The impact of dosage timing for inhaled corticosteroids in asthma: a randomised three-way crossover trial

Background: Asthma demonstrates a robust daily rhythm, with airflow obstruction and airway inflammation peaking overnight. Aligning the timing of drug administration with rhythms in disease (chronotherapy) may improve therapeutic efficacy. We aimed to evaluate the impact of dosage timing for inhaled corticosteroids in asthma. Methods: This is a randomised three-way crossover trial. Participants with mild to moderate atopic asthma were randomised to beclometasone dipropionate: (1) 400μg once daily between 08:00 and 09:00 (OD_AM); (2) 400μg once daily between 15:00 and 16:00 (OD_PM); and (3) 200μg twice daily between 08:00 and 09:00 and between 20:00 and 21:00 (BD) for 28 days, with a 2week washout period in between treatment periods. Six-hourly spirometry and biomarkers were measured over 24 hours following the run-in period and at the end of each treatment period. Results: Of 25 participants, 21 completed all regimens. OD_PM was superior in improving 22:00 FEV₁ (median (IQR): +160 (+70, +270) ml) compared with OD_AM (-20 (-80, +230) ml) and BD (+80 (-20, +200) ml). OD_PM resulted in better overnight (22:00 and 04:00) suppression in blood eosinophil counts compared with BD and OD_AM. All regimens improved asthma control and reduced fractional exhaled nitric oxide and serum cortisol levels with no difference among dosing regimens. Conclusion: OD_PM better suppresses the nocturnal dip in lung function and peak of blood eosinophil counts compared with BD and OD_AM; this was without an increase in adverse events. Future trials are warranted to validate these findings in real-life settings and to determine which population may best benefit from chronotherapy.