Results from the largest asthma safety trial in the United States suggest that combination therapies containing both inhaled corticosteroids and long-acting beta agonists (LABAs) do not significantly increase the risk of serious asthma-related events as compared with inhaled corticosteroids alone.

The report, led by the University of Wisconsin School of Medicine and Public Health (SMPH), was published in the New England Journal of Medicine.

The findings close a long-running debate about one of the most commonly prescribed therapies for asthma management in adults. Following safety concerns in 2003, the US Food and Drug Administration (FDA) issued a public health advisory stating that LABAs—a class of medications that helps keep muscles around the airways relaxed to prevent wheezing, coughing, chest tightness, and shortness of breath—should not be used as a first-line therapy for asthma.

The agency also required all products containing LABAs to carry a “Black Box” warning for consumers and mandated the four pharmaceutical companies that sold combination drug products to conduct large trials evaluating the risk of serious asthma outcomes (hospitalizations, endotracheal intubations, and death). Each company (Astra Zeneca, GlaxoSmithKline, Merck, and Novartis) evaluated its own LABA-containing drugs: Symbicort, Advair Diskus, Dulera, and Foradil, respectively.

An independent joint oversight committee, led by William Busse, MD, professor of medicine at the UW School of Medicine and Public Health, performed the final combined analysis of the four trials.

“Our report should provide assurance to physicians and patients alike that this type of combination therapy is safe for adults when used as prescribed,” said Busse. “Not only did the study show that these combination therapies do not pose a higher risk than monotherapies alone, we found that they significantly decrease the number of asthma exacerbations in adults.”

Based on these results, the FDA approved the removal of the boxed warning from LABA drugs’ labels in December 2017.

“The FDA’s approval to remove the Boxed Warning from a class of medications known as LABAs used in combination with inhaled corticosteroid shows that data from the post-market studies we require gave the agency actionable safety information on approved drug products,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to an informed and comprehensive approach to monitoring the safety of approved drugs and we adjust our regulatory actions as appropriate based on additional information."

Each of the four studies—the protocols for which were harmonized to allow for consistent combined analysis by the independent committee—were randomized, double-blinded, and lasted 6 months. Enrollees had a history of at least one asthma exacerbation in the previous 12 months and were thought to be at risk for additional exacerbations. Participants were randomly assigned to receive an inhaled glucocorticoid plus a LABA (combination therapy) or an inhaled glucocorticoid alone.

In total, 36,010 patients participated in the trial, and three of the four pharmaceutical companies completed their studies and reported the results. Novartis terminated its trial early after removing its drug from the market in 2015.

Among those enrolled, there were three asthma-related intubations and two asthma-related deaths in four patients. In the secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death) 108 of 18,006 patients were in the inhaled glucocorticoid group and 119 of 18,004 patients were in the combination therapy group.

In the inhaled glucocorticoid group, 2,100 patients had at least one episode of worsening symptoms but only 1,768 in the combination therapy group had such an episode. The lower risk for exacerbation among patients in the combination therapy group was consistent across all four individual trials.

People with life-threatening asthma were excluded from the study because of safety and ethical concerns, so the results cannot be generalized to these patients.