Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

National Early Warning Score 2 (NEWS2) on admission predicts severe disease and in-hospital mortality from Covid-19 - a prospective cohort study.

BACKGROUND: There is a need for validated clinical risk scores to identify patients at risk of severe disease and to guide decision-making during the covid-19 pandemic. The National Early Warning Score 2 (NEWS2) is widely used in emergency medicine, but so far, no studies have evaluated its use in patients with covid-19. We aimed to study the performance of NEWS2 and compare commonly used clinical risk stratification tools at admission to predict risk of severe disease and in-hospital mortality in patients with covid-19. METHODS: This was a prospective cohort study in a public non-university general hospital in the Oslo area, Norway, including a cohort of all 66 patients hospitalised with confirmed SARS-CoV-2 infection from the start of the pandemic; 13 who died during hospital stay and 53 who were discharged alive. Data were collected consecutively from March 9th to April 27th 2020. The main outcome was the ability of the NEWS2 score and other clinical risk scores at emergency department admission to predict severe disease and in-hospital mortality in covid-19 patients. We calculated sensitivity and specificity with 95% confidence intervals (CIs) for NEWS2 scores ≥5 and ≥ 6, quick Sequential Organ Failure Assessment (qSOFA) score ≥ 2, ≥2 Systemic Inflammatory Response Syndrome (SIRS) criteria, and CRB-65 score ≥ 2. Areas under the curve (AUCs) for the clinical risk scores were compared using DeLong's test. RESULTS: In total, 66 patients (mean age 67.9 years) were included. Of these, 23% developed severe disease. In-hospital mortality was 20%. Tachypnoea, hypoxemia and confusion at admission were more common in patients developing severe disease. A NEWS2 score ≥ 6 at admission predicted severe disease with 80.0% sensitivity and 84.3% specificity (Area Under the Curve (AUC) 0.822, 95% CI 0.690-0.953). NEWS2 was superior to qSOFA score ≥ 2 (AUC 0.624, 95% CI 0.446-0.810, p < 0.05) and other clinical risk scores for this purpose. CONCLUSION: NEWS2 score at hospital admission predicted severe disease and in-hospital mortality, and was superior to other widely used clinical risk scores in patients with covid-19.

Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation.

OBJECTIVES: To determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients, and the impact of dexamethasone as standard therapy. METHODS: This multicentre, observational, retrospective study included patients ≥ 18 years admitted from March 1st 2020 to January 31st 2021 with COVID-19 infection who received mechanical ventilation. Patient characteristics, clinical characteristics, therapy and survival were examined. RESULTS: 155/156 patients (115 men, mean age 62 years, range 26-84 years) were included. 67 patients (43%) had 90 superinfections, pneumonia dominated (78%). Superinfections were associated with receiving dexamethasone (66% vs 32%, p<0.0001), autoimmune disease (18% vs 5.7%, p<0.016) and with longer ICU stays (26 vs 17 days, p<0,001). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [8/67 (12%) vs 0/88 (0%), p<0.0001]. Unadjusted 90-day survival did not differ between patients with or without superinfections (64% vs 73%, p=0.25), but was lower in patients receiving dexamethasone versus not (58% vs 78%, p=0.007). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 3.7 (1.80-7.61), p<0.001], pre-existing autoimmune disease [OR 3.82 (1.13-12.9), p=0.031] and length of ICU stay [OR 1.05 p<0.001]. CONCLUSIONS: In critically ill COVID-19 patients, dexamethasone as standard of care was strongly and independently associated with superinfections.