Abstract
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 coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.
Methods: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial ( NCT04315948 , EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely.
Results: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). 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-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.
Keywords: COVID-19; Hydroxychloroquine; Interferon β-1a; Lopinavir/ritonavir; Randomized controlled trial; SARS-CoV-2.
【저자키워드】 COVID-19, Randomized controlled trial, SARS-CoV-2, Lopinavir/ritonavir, Hydroxychloroquine, Interferon β-1a, 【초록키워드】 Randomized controlled trial, Treatment, SARS-CoV-2, coronavirus, Lopinavir/ritonavir, Trial, Open-label, Hydroxychloroquine, adaptive, Lopinavir, Ritonavir, Remdesivir, oxygen, outcome, severe acute respiratory syndrome Coronavirus, clinical status, Randomized, male, Controlled trial, age, multicentre, quantification, Ordinal Scale, pharmacokinetic, Interferon β-1a, respiratory specimens, severe disease, regimen, ventilatory support, Standard of care, Inpatient, ARMS, plasma concentration, Serious Adverse Events, Serious Adverse Event, acute respiratory syndrome, Virological, adjusted odds ratio, Primary outcome, not improved, 95%CI, acute respiratory syndrome coronavirus, no significant effect, significant effect, acute respiratory syndrome coronavirus 2, 95% confidence interval, Secondary outcomes, intention-to-treat population, median age, coronavirus 2019 disease, participant, treat, LOPINAVIR AND RITONAVIR, SARS-CoV-2 clearance, trough, respiratory tract specimens, solidarity, Arm, secondary, seven-point ordinal scale, Solidarity trial, Occurrence, respiratory specimen, evaluated, conducted, significantly higher, the WHO, expected, analyses, adults hospitalized, IQR, the median, 【제목키워드】 Lopinavir/ritonavir, Open-label, Hydroxychloroquine, hospitalized patient, with COVID-19,