. Among participants who received omalizumab, those with the greatest increase in interferon-alpha experienced fewer exacerbations. Future work may provide additional insight into the causes of fall asthma exacerbations and how best to prevent them.
This work was funded by NIAID, NIH, under contract numbers HHSN272200900052C and HHSN272201000052I and grant numbers R01AI098077 and UM1AI109565. Additional support was provided by the National Center for Advancing Translational Sciences, NIH, under grant numbers UL1TR000451, 1UL1RR025780, UL1TR000075, UL1TR000154, UL1TR000077, UL1TR000040, UL1TR000150 and UL1TR001105. Novartis donated omalizumab and matching placebo, GlaxoSmithKline donated the inhaled corticosteroid fluticasone and matching placebo and Mylan donated epinephrine autoinjectors (EpiPens). The ClinicalTrials.gov identifier for the study Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations (PROSE) is NCT01430403.
SJ Teach et al. Pre-seasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2015.09.008 (2015).