The Efficacy and Safety of Fluticasone/Salmeterol Compared to Fluticasone in Children Younger Than Four Years of Age

Abstract

The combination of inhaled corticosteroid (ICS) and long-acting β-2 agonist (LABA) is widely used as maintenance therapy for children with asthma. However, use in young children has not been well studied. This study investigates the efficacy and safety of combination therapy with fluticasone propionate 50 µg and salmeterol xinafoate 25 µg in children up to 4 years of age.Study participants were children aged 6 months to 4 years with asthma diagnosed according to the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 and in whom ICS and LABA was considered necessary by their physician.This 27-week double-blind, randomized controlled trial was conducted from May 2014 to October 2016 in 70 Japanese pediatric centers. The study consisted of 4 time intervals: (1) a 2-week run-in period, during which all children received inhaled fluticasone propionate twice daily; (2) an 8-week randomized treatment period, during which fluticasone only or fluticasone and salmeterol was administered twice daily; (3) a 16-week open-label period, during which all children received fluticasone and salmeterol twice daily; and (4) a 1-week follow-up period, during which children received care that the investigator felt was appropriate. Children <2 years received 1 inhalation per dose, whereas children 2 years or older received 1 to 2 inhalations per dose, according to the investigator’s judgment. The number of inhalations remained consistent during the run-in and treatment phases but could be adjusted during the open-label phase, if appropriate. As needed, salbutamol 100 µg was allowed as a rescue inhaler. Study endpoints and compliance were assessed via twice-daily recordings in a patient diary by the parent or legal guardian.A total of 300 patients were randomized 1:1 to the double-blind period, of whom 148 completed treatment with ICS and LABA, and 142 completed treatment with ICS only. The study was completed by 268 patients. In both treatment groups, boys predominated, and the majority (≥90%) of patients had moderate or severe persistent asthma. Both groups showed reduction in total asthma symptom scores; however, the primary end point of mean change in total asthma symptom scores from baseline to the last 7 days of the treatment period was not significantly different between the 2 groups (−3.97 for ICS and LABA versus −3.01 for ICS only, P = .21). Secondary outcome analysis showed fewer exacerbations in the ICS and LABA group (3% vs 5% in the ICS group) and statistically greater mean change from baseline in Japanese Pediatric Asthma Control scores in the ICS and LABA group (0.4 points vs −0.3 points for ICS only, P = .04). Little change from baseline in daily rescue medication use or percentage of rescue-free days was seen, with no statistically significant differences between the groups. Incidence of adverse effects was virtually identical between the ICS and LABA (74%) and ICS only (73%) groups and was not associated with age or number of inhalations. No new safety concerns were identified during the open-label period. Decreased plasma cortisol was reported in 6 children during the open-label and follow-up periods, although most values normalized on recheck. No serious adverse effects were considered by the investigators to be drug related.Combination therapy with ICS and LABA showed similar safety profiles to ICS alone in children with asthma up to 4 years of age. Although combination therapy improved total asthma symptom scores, it did not show superior efficacy to ICS alone.Asthma management in young children is challenging because of inability to perform pulmonary function tests and the intermittent nature of symptoms, with many children being clinically well in between exacerbations. Importantly, this study provides new evidence regarding the safety of ICS and LABA use in young children. Regarding efficacy, statistically significant differences were seen for some secondary outcomes, which may suggest better symptom control with ICS and LABA, although it is unclear if these differences warrant the use of ICA and LABA over ICS only in this age group. Further studies are needed to make this determination and support the findings in this study.