A randomized, double-blind, placebo-controlled, parallel-group study of once-daily inhaled fluticasone furoate on the hypothalamic–pituitary–adrenocortical axis of children with asthma

Abstract

Background: To evaluate the effects of fluticasone furoate on the hypothalamic-pituitary-adrenocortical axis, and the safety and tolerability of fluticasone furoate treatment in children with asthma. Methods: This was a randomized, double-blind, placebo-controlled, multicenter, stratified, parallel-group, noninferiority study of fluticasone furoate 50 µg inhalation powder administered once daily. The study enrolled children (aged 5-11 years inclusive) with a documented diagnosis of asthma for ≥ 6 months and a Childhood Asthma Control Test score of > 19. After a 7-14-day run-in period, eligible subjects were stratified by age and randomized to fluticasone furoate 50 µg once daily or placebo once daily via ELLIPTA for 6 weeks. The primary endpoint was the change from baseline (expressed as a ratio) in 0-24-h weighted mean serum cortisol at the end of the treatment period. Results: Fifty-six randomized subjects received fluticasone furoate 50 µg once daily and 55 received placebo. The primary analysis was performed in the serum cortisol population (n = 104) and demonstrated that fluticasone furoate 50 µg once daily was non-inferior to placebo (ratio = 0.93; 95% confidence interval 0.8096, 1.0620), as the lower limit of the 95% confidence interval for the geometric mean treatment ratio of fluticasone furoate 50 µg once daily versus placebo was greater than 0.80. Findings from the intent-to-treat population (n = 111) were similar. Conclusions: Six weeks of treatment with inhaled fluticasone furoate 50 µg once daily had no clinically relevant effect on the hypothalamic-pituitary-adrenocortical axis function of children, as measured by 24-h serum cortisol profiles. The primary analysis showed that fluticasone furoate 50 µg once daily was non-inferior to placebo. Fluticasone furoate 50 µg once daily was well tolerated and no new safety concerns emerged during the study.

Glucocorticoid induced adrenal insufficiency

“…Fluticasone furoate has the same steroidal backbone as fluticasone propionate but a different ester substituent and has a longer retention time in respiratory tissues 65. This may explain the lower levels of systemic absorption and the low impact on the HPAA observed in both children and adults (box 1),66676869 although East Asian people may have a higher risk of systemic exposure to the drug 69. Ciclesonide and its active metabolite desisobutyryl-ciclesonide have high concentrations of plasma protein binding (that is, reduced biological activity) and high clearance rate (that is, reduced systemic exposure)5270; this might explain the low degree of HPAA suppression observed with this compound 717273.…”

“…In children and adults with asthma, most studies did not find GI-AI when inhaled glucocorticoids were used at fluticasone equivalent doses below 400 µg/day and 500 µg/day, respectively 5277787980. However, long term users of inhaled glucocorticoids (>6-12 months) can develop GI-AI even at intermediate and low doses 687581. A study in 70 children with asthma treated with inhaled glucocorticoids for at least six months found GI-AI in 24% of cases, with most being treated for more than 24 months at fluticasone equivalent doses above 400 µg/day 82…”