FDA-Mandated Trials: No Excess Risk With LABA Combo in Asthma

Diana Phillips

July 04, 2018

Adding long-acting beta-agonists (LABAs) to treatment with inhaled corticosteroids does not increase the risk of serious asthma-related events, a combined analysis of trials mandated by the US Food and Drug Administration (FDA) shows.

The findings support the FDA's decision in December 2017 to remove the boxed warning from combination products. Led by William W. Busse, MD, professor of medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health in Madison, the study was published June 28 in the New England Journal of Medicine (2018;378:2497-2505).

The boxed warning was initially mandated in 2003 based on trial data linking LABAs to increased asthma exacerbations and serious asthma-related events. Although patients in the early LABAs trials were not necessarily using inhaled corticosteroids, the FDA extended the boxed warning to combination therapy products pending the findings of mandated prospective randomized controlled trials comparing the safety and efficacy of combination LABA and inhaled glucocorticoid therapy with inhaled glucocorticoid treatment alone.

The newly reported findings reflect a combined analysis conducted by an independent joint oversight committee of four of five mandated trials. Busse and colleagues note that the one pediatric trial was not included in the analysis.

By design, the trials shared independent steering, adjudication, and data monitoring committees so the results could be combined. Combining the data allowed investigators to assess rare serious events, including intubation or death, as a primary outcome, and a composite measure for the frequency of serious asthma-related events (intubation, hospitalization, or death) as a secondary outcome.

In total, 36,010 adolescents and adults (12 years and older) were included in the intent-to-treat analysis. Approximately half were randomly assigned to combination therapy (n = 18,004) and half to monotherapy (n = 18,006).

Overall, there were three asthma-related intubations, including two in the monotherapy group and one in the combination therapy group, and two asthma-related deaths, both in the combination therapy group.

With respect to serious asthma-related events, rates were similar across groups, occurring in 108 patients (0.60%) in the monotherapy group and 119 patients (0.66%) in the combination-therapy group (relative risk [RR], 1.09; 95% confidence interval [CI], 0.83 – 1.43; P = .55).

In a modified intention-to-treat population that included only patients who received at least one dose of a blinded trial drug were similar, with no significant increase in risk of serious asthma-related events among those in the combination versus monotherapy group (RR, 1.24; 95% CI, 0.94 – 1.65; P = .13) to the intention-to-treat population.

At least one asthma exacerbation occurred in 2100 (11.7%) patients in the inhaled-glucocorticoid group and in 1768 (9.8%) patients in the combination-therapy group (RR, 0.83; 95% CI, 0.78 – 0.89).

"The lower risk of exacerbation among patients in the combination therapy group than in the inhaled-glucocorticoid group was consistent across the four individual trials," the authors write.

Moreover, in the subgroup analysis looking at patients thought to be at increased risk for adverse events based on age, ethnicity, or weight status, there were no significant increases in the relative risk of serious asthma-related events or asthma exacerbations associated with combination therapy.

Asthma-related death rates observed in this analysis were lower than the anticipated rate of 0.06% over the trial durations. However, the anticipated rate was calculated based on meta-analyses previously reported by the FDA that were heavily influenced by a trial that did not require or monitor inhaled glucocorticoid use, according to the authors. The observed rates are consistent with those reported in the wider global literature, however.

"Our analysis also confirmed a lower relative risk of asthma exacerbations of 17% with combination therapy than with an inhaled glucocorticoid alone. This finding corresponds to the lower relative rates of asthma exacerbations that were reported in the sponsored individual trials," the authors write.

Despite some limitations, including the heterogeneity of products from different manufacturers and the exclusion of patients with a history of life-threatening asthma events from enrollment, which precludes definition of comparative safety aspects of LABA use in extremely high-risk patients, the finding that combination treatment is noninferior from a safety perspective to monotherapy and offers potential efficacy benefit "provide support for the treatment guidelines of both the Global Initiative for Asthma and the Expert Panel Report of the National Asthma Education and Prevention Program, which recommend the use of a low-dose glucocorticoid (step 3) and a medium-dose glucocorticoid (step 4), plus a LABA, with the caution that LABAs should not be used as monotherapy in asthma; the convenience and safety of a combination inhaler is a likely plus," the authors write.

In an accompanying commentary (N Engl J Med. 2018;378:2461-2463), Sally M. Seymour, MD, from the FDA's Office of New Drugs, and colleagues observe that the decision to remove the boxed warning from the LABA combination products was based on the "strong and consistent evidence" presented in these trials.

"Admittedly, the results from these trials cannot answer all questions regarding the safety of LABAs. Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone," the commenters write.

"Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations," the commenters explain. Additionally, the findings cannot be generalized to extremely high-risk asthma patients because they were excluded from the analyses, nor can they be generalized to pediatric patients because the pediatric trial was not included in the combined analysis.

"Despite these uncertainties and limitations, the trials provided reassuring safety information and demonstrated additional benefits associated with combination therapy," the commentary authors write.

Although it is uncommon for the FDA to remove a boxed warning from a product, "the evidence in this instance was decisive," Seymour and colleagues note. "The FDA's decision to remove the boxed warning from combination products was based on our assessment of data from FDA-required trials. Any FDA mandate for large safety trials should be predicated on science and patient welfare and established for the purpose of answering important safety questions to improve healthcare providers' knowledge and patient care."

The authors have disclosed financial relationships with organizations including 3M, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi/Regeneron, Teva, Boston Scientific, Genentech, Cipla ALK, Vectura Group, Merck, Takeda, Hoffmann–La Roche, Actelion, Chiesi, Sanofi-Aventis, Cephalon, Menarini, MedImmune, InterMune, Chiesi, and Berlin-Chemie.

N Engl J Med. 2018;378:2497-2505. Abstract

N Engl J Med. 2018;378:2461-2463. Editorial

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