Pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, for COVID-19-related moderate pneumonia: a randomized, double-blind, placebo-controlled, phase IIa study

BackgroundWe assessed the pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2, in COVID-19-related moderate pneumonia. In vitro, 100% neutralization activity is seen with XAV-19 concentrations above 5 g/mL. MethodsIn this phase 2a trial, adults with COVID-19-related moderate pneumonia of [≤]10 days duration were randomized to infusion of XAV-19 0.5 mg/kg at day 1 and day 5 (group 1), 2 mg/kg at day 1 and day 5 (group 2), 2 mg/kg at day 1 (group 3) or placebo. ResultsEighteen patients (n=7 for group 1, n=1 for group 2, n=5 for group 3, and n=5 for placebo) were enrolled. Baseline characteristics were similar across groups, XAV-19 serum concentrations (g/mL, median, range) at Cmax and at day 8 were 9.1 (5.2-18.1) and 6.4 (2.8-11.9), 71.5 and 47.2, and 50.4 (29.1-55.0) and 20.3 (12.0-22.7) for groups 1, 2 and 3, respectively (p=0.012). Terminal half-life (median, range) was estimated at 11.4 (5.5-13.9) days for 2 mg/kg of XAV-19 at day 1. Serum XAV-19 concentrations were above the target concentration of 10 g/mL (tow fold the in vitro 100% inhibitory concentration [IC100]) from the end of perfusion to more than 8 days for XAV-19 2 mg/kg at day 1. No hypersensitivity or infusion-related reactions were reported during treatment, there was no discontinuation for adverse events and no serious adverse events related to study drug. ConclusionsSingle intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability. Trial registrationClinicalTrials.gov Identifier: NCT04453384 Main pointIn this first-in-human trial including patients with COVID-19-related pneumonia, a single 2mg/kg dose of a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, achieved serum concentrations above the target of neutralization threshold for 8 days in all patients, with good tolerability and safety.

Point-of-care ultrasonography for risk stratification of non-critical suspected COVID-19 patients on admission (POCUSCO): a prospective binational study

BackgroundLung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may allow early identification of patients who are likely to develop an acute respiratory distress syndrome (ARDS). We hypothesized that L-POCUS performed during the initial examination would identify non-severe COVID-19 patients with a high risk of getting worse. MethodsPOCUSCO was a prospective, multicenter study. Non-critical adult patients who were admitted to the emergency department (ED) for suspected or confirmed COVID-19 were included and had L-POCUS performed within 48 hours following admission. The severity of lung damage was assessed using the L-POCUS score based on 36 points for ARDS. The primary outcome was the rate of patients requiring intubation or who died within 14 days following inclusion. ResultsAmong 296 participating patients, 8 (2.7%) had primary outcome. The area under the curve (AUC) of the receiver operating characteristic of L-POCUS was 0.80 [95%CI:0.60-0.94]. The score values which achieved a sensibility > 95% in defining low-risk patients and a specificity > 95% in defining high-risk patients were <1 and [≥]16, respectively. The rate of patients with an unfavorable outcome was 0/95 (0%[95%CI:0-3.9]) for low-risk patients (score=0) versus 4/184 (2.17%[95%CI:0.8-5.5]) for intermediate-risk patients (score 1-15) and 4/17 (23.5%[95%CI:11.4-42.4]) for high-risk patients (score [≥]16). In patients with confirmed COVID-19 (n=58), the AUC of L-POCUS was 0.97 [95%CI:0.92-1.00]. ConclusionsL-POCUS allows risk-stratification of patients with suspected or confirmed COVID-19. These results should be confirmed in a population with a higher risk of an unfavorable outcome. Trial registration numberNCT04338100

A placebo-controlled double blind trial of hydroxychloroquine in mild-to-moderate COVID-19

BackgroundThe efficacy of hydroxychloroquine in coronavirus disease 2019 (COVID-19) remains controversial. MethodsWe conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: age [≥]75 years, age between 60 and 74 years, and presence of at least one comorbidity, or need for supplemental oxygen ([≤]3 L/min). Eligible patients were randomized in a 1:1 ratio to receive either 800mg hydroxychloroquine on Day 0 followed by 400mg per day for 8 days or a placebo. The primary endpoint was a composite of death or tracheal intubation within 14 days following randomization. Secondary endpoints included mortality and clinical evolution at Day 14 and 28, viral shedding at Day 5 and 10. ResultsThe trial was stopped after 250 patients were included due to a slowdown of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years and 151 patients required oxygen therapy. The primary endpoint occurred in nine patients in the hydroxychloroquine group and eight patients in the placebo group (relative risk 1.12; 95% confidence interval 0.45- 2.80; P=0.82). No difference was observed between the two groups in any of the secondary endpoints. ConclusionIn this trial involving mainly older patients with mild-to-moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo.

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We conducted a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine was 1.11 (95% CI: 1.02, 1.20; I2=0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I2=0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine was associated with increased mortality in COVID-19 patients, and there was no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.