Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76–2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, time to defervescence was 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95%CI, 0.81–4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by RT-PCR by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred to any of the patients in either treatment group during the 28-day participation (Japan Registry of Clinical Trials jRCTs041190120).
Background
COVID-19 has worse mortality than influenza in American and European studies, but evidence from the Western Pacific region is scarce.
Methods
Using a large-scale multicenter inpatient claims data in Japan, we identified individuals hospitalised with COVID-19 in 2020 or influenza in 2017–2020. We compared patient characteristics, supportive care, and in-hospital mortality, with multivariable logistic regression analyses for in-hospital mortality overall, by age group, and among patients with mechanical ventilation.
Findings
We identified 16,790 COVID-19 patients and 27,870 influenza patients, with the different age distribution (peak at 70–89 years in COVID-19 vs. bimodal peaks at 0–9 and 80–89 years in influenza). On admission, the use of mechanical ventilation was similar in both groups (1·4% vs. 1·4%) but higher in the COVID-19 group (3·3% vs. 2·5%; p<0·0001) during the entire hospitalisation. The crude in-hospital mortality was 5·1% (856/16,790) for COVID-19 and 2·8% (791/27,870) for influenza. Adjusted for potential confounders, the in-hospital mortality was higher for COVID-19 than for influenza (adjusted odds ratio [aOR] 1·83, 95% confidence interval [CI] 1·64–2·04). In age-stratified analyses, the aOR (95%CI) were 0·78 (0·56–1·08) and 2·05 (1·83–2·30) in patients aged 20–69 years and ≥70 years, respectively (p-for-interaction<0·0001). Among patients with mechanical ventilation, the aOR was 0·79 (0·59–1·05).
Interpretation
Patients hospitalised with COVID-19 in Japan were more likely to die than those with influenza. However, this was mainly driven by findings in older people, and there was no difference once mechanical ventilation was started.
Funding
Ministry of Health, Labour and Welfare of Japan (21AA2007).
Human-factor issues were the most frequent reasons in both settings, while knowledge-based error rates were higher in general care. Our results suggest that proper education and training is needed to minimize patient safety incidents in facilities without respiratory therapists.
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