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) 400 µg once daily between 08:00 and 09:00 (ODAM); (2) 400 µg once daily between 15:00 and 16:00 (ODPM); and (3) 200 µg twice daily between 08:00 and 09:00 and between 20:00 and 21:00 (BD) for 28 days, with a 2 week 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. ODPM was superior in improving 22:00 FEV1 (median (IQR): +160 (+70, +270) ml) compared with ODAM (−20 (−80, +230) ml) and BD (+80 (−20, +200) ml). ODPM resulted in better overnight (22:00 and 04:00) suppression in blood eosinophil counts compared with BD and ODAM. All regimens improved asthma control and reduced fractional exhaled nitric oxide and serum cortisol levels with no difference among dosing regimens. Conclusion ODPM better suppresses the nocturnal dip in lung function and peak of blood eosinophil counts compared with BD and ODAM; 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. Data are available upon reasonable request. The study protocol is available on trial registration website. Individual participant data that underlie the results reported in this article after deidentification will be shared 3 years following article publication with investigators whose proposed use of data has been approved by the study sponsor. Proposal will be directed to pmoore@crosolutions.co.uk. To gain access, data requestors will need to sign a data access agreement.