ABSTRACT
BackgroundThe antibacterial, anti-inflammatory and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-moderate disease are lacking. We assessed whether azithromycin is effective in reducing hospitalisation in patients with mild-moderate COVID-19. MethodsThis open-label, randomised superiority clinical trial at 19 centres in the United Kingdom enrolled adults, [≥]18 years, presenting to hospitals with clinically-diagnosed highly-probable or confirmed COVID-19 infection, with <14 days symptoms, considered suitable for initial ambulatory management. Patients were randomised (1:1) to azithromycin (500 mg daily orally for 14 days) or to standard care without macrolides. The primary outcome was the difference in proportion of participants with death or hospital admission from any cause over the 28 days from randomisation, assessed according to intention-to-treat (ITT). Trial registration: ClinicalTrials.gov, NCT04381962, Study closed. Findings298 participants were enrolled from 3rd June 2020 to 29th January 2021. The primary outcome was assessed in 292 participants. The primary endpoint was not significantly different between the azithromycin and control groups (Adjusted OR 0{middle dot}91 [95% CI 0{middle dot}43-1{middle dot}92], p=0{middle dot}80). Rates of respiratory failure, progression to pneumonia, all-cause mortality, and adverse events, including serious cardiovascular events, were not significantly different between groups. InterpretationIn patients with mild-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospitalisation or death. Our findings do not support the use of azithromycin in patients with mild-moderate COVID-19. FundingNIHR Oxford BRC, University of Oxford and Pfizer Inc. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE and the Cochrane Central register of Controlled Trials (CENTRAL) with the terms ("azithromycin") AND ("COVID" OR "COVID-19") AND ("clinical trials"), until March 25, 2021, with no language restrictions. We identified 42 studies, among which there were four completed randomised trials of azithromycin (with or without hydroxychloroquine) in hospitalised patients with severe disease, and three completed randomised trials of azithromycin in mild COVID-19 in primary care. The four trials in hospitalised patients randomised 8,988 participants to azithromycin or standard care or hydroxychloroquine and found no evidence of a difference in mortality, duration of hospital stay or peak disease severity. Of the three trials in primary care, these randomised participants with early disease to 3 or 5 days of therapy, of which only one assessed azithromycin as standalone therapy. This large, adaptive platform trial in the UK randomised 540 participants in primary care to 3 days treatment with azithromycin versus 875 to standard care alone and found no meaningful difference in time to first reported recovery, or of rates of hospitalisation (3% versus 3%) and there were no deaths. We did not identify any randomised trials in patients with COVID-19 managed in ambulatory care. Added value of this studyThe ATOMIC2 trial was uniquely-designed to assess azithromycin as a standalone therapy in those with mild-moderately COVID-19 presenting to emergency care, but assessed as appropriate for initial ambulatory management without hospital admission. ATOMIC2 also uniquely assessed high-dose, long-duration treatment to investigate the efficacy of putative anti-inflammatory effects. We found that azithromycin 500 mg daily for 14 days did not reduce the proportion of participants who died or required hospital admission from any cause over the 28 days from randomisation. Implications of all the available evidenceOur findings, taken together with existing data, suggest there is no evidence that azithromycin reduces hospitalisation, respiratory failure or death compared with standard care, either in early disease in the community, or those hospitalised with severe disease, or in those with moderate disease managed on an ambulatory pathway.
ABSTRACT
The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via Spike glycoprotein binding angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organisms response to its environment and can regulate host susceptibility to virus infection. We demonstrate a circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with a synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced a wide spectrum of interferon stimulated genes in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to dampen SARS-CoV-2 infection. Our study suggests new approaches to understand and improve therapeutic targeting of SARS-CoV-2.
ABSTRACT
BackgroundMultiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. MethodsWe conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. ConclusionEarly administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection. (Funded by Oxford NIHR Biomedical Research Centre and AstraZeneca; ClinicalTrials.gov number, NCT04416399) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe majority of interventions studied for the COVID-19 pandemic are focused on hospitalised patients. Widely available and broadly relevant interventions for mild COVID-19 are urgently needed. Added value of this studyIn this open label randomised controlled trial, inhaled budesonide, when given to adults with early COVID-19 illness, reduces the likelihood of requiring urgent care, emergency department consultation or hospitalisation. There was also a quicker resolution of fever, a known poor prognostic marker in COVID-19 and a faster self-reported and questionnaire reported symptom resolution. There were fewer participants with persistent COVID-19 symptoms at 14 and 28 days after budesonide therapy compared to usual care. Implications of all the available evidenceThe STOIC trial potentially provides the first easily accessible effective intervention in early COVID-19. By assessing health care resource utilisation, the study provides an exciting option to help with the worldwide pressure on health care systems due to the COVID-19 pandemic. Data from this study also suggests a potentially effective treatment to prevent the long term morbidity from persistent COVID-19 symptoms.
