DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function.

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.

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Recovery of cardiac function following COVID-19 - ECHOVID-19: a prospective longitudinal cohort study.

AIMS: The degree of cardiovascular sequelae following COVID-19 remains unknown. The aim of this study was to investigate whether cardiac function recovers following COVID-19. METHODS AND RESULTS: A consecutive sample of patients hospitalized with COVID-19 was prospectively included in this longitudinal study. All patients underwent an echocardiographic examination during hospitalization and 2 months later. All participants were successfully matched 1:1 with COVID-19-free controls by age and sex. A total of 91 patients were included (mean age 63 ± 12 years, 59% male). A median of 77 days (interquartile range: 72-92) passed between the two examinations. Right ventricular (RV) function improved following resolution of COVID-19: tricuspid annular plane systolic excursion (TAPSE) (2.28 ± 0.40 cm vs. 2.11 ± 0.38 cm, P < 0.001) and RV longitudinal strain (RVLS) (25.3 ± 5.5% vs. 19.9 ± 5.8%, P < 0.001). In contrast, left ventricular (LV) systolic function assessed by global longitudinal strain (GLS) did not significantly improve (17.4 ± 2.9% vs. 17.6 ± 3.3%, P = 0.6). N-terminal pro-B-type natriuretic peptide decreased between the two examinations [177.6 (80.3-408.0) ng/L vs. 11.7 (5.7-24.0) ng/L, P < 0.001]. None of the participants had elevated troponins at follow-up compared to 18 (27.7%) during hospitalization. Recovered COVID-19 patients had significantly lower GLS (17.4 ± 2.9% vs. 18.8 ± 2.9%, P < 0.001 and adjusted P = 0.004), TAPSE (2.28 ± 0.40 cm vs. 2.67 ± 0.44 cm, P < 0.001 and adjusted P < 0.001), and RVLS (25.3 ± 5.5% vs. 26.6 ± 5.8%, P = 0.50 and adjusted P < 0.001) compared to matched controls. CONCLUSION: Acute COVID-19 affected negatively RV function and cardiac biomarkers but recovered following resolution of COVID-19. In contrast, the observed reduced LV function during acute COVID-19 did not improve post-COVID-19. Compared to the matched controls, both LV and RV function remained impaired.