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

Ader, Florence; Peiffer-Smadja, Nathan; Poissy, Julien; Bouscambert‐Duchamp, Maude; Belhadi, Drifa; Diallo, Alpha; Delmas, Christelle; Saillard, Juliette; Dechanet, Aline; Mercier, Noémie; Dupont, Axelle; Alfaiate, Toni; Lescure, François-Xavier; Raffi, François; Goehringer, François; Kimmoun, Antoine; Jauréguiberry, Stéphane; Reignier, Jean; Nseir, Saad; Danion, François; Clère-Jehl, Raphaël; Bouiller, Kévin; Navellou, Jean-Christophe; Tolsma, V.; Cabie, André; Dubost, C; Courjon, Johan; Leroy, Sylvie; Mootien, Joy; Gaci, Rostane; Mourvillier, Bruno; Faure, Emmanuel; Pourcher, Valérie; Gallien, Sébastien; Launay, Odile; Lacombe, Karine; Lanoix, Jean‐Philippe; Makinson, Alain; Martin‐Blondel, Guillaume; Bouadma, Lila; Botelho-Nevers, Élisabeth; Gagneux‐Brunon, Amandine; Épaulard, Olivier; Piroth, Lionel; Wallet, Florent; Richard, Jean-Christophe; Reuter, Jean; Staub, Thérèse; Lina, Bruno; Noret, Marion; Andréjak, Claire; Lê, Minh Patrick; Peytavin, Gilles; Hites, Maya; Costagliola, Dominique; Yazdanpanah, Yazdan; Burdet, Charles; Mentré, France

doi:10.1016/j.cmi.2021.05.020

Cited by 87 publications

(85 citation statements)

References 29 publications

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“…The hospital discharge rate was reported in 65 studies including 53,636 patients and 34,247 events. Treatment nodes included in the network were azithromycin, bamlanivimab, baricitinib plus remdesivir, camostat mesilate, canakinumab, convalescent plasma, dapagliflozin, dexamethasone, favipiravir, hydroxychloroquine, hydroxychloroquine plus azithromycin, hydroxychloroquine plus favipiravir, interferon beta, ivermectin, lopinavir/ritonavir, mesenchymal stem cells, remdesivir, sarilumab, tocilizumab, tofacitinib and SOC, which were investigated in 48 studies ( 3 , 6 , 22 – 26 , 31 , 43 , 46 , 55 , 57 , 64 , 71 – 73 , 76 , 80 , 82 , 84 , 89 , 91 , 93 , 96 – 98 , 100 , 101 , 106 , 107 , 109 , 110 , 115 , 116 , 121 , 122 , 124 , 126 , 128 – 132 , 145 – 147 , 157 , 158 ). Out of the 48 studies included in the NMA, 19 were evaluated as low risk ( Supplementary Table 7 ).…”

Section: Resultsmentioning

confidence: 99%

“…A total of 45 studies including 6,631 patients reported viral clearance rates and after eliminating treatments with inadequate numbers of patients, 32 studies were considered in the NMA ( 36 , 53 , 54 , 56 , 57 , 59 , 65 , 68 , 71 , 72 , 76 , 78 , 80 , 91 , 106 , 109 , 119 , 132 , 136 , 137 , 141 , 153 , 157 – 166 ), of which 10 were assessed as low risk ( Supplementary Table 8 ). Treatment nodes in the network included bamlanivimab, bamlanivimab plus etesevimab, convalescent plasma, favipiravir, hydroxychloroquine, hydroxychloroquine plus azithromycin, hydroxychloroquine plus favipiravir, ivermectin, ivermectin plus doxycycline, lopinavir/ritonavir, methylprednisolone, nitazoxanide, proxalutamide, remdesivir and SOC.…”

Section: Resultsmentioning

confidence: 99%

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Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Zhang

Jin

Wen

et al. 2021

Front. Public Health

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Background: We provided a comprehensive evaluation of efficacy of available treatments for coronavirus disease 2019 (COVID-19).Methods: We searched for candidate COVID-19 studies in WHO COVID-19 Global Research Database up to August 19, 2021. Randomized controlled trials for suspected or confirmed COVID-19 patients published on peer-reviewed journals were included, regardless of demographic characteristics. Outcome measures included mortality, mechanical ventilation, hospital discharge and viral clearance. Bayesian network meta-analysis with fixed effects was conducted to estimate the effect sizes using posterior means and 95% equal-tailed credible intervals (CrIs). Odds ratio (OR) was used as the summary measure for treatment effect. Bayesian hierarchical models were used to estimate effect sizes of treatments grouped by the treatment classifications.Results: We identified 222 eligible studies with a total of 102,950 patients. Compared with the standard of care, imatinib, intravenous immunoglobulin and tocilizumab led to lower risk of death; baricitinib plus remdesivir, colchicine, dexamethasone, recombinant human granulocyte colony stimulating factor and tocilizumab indicated lower occurrence of mechanical ventilation; tofacitinib, sarilumab, remdesivir, tocilizumab and baricitinib plus remdesivir increased the hospital discharge rate; convalescent plasma, ivermectin, ivermectin plus doxycycline, hydroxychloroquine, nitazoxanide and proxalutamide resulted in better viral clearance. From the treatment class level, we found that the use of antineoplastic agents was associated with fewer mortality cases, immunostimulants could reduce the risk of mechanical ventilation and immunosuppressants led to higher discharge rates.Conclusions: This network meta-analysis identified superiority of several COVID-19 treatments over the standard of care in terms of mortality, mechanical ventilation, hospital discharge and viral clearance. Tocilizumab showed its superiority compared with SOC on preventing severe outcomes such as death and mechanical ventilation as well as increasing the discharge rate, which might be an appropriate treatment for patients with severe or mild/moderate illness. We also found the clinical efficacy of antineoplastic agents, immunostimulants and immunosuppressants with respect to the endpoints of mortality, mechanical ventilation and discharge, which provides valuable information for the discovery of potential COVID-19 treatments.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Zhang

Jin

Wen

et al. 2021

Front. Public Health

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“…Eleven new RCTs were retrieved by the SLR search update, adding to the existing eight RCTs on HCQ included in the previous SLR. Out of these 11 new studies, 4 have been stopped early for futility, 4–7 2 have been stopped for harmful effects of one or several compounds in the intervention arms, 8 9 and 1 is underpowered, 10 hence the results are not described in this manuscript. Out of the six studies that included patients with moderate to severe COVID-19, one compared HCQ to chloroquine or ivermectine showing no efficacy on death, progression to invasive mechanical ventilation (IMV) or admission to intensive care unit (ICU) at day 90.…”

Section: Resultsmentioning

confidence: 99%

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider

et al. 2021

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ObjectiveTo update the EULAR 2020 systematic literature review (SLR) on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.MethodsAs part of a EULAR taskforce, a systematic literature search update was conducted from 11 December 2020 to 14 July 2021. Two reviewers independently identified eligible studies and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage of disease. The risk of bias (RoB) was assessed with validated tools.ResultsOf the 26 959 records, 520 articles were eligible for inclusion. Studies were mainly at high or unclear RoB. New randomised controlled trials (RCTs) on tocilizumab clarified its benefit in patients with severe and critical COVID-19, mainly if associated with glucocorticoids. There are emergent data on the usefulness of baricitinib and tofacitinib in severe COVID-19. Other therapeutic strategies such as the use of convalescent plasma and anti-SARS-CoV-2 monoclonal antibodies showed efficacy in subjects not mounting normal anti-SARS-CoV-2 antibody responses.ConclusionThis new SLR confirms that some immunomodulators (tocilizumab and JAK inhibitors) have a role for treating severe and critical COVID-19. Although better evidence is available compared with the previous SLR, the need of RCT with combination therapy (glucocorticoids+anti-cytokines) versus monotherapy with glucocorticoids still remains alongside the need for standardisation of inclusion criteria and outcomes to ultimately improve the care and prognosis of affected people. This SLR informed the 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

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“…Participants were randomly assigned 1:1:1:1:1 when five groups were initially implemented, and were then assigned 1:1 to receive either standard of care or standard of care plus remdesivir, once the other three treatment groups had been stopped for futility. 2 Participants allocated to standard of care alone or in combination with remdesivir were recruited contemporaneously.…”

Section: Randomisation and Maskingmentioning

confidence: 99%

“…1 Results for lopinavir-ritonavir, lopinavirritonavir plus interferon beta-1a, and hydroxychloroquine have been reported elsewhere. 2 Remdesivir is a small molecule that is formulated with sulfobutylether B-cyclodextrin sodium for injection, is dialysable, is known to penetrate well into deep compartments, and is devoid of drug interactions via CYP450. 3,4 Remdesivir is a nucleotide analogue prodrug that is intracellularly metabolised to an analogue of ATP, which inhibits RNA polymerase activity in some pathogenic coronaviruses.…”

Section: Introductionmentioning

confidence: 99%

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

Egle¹,

Greil

Joannidis³

et al. 2022

The Lancet Infectious Diseases

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273

269

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Background The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h 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. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov , NCT04315948 . Findings Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporea...

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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

Abstract: C, Mentre F, on behalf of the DisCoVeRy study group, An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with Clinical Microbiology and Infection,

Cited by 87 publications

References 29 publications

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

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