ABSTRACT
Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring. Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948, EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-beta-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population. Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420). At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29). Interpretation: Remdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15. Funding: European Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER "European Regional Development Fund", Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.
Subject(s)
COVID-19 , Renal Insufficiency, Chronic , PneumoniaABSTRACT
Objectives We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. Methods We conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity ( NCT04315948 , EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely. Results The intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. Conclusion In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.
Subject(s)
COVID-19ABSTRACT
B.1.1.529 is the SARS-CoV-2 variant designated Omicron by the WHO in November 2021. It is a highly divergent variant with a high number of mutations, including 26-32 mutations in the spike protein among which 15 in the Receptor Binding Domain (RBD) including at the human angiotensin converting enzyme 2 (ACE-2) receptor interacting interface. Because of a decreased affinity for the ACE-2 receptor and a geometric reorganization of the S1-S2 cleavage site, the Omicron variant is predicted to not have a significant infectivity advantage over the delta variant and to be less pathogenic than Delta. However, in Omicron, neutralizing epitopes are greatly affected, suggesting that current vaccines and neutralizing monoclonal antibodies might confer reduced protection against this variant. In contrast, we and others previously demonstrated that polyclonal antibodies against SARS-CoV-2 RBD obtained from hyperimmunized animal hosts do maintain their neutralizing properties against Alpha to Delta. Here, we confirmed these findings by showing that XAV-19, a swine glyco-humanized polyclonal antibody retains full neutralizing activity against Omicron.
ABSTRACT
Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in patients with COVID-19 requiring oxygen and/or ventilator support.Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial in adults hospitalised with COVID-19 (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care alone or in combination with intravenous remdesivir (200 mg on day 1, then 100 mg once-daily for 9 days or until discharge). Treatment assignation was performed via web-based randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 832 participants were included for the evaluation of remdesivir (control, n=418; remdesivir, n=414). There was no difference in the clinical status neither at day 15 between treatment groups (OR for remdesivir, 0.98, 95% CI, 0.77 to 1.25, P=0.85) nor at day 29. The proportion of deaths at day 28 was not significantly different between control (8.9%) and remdesivir (8.2%) treatment groups (OR for remdesivir, 0.93 95%CI 0.57 to 1.52, P=0.77). There was also no difference on SARS-CoV-2 viral kinetics (effect of remdesivir on viral load slope, -0.004 log10 cp/10,000 cells/day, 95% CI, -0.03 to 0.02, P=0.75). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups.Interpretation: The use of remdesivir for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15 or day 29, nor with a reduction in mortality, nor with a reduction in SARS-CoV-2 RNA.Trial Registration: DisCoVeRy, NCT04315948; EudraCT2020-000936-23Funding: European Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE)Declaration of Interests: Dr. Costagliola reports grants and personal fees from Janssen, personal fees from Gilead, outside the submitted work. Dr. Mentré reports grants from INSERM Reacting (French Government), grants from Ministry of Health (French Government), grants from European Commission, during the conduct of the study; grants from Sanofi, grants from Roche, outside the submitted work. Dr. Hites reports grants from The Belgian Center for Knowledge (KCE), grants from Fonds Erasme-COVID-ULB, during the conduct of the study; personal fees from Gilead, outside the submitted work. Dr. Mootien reports non-financial support from GILEAD, outside the submitted work. Dr. Gaborit reports non-financial support from Gilead, non- financial support from MSD, outside the submitted work. Dr. Botelho-Nevers reports other from Pfizer, other from Janssen, outside the submitted work. Dr. Lacombe reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Dr. Wallet reports personal fees and non-financial support from Jazz pharmaceuticals, personal fees and non-financial support from Novartis, personal fees and nonPage financial support from Kite-Gilead, outside the submitted work. Dr. Kimmoun reports personal fees from Aguettan, personal fees from Aspen, outside the submitted work. Dr. Thiery reports personal fees from AMGEN, outside the submitted work. Dr. Burdet reports personal fees from Da Volterra, personal fees from Mylan Pharmaceuticals, outside the submitted work. Dr. Poissy reports personal fees from Gilead for lectures, outside the submitted work. Dr. Goehringer reports personal fees from Gilead Sciences, non-financial support from Gilead Sciences, grants from Biomerieux, non-financial support from Pfizer, outside the submitted work. Dr. Peytavin reports personal fees from Gilead Sciences, personal fees from Merck France, personal fees from ViiV Healthcare, personal fees from TheraTechnologies, outside the submitted work. Dr. Danion reports personal fees from Gilead, outside the submitted work. Dr. Raffi reports personal fees from Gilead, personal fees from Janssen, personal fees from MSD, personal fees from Abbvie, personal fees from ViiV Healthcare, personal fees from Theratechnologies, personal fees from Pfizer, outside the submitted work. Dr. Gallien reports personal fees from Gilead, personal fees from Pfizer, personal fees from ViiV, personal fees from MSD, outside the submitted work; and has received consulting fee from Gilead in August 2020 to check the registration file of remdesivir for the French administration. Dr. Nseir reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomérieux, personal fees from BioRad, outside the submitted work. Dr. Lefèvre reports personal fees from Mylan, personal fees from Gilead, outside the submitted work. Dr. Guedj reports personal fees from Roche, outside the submitted work. Other authors have nothing to disclose.Ethics Approval Statement: The trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744), and is sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France); it was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all included participants (or their legal representatives if unable to consent). The present analysis is based on the protocol v11.0 of December 12th, 2020.
Subject(s)
COVID-19 , Multiple Sulfatase Deficiency DiseaseABSTRACT
Background: We 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 microg/mL. Methods: In 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. Results: Eighteen 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 (microg/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 microg/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. Conclusions: Single intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability.
Subject(s)
COVID-19 , Pneumonia , Drug HypersensitivityABSTRACT
Amino acid substitutions and deletions in spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. We report on XAV-19, a swine glyco-humanized polyclonal antibody (GH-pAb) raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 spike protein of SARS-CoV-2. XAV-19 target epitopes are distributed all over the RBD and particularly cover the receptor binding motives (RBM), on direct contact sites with the Angiotensin Converting Enzyme-2 (ACE-2). Using spike/ACE2 interaction assays, we analyzed in vitro the impact of punctual and grouped mutations in the S protein corresponding to the B.1.1.7 (British form; UK) and B.1.351 (South-African form, SA) variants and recorded that neutralization by XAV-19 exhibited little if any sensitivity to these mutations. These results were confirmed by two independent tissue culture infective doses assays (TCID) showing 100% neutralization of the variants at close concentrations. XAV-19, which is currently evaluated in patients hospitalized for coronavirus disease 2019 (Covid-19) in the phase 2a-2b of the POLYCOR study (ClinicalTrial.gov, NCT04453384), may provide a novel effective therapeutic tool to combat coronavirus disease 2019 (Covid-19), caused by the original Wuhan form and by the UK/SA variants of concern.
Subject(s)
Coronavirus Infections , COVID-19ABSTRACT
Background: Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective: To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design: Open-label, randomized, adaptive, controlled trial. Setting: Multi-center trial with patients from France. Participants: 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention: Standard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-beta-1a (44 micrograms of subcutaneous IFN-beta-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). Measurements: The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses. Results: Adjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-beta-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. Limitations: Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion: No improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. Registration: NCT04315948. Funding: PHRC 2020, Dim OneHealth, REACTing