Inhaled beclomethasone in the treatment of early COVID-19: a double-blind, placebo-controlled, randomised, hospital-based trial in Sri Lanka
Chamila Mettananda, Chathura Peiris, Dharani Abeyrathna, Aloka Gunasekara, Thimira Egodage, Channaka Dantanarayana, Arunasalam Pathmeswaran, Channa Ranasinha
BMJ Open, doi:10.1136/bmjopen-2023-075803
Objectives To study if early initiation of inhaled beclomethasone 1200 mcg in patients with asymptomatic, mild or moderate COVID-19 reduces disease progression to severe COVID-19. Design Double-blinded, parallel-groups, randomised, placebo-controlled trial. Setting A hospital-based study in Sri Lanka. Participants Adults with asymptomatic, mild or moderate COVID-19, presenting within the first 7 days of symptom onset or laboratory diagnosis of COVID-19, admitted to a COVID-19 intermediate treatment centre in Sri Lanka between July and November 2021. Interventions All participants received inhaled beclomethasone 600 mcg or placebo two times per day, for 10 days from onset of symptoms/COVID-19 test becoming positive if asymptomatic or until reaching primary endpoint, whichever is earlier. Primary outcome measure Progression of asymptomatic, mild or moderate COVID-19 to severe COVID-19. Secondary outcome measures The number of days with a temperature of 38°C or more and the time to selfreported clinical recovery. Results A total of 385 participants were randomised to receive beclomethasone(n=193) or placebo(n=192) stratified by age (≤60 or >60 years) and sex. One participant from each arm withdrew from the study. All participants were included in final analysis. Primary outcome occurred in 24 participants in the beclomethasone group and 26 participants in the placebo group (RR 0.90 ; p=0.763). The median time for selfreported clinical recovery in all participants was 5 days (95% CI 3 to 7) in the beclomethasone group and 5 days (95% CI 3 to 8) in the placebo group (p=0.5). The median time for self-reported clinical recovery in patients with moderate COVID-19 was 5 days (95% CI 3 to 7) in the beclomethasone group and 6 days (95% CI 4 to 9) in the placebo group (p=0.05). There were no adverse events. Conclusions Early initiation of inhaled beclomethasone in patients with asymptomatic, mild or moderate COVID-19 did not reduce disease progression to severe COVID-19. Trial registration number Sri Lanka Clinical Trials Registry; SLCTR/2021/017. ⇒ This is a randomised double-blind adequately powered placebo-controlled trial. ⇒ This study brings evidence from low-middle-income countries and South Asians. ⇒ Patients were recruited irrespective of having symptoms or not. ⇒ Patients were recruited irrespective of their risk of developing complications. ⇒ Patients were randomised irrespective of their vaccination status.
Competing interests None declared. Provenance and peer review Not commissioned; externally peer reviewed.
References
Beasley, Harper, Bird, Inhaled corticosteroid therapy in adult asthma. time for a new therapeutic dose terminology, Am J Respir Crit Care Med,
doi:10.1164/rccm.201810-1868CICampbell, Julious, Altman, Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons, BMJ,
doi:10.1136/bmj.311.7013.1145Clemency, Varughese, Gonzalez-Rojas, Efficacy of inhaled Ciclesonide for outpatient treatment of adolescents and adults with symptomatic COVID-19: A randomized clinical trial, JAMA Intern Med,
doi:10.1001/jamainternmed.2021.6759Duvignaud, Lhomme, Onaisi, Inhaled Ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE), Clin Microbiol Infect,
doi:10.1016/j.cmi.2022.02.031Ezer, Belga, Daneman, Inhaled and intranasal Ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN phase II randomised controlled trial, BMJ,
doi:10.1136/bmj-2021-068060Gomes, Jeewandara, Jayadas, Surveillance of SARS-CoV-2 variants of concern by identification of single nucleotide Polymorphisms in the spike protein by a Multiplex real-time PCR, J Virol Methods,
doi:10.1016/j.jviromet.2021.114374Marconi, Ramanan, De Bono, Efficacy and safety of Baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallelgroup, placebo-controlled phase 3 trial, Lancet Respir Med,
doi:10.1016/S2213-2600(21)00331-3Mariette, Hermine, Tharaux, Effectiveness of Tocilizumab in patients hospitalized with COVID-19: A follow-up of the CORIMUNO-TOCI-1 randomized clinical trial, JAMA Intern Med,
doi:10.1001/jamainternmed.2021.2209Nice, Inhaled corticosteroid doses for NICE's asthma guideline2018 05.06
Powers, Bacci, Leidy, Performance of the inFLUenza patient-reported outcome (FLU-PRO) diary in patients with influenzalike illness (ILI), PLoS ONE,
doi:10.1371/journal.pone.0194180Ramakrishnan, Nicolau, Langford, Inhaled Budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial, Lancet Respir Med,
doi:10.1016/S2213-2600(21)00160-0Song, Yoon, Seo, Ciclesonide Inhaler treatment for mild-to-moderate COVID-19: A randomized, open-label, phase 2 trial, J Clin Med,
doi:10.3390/jcm10163545Wu, Daouk, Kebbe, Low-dose versus high-dose dexamethasone for hospitalized patients with COVID-19 pneumonia: A randomized clinical trial, PLOS ONE,
doi:10.1371/journal.pone.0275217Yu, Bafadhel, Dorward, Inhaled Budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial, Lancet,
doi:10.1016/S0140-6736(21)01744-XYu, Bafadhel, Dorward, Inhaled Budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial, medRxiv
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'beclomethasone 1200 mcg in patients with asymptomatic, mild or moderate COVID-19 reduces '
'disease progression to severe '
'COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Double-blinded, '
'parallel-groups, randomised, placebo-controlled '
'trial.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>A hospital-based '
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'Lanka.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Adults with '
'asymptomatic, mild or moderate COVID-19, presenting within the first 7 days of symptom onset '
'or laboratory diagnosis of COVID-19, admitted to a COVID-19 intermediate treatment centre in '
'Sri Lanka between July and November '
'2021.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>All '
'participants received inhaled beclomethasone 600 mcg or placebo two times per day, for 10 '
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'recovery.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 385 '
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'Ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN '
'phase II randomised controlled trial. BMJ 2021;375:e068060. '
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'DOI': '10.1183/13993003.02921-2021'},
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'doi-asserted-by': 'crossref',
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'doi-asserted-by': 'crossref',
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