esearchTrial (SMART)]. Available data from controlled clinical trials also suggest that use of LABA asmonotherapy increases the risk of asthma-related hospitalization in pediatric and adolescentpatients. These findings are considered a class effect of LABA monotherapy. When LABA areused in fixed-dose combination with ICS, data from large clinical trials do not show a significantincrease in the risk of serious asthma-related events (hospitalizations, intubations, death)compared with ICS alone [see Serious Asthma-Related Events with Inhaled Corticosteroid/Longacting
Beta2-adrenergic Agonists].
Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic
Agonists
Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conductedto eva luate the risk of serious asthma-related events when LABA were used in fixed-dosecombination with ICS compared with ICS alone in subjects with asthma.
Three (3) trialsincluded adult and adolescent subjects aged 12 years and older: 1 trial comparedbudesonide/formoterol to budesonide, 1 trial compared fluticasone propionate/salmeterolinhalation powder to fluticasone propionate inhalation powder, and 1 trial compared mometasonefuroate/formoterol to mometasone furoate. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder to fluticasone
propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthmarelatedevents (hospitalizations, intubations, death). A blindedadjudication committee
determined whether events were asthma-related.
The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatrictrial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specifiedobjective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3adult and adolescent trials did not show a significant increase in risk of a serious asthma-relatedevent with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trialswere not designed to rule out all risk for serious asthma-related events with ICS/LABAcompared with ICS.
Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12
Years and Older
ICS/LABA
(n =17,537)
a
ICS
(n = 17,552) a
ICS/LABA vs.
ICS
Hazard Ratio
(95% CI)b
Serious asthma-related event c
116 105 1.10 (0.85, 1.44)
Asthma-related death 2 0
Asthma-related intubation
(endotracheal)
1 2
Asthma-related hospitalization
(≥24-hour stay)
115 105
ICS = Inhaled Corticosteroid; LABA = Long-acting Beta2-adrenergic Agonist.
a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used foranalysis.
b Estimated using a Cox proportional hazards model for time to first event with baseline hazardsstratified by each of the 3 trials.
c Number of subjects with events that occurred within 6 months after the first use of study drug or 7days after the last date of study drug, whichever date was later. Subjects can have one or more events,but only the first event was counted for analysis. A single, blinded, independent adjudicationcommittee determined whether events were asthma related.
The pediatric safety trial included 6,208 pediatric patients aged 4 to 11 years who receivedICS/LABA (flutic |
