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
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
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 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.
Article activity feed
-
SciScore for 10.1101/2022.02.16.22271064: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France), the trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744).
Consent: Written informed consent was obtained from all included participants or their legal representative, when unable to consent.Sex as a biological variable not detected. Randomization Trial design and oversight: DisCoVeRy is a phase 3 open-label, adaptive, multicenter, randomized, superiority-controlled trial which evaluates the efficacy and safety of repurposed drugs in adults hospitalized for COVID-19. Blinding Virological methods: Determination of normalized viral load blinded to treatment arm … SciScore for 10.1101/2022.02.16.22271064: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France), the trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744).
Consent: Written informed consent was obtained from all included participants or their legal representative, when unable to consent.Sex as a biological variable not detected. Randomization Trial design and oversight: DisCoVeRy is a phase 3 open-label, adaptive, multicenter, randomized, superiority-controlled trial which evaluates the efficacy and safety of repurposed drugs in adults hospitalized for COVID-19. Blinding Virological methods: Determination of normalized viral load blinded to treatment arm was performed on NPS and LRT specimens by RNA extraction on the EMAG® platform (bioMerieux, Marcy-l’Étoile, France). Power Analysis Sample size calculation: The sample size was determined assuming the following scenario under SoC for each item of the ordinal scale at day 15: 1, 42%; 2, 38%; 3, 8%; 4, 7%; 5, 2%; 6, 1%; 7, 2%. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The trial has limitations: the complexity of blinding treatments with different routes of administration and the need to initiate the trial very rapidly led to choose an open-labelled design. The trial did not target patients at the early phase of the disease nor include arms testing anti-inflammatory agents that could be used as part of the SoC in any arm. In addition, the trial was performed in the early phase of the COVID-19 pandemics and the SoC underwent substantial changes over time, adapting to knowledge acquisition, especially regarding the use of corticosteroids in COVID-19.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04315948 Recruiting Trial of Treatments for COVID-19 in Hospitalized Adults Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
-
-
-
SciScore for 10.1101/2021.01.08.20248149: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France), the trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744).
Consent: Written informed consent was obtained from all included participants or their legal representative if they were not able to consent.Randomization Trial design and oversight: DisCoVeRy is an open-label, adaptive, multicenter, randomized controlled trial which evaluates the efficacy and safety of drugs in adults hospitalized for COVID-19. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources …
SciScore for 10.1101/2021.01.08.20248149: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France), the trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744).
Consent: Written informed consent was obtained from all included participants or their legal representative if they were not able to consent.Randomization Trial design and oversight: DisCoVeRy is an open-label, adaptive, multicenter, randomized controlled trial which evaluates the efficacy and safety of drugs in adults hospitalized for COVID-19. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The trial has some limitations: it is not a placebo-controlled, double-blinded trial due to the complexity of blinding treatments with different mode of administration (intravenous, subcutaneous or oral) and the need to initiate the trial very rapidly. DisCoVeRy did not target patients at the early phase of the disease nor include arms testing anti-inflammatory agents that can be used as part of the standard of care in any arm.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04315948 Active, not recruiting Trial of Treatments for COVID-19 in Hospitalized Adults Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
SciScore for 10.1101/2021.01.08.20248149: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France), the trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744). Randomization 50 Université Picardie Jules Verne, AGIR UR UPJV 4294, CURS, F-80000 Amiens, France. randomized controlled trial Abstract Background: Open-label, randomized, adaptive, controlled trial. Blinding not detected. Power Analysis not detected. Sex as a biological variable The median age was 63 years (IQR, 54; 71) and participants were mostly male (n=418, 71.7%). Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not …
SciScore for 10.1101/2021.01.08.20248149: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France), the trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744). Randomization 50 Université Picardie Jules Verne, AGIR UR UPJV 4294, CURS, F-80000 Amiens, France. randomized controlled trial Abstract Background: Open-label, randomized, adaptive, controlled trial. Blinding not detected. Power Analysis not detected. Sex as a biological variable The median age was 63 years (IQR, 54; 71) and participants were mostly male (n=418, 71.7%). Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
The trial has some limitations: it is not a placebo-controlled, double-blinded trial due to the complexity of blinding treatments with different mode of administration (intravenous, subcutaneous or oral) and the need to initiate the trial very rapidly. DisCoVeRy did not target patients at the early phase of the disease nor include arms testing anti-inflammatory agents that can be used as part of the standard of care in any arm.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04315948 Recruiting Trial of Treatments for COVID-19 in Hospitalized Adults Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
-