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BACKGROUND: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. METHODS: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. FINDINGS: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. INTERPRETATION: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04382053.
RESUMEN
Objective: This study examined cumulative excess mortality in European countries in the year of the Covid-19 pandemic and characterized the dynamics of the pandemic in different countries, focusing on Hungary and the Central and Eastern European region. Methods: Age-standardized cumulative excess mortality was calculated based on weekly mortality data from the EUROSTAT database, and was compared between 2020 and the 2016-2019 reference period in European countries. Results: Cumulate weekly excess mortality in Hungary was in the negative range until week 44. By week 52, it reached 9,998 excess deaths, corresponding to 7.73% cumulative excess mortality vs. 2016-2019 (p-value = 0.030 vs. 2016-2019). In Q1, only Spain and Italy reported excess mortality compared to the reference period. Significant increases in excess mortality were detected between weeks 13 and 26 in Spain, United Kingdom, Belgium, Netherland and Sweden. Romania and Portugal showed the largest increases in age-standardized cumulative excess mortality in the Q3. The majority of Central and Eastern European countries experienced an outstandingly high impact of the pandemic in Q4 in terms of excess deaths. Hungary ranked 11th in cumulative excess mortality based on the latest available data of from the EUROSTAT database. Conclusion: Hungary experienced a mortality deficit in the first half of 2020 compared to previous years, which was followed by an increase in mortality during the second wave of the COVID-19 pandemic, reaching 7.7% cumulative excess mortality by the end of 2020. The excess was lower than in neighboring countries with similar dynamics of the pandemic.