Tixagevimab-cilgavimab (AZD7442) for the treatment of patients hospitalized with COVID-19 (DisCoVeRy): A phase 3, randomized, double-blind, placebo-controlled trial (preprint)

Background Tixagevimab and cilgavimab (AZD7442) are two monoclonal antibodies developed by AstraZeneca for the pre-exposure prophylaxis and treatment of patients infected by SARS-CoV-2. Its effectiveness and safety in patients hospitalized with COVID-19 was not known at the outset of this trial. Methods DisCoVeRy is a phase 3, adaptive, multicentre, randomized, controlled trial conducted in 63 sites in Europe. Participants were randomly assigned (1:1) to receive placebo or tixagevimab-cilgavimab in addition to standard of care. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale. Several clinical, virological, immunological and safety endpoints were also assessed. Findings Due to slow enrolment, recruitment was stopped on July 1st, 2022. The antigen positive modified intention-to-treat population (mITT) was composed of 173 participants randomized to tixagevimab-cilgavimab (n=91) or placebo (n=82), 91.9% (159/173) with supplementary oxygen, and 47.4% (82/173) previously vaccinated at inclusion. There was no significant difference in the distribution of the WHO ordinal scale at day 15 between the two groups (odds ratio (OR) 0.93, 95%CI [0.54-1.61]; p=0.81) nor in any clinical, virological or safety secondary endpoints. In the global mITT (n=226), neutralization antibody titers were significantly higher in the tixagevimab-cilgavimab group/patients compared to placebo at day 3 (Least-square mean differences (LSMD) 1.44, 95% Confidence interval (CI) [1.20-1.68]; p < 10-23) and day 8 (LSMD 0.91, 95%CI [0.64-1.18]; p < 10-8) and it was most important for patients infected with a pre-omicron variant, both at day 3 (LSMD 1.94, 95% CI [1.67-2.20], p < 10-25) and day 8 (LSMD 1.17, 95% CI [0.87-1.47], p < 10-9), with a significant interaction (p < 10-7 and p=0.01 at days 3 and 8, respectively). Interpretation There were no significant differences between tixagevimab-cilgavimab and placebo in clinical endpoints, however the trial lacked power compared to prespecified calculations. Tixagevimab-cilgavimab was well tolerated, with low rates of treatment related events.

Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial (preprint)

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.

An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19 – Final results from the DisCoVeRy trial (preprint)

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.

High mortality of COVID-19 associated mucormycosis in France: a nationwide retrospective study (preprint)

We studied COVID-19 associated mucormycosis based on 17 cases reported nationwide and assessed the differences with India. They differed by frequencies of diabetes mellitus (47% in France versus 95% in India), hematological malignancies (35% versus 1%), anatomical sites (53% lung versus >80% rhino-orbito-cerebral) and prognosis (>80% mortality versus <50%).

Identification of driver genes for severe forms of COVID-19 in a deeply phenotyped young patient cohort (preprint)

The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (age and co-morbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major co-morbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 "critical" (in the ICU under mechanical ventilation) and 25 "non-critical" (in a noncritical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammation, perturbed lymphoid/myeloid compartments, coagulation and viral cell biology. Within a unique gene signature that differentiated critical from noncritical patients, several driver genes promoted severe COVID-19 among which the upregulated metalloprotease ADAM9 was key. This gene signature was replicated in an independent cohort of 81 critical and 73 recovered COVID-19 patients, as were ADAM9 transcripts, soluble form and proteolytic activity. Ex vivo ADAM9 inhibition affected SARS-CoV-2 uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, COVID-19 cohort, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. The key driver, ADAM9, interfered with SARS-CoV-2 biology. A repositioning strategy for anti-ADAM9 therapeutic is feasible. One sentence summaryEtiopathogenesis of severe COVID19 in a young patient population devoid of comorbidities.

Remdesivir for the Treatment of Hospitalised Patients with COVID-19 (DisCoVeRy): A Randomised, Controlled, Open-Label Trial (preprint)

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.

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial (preprint)

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

Evaluation of the performance of SARS-CoV-2 serological tools and their positioning in COVID-19 diagnostic strategies. (preprint)

Rapid and accurate diagnosis is crucial for successful outbreak containment. During the current coronavirus disease 2019 (COVID-19) public health emergency, the gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis is the detection of viral RNA by reverse transcription (RT)-PCR. Additional diagnostic methods enabling the detection of current or past SARS-CoV-2 infection would be highly beneficial to ensure the timely diagnosis of all infected and recovered patients. Here, we investigated several serological tools, i.e., two immunochromatographic lateral flow assays (LFA-1 (Biosynex COVID-19 BSS) and LFA-2 (COVID-19 Sign IgM/IgG)) and two enzyme-linked immunosorbent assays (ELISAs) detecting IgA (ELISA-1 Euroimmun), IgM (ELISA-2 EDI) and/or IgG (ELISA-1 and ELISA-2) based on well-characterized panels of serum samples from patients and healthcare workers with PCR-confirmed COVID-19 and from SARS-CoV-2-negative patients. A total of 272 serum samples were used, including 62 serum samples from hospitalized patients (panel 1 and panel 3), 143 serum samples from healthcare workers (panel 2) diagnosed with COVID-19 and 67 serum samples from negative controls. Diagnostic performances of each assay were assessed according to days after symptom onset (dso) and the antigenic format used by manufacturers. We found overall sensitivities ranging from 69% to 93% on panels 1 and 2 and specificities ranging from 83% to 98%. The clinical sensitivity varied greatly according to the panel tested and the dso. The assays we tested showed poor mutual agreement. A thorough selection of serological assays for the detection of ongoing or past infections is advisable.

Prognostic value of visual quantification of lesion severity at initial chest CT in confirmed Covid-19 infection: a retrospective analysis on 216 patients (preprint)

Rationale and Objectives Studies suggest an association between chest CT findings assessed with semiquantitative CT score and gravity of Covid-19. The objective of this work is to analyze potential correlation between visual quantification of lesion severity at initial chest CT and clinical outcome in confirmed Covid-19 patients. Materials and Methods From March 5 th to March 21 st , 2020, all consecutive patients that underwent chest CT for clinical suspicion of Covid-19 at a single tertiary center were retrospectively evaluated for inclusion. Patients with lung parenchyma lesions compatible with Covid- 19 and positive RT-PCR were included. Global extensiveness of abnormal lung parenchyma was visually estimated and classified independently by 2 readers, following the European Society of Thoracic Imaging Guidelines. Death and/or mechanical ventilation within 30 days following the initial chest CT was chosen as the primary hard endpoint. Results 216 patients (124 men, 62 years-old, range 22 ; 94 yo) corresponding to 216 chest CT were included. Correlation between lesion severity and percentage of patients that met the primary endpoint was high, with a coefficient p; of 0.87 (p = 0.05). A greater than 25% involvement was significantly associated with a higher risk of mechanical ventilation or death at 30 days, with a Risk Ratio of 5.00 (95% CI [3.59- 6.99]). Conclusion This retrospective cohort confirms a correlation between visual evaluation of lesions severity at initial chest CT and the 30 days clinical outcome of Covid-19 patients and suggests using a threshold of greater than 25% involvement to identify patients at risk.