Mid-afternoon dosing with an inhaler has the biggest impact on the chances of night-time asthma worsening, British researchers of a small randomised trial have suggested, saying that for mild to moderate cases, using inhaled beclomethasone at this time reduced the likelihood, more than other dosing strategies, of nocturnal lung function deterioration.
The open-label trial showed that a single 400-μg dose at 3pm to 4pm improved night-time forced expiratory volume in one second (FEV1 at 10pm) by a median 160 mL compared with baseline, whereas it fell by 20 mL from baseline with the same dose given at 8am to 9am, and increased by 80mg with twice daily dosing (P<0.01).
An afternoon dose also yielded significantly better overnight (10pm to 4am) suppression in blood eosinophil counts as a marker of airway inflammation compared with the other two groups, although overall asthma control remained comparable across chronotherapy groups.
“Our findings further support the hypothesis that the optimal timing of ICS (inhaled corticosteroid) administration is at 4pm, coincident with enhanced glucocorticoid sensitivity at that time,” Hannah Jane Durrington, MB BChir, PhD, of the University of Manchester, and colleagues reported in Thorax.
MedPage Today reports that asthma has a distinct daily rhythm, with the inflammatory cascade thought to start mid-afternoon as a cause of the known peak in airflow obstruction and airway inflammation overnight.
The group acknowledged that mid-afternoon dosing could be complicated in patients who already have adherence challenges but that it might overcome barriers as well by achieving efficacy with lower cost due to fewer doses a day.
“New strategies to manage this could be implemented leveraging smartphone applications, timed alarms, and adherence reminders to ensure patients consistently follow their prescribed regimens,” suggested Nicola Smallcombe, MBBS, of the Royal Free London NHS Foundation Trust, and Richard Edward Russell, MBBS, PhD, of King’s College London.
Lack of translation of the lung function and inflammation findings to better symptomatic control could have been due to short duration of follow-up, small numbers (25 randomised to sequential crossover, with 21 completing it), and relatively low symptom burden at baseline, “so there was no headroom for improvement”, Smallcombe and Russell wrote in an accompanying editorial.
“This is likely to be the case as it is noteworthy that no patients dropped out in either the run-in or wash-out periods when they were not taking ICS-containing medication, and it would usually be expected that an improvement of 170 ml in FEV1 would lead to a measurable symptomatic improvement,” they suggested.
While the trial included adults with a mild to moderate allergic asthma phenotype, afternoon dosing “is most likely to benefit those with more severe asthma, where marginal gains in lung function and a reduced eosinophil count are more likely to translate into better control and risk reduction”, Smallcombe and Russell added.
Also, guidelines now recommend combined inhaled corticosteroid and long-acting beta agonist (LABA) inhalers as the standard of care, they noted. “The results of this current study need to be validated in a larger trial with longer follow-up, using LABA/ICS in real-world settings to best evaluate the feasibility and practical implementation.”
The trial recruited patients with physician-diagnosed mild to moderate allergic asthma who stopped their usual asthma treatment in the run-in period for two to three weeks.
They then completed three-way cross-over periods of 28 days of treatment with beclomethasone dipropionate at 400 μg once daily between 8am and 9am, 400 μg once daily between 3pm and 4pm, and 200 μg twice daily between 8am and 9am and between 8pm and 9pm. Participants all had similar typical sleep and wake times.
All regimens improved fractional exhaled nitric oxide and serum cortisol levels similarly. FEV1 comparisons didn’t differ significantly between groups at lung function checks at 4am, 10am, or 4pm.
“A future large, real-world chronotherapy study framed within the new asthma guidelines, using formoterol/ICS, will determine if afternoon dosing leads to a reduction in exacerbations, better overall symptom control, health-economic benefits, and crucially, determine patient preference for afternoon dosing,” the researchers concluded.
Study details
The impact of dosage timing for inhaled corticosteroids in asthma: a randomised three-way crossover trial
Ran Wang, Robert Maidstone, Dave Singh et al.
Published in The BMJ Thorax on 15 April 2025
Abstract
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.
BMJ Thorax comment – Chronotherapy in asthma: BD or not BD? That is the question (Open access)
MedPage Today article – Best Time of Day for Asthma Inhaler? (Open access)
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