key: cord-0898942-up0e0pi0
authors: ADER, F.; PEIFFER-SMADJA, N.; POISSY, J.; BOUSCAMBERT-DUCHAMP, M.; BELHADI, D.; DIALLO, A.; DELMAS, C.; SAILLARD, J.; DECHANET, A.; MERCIER, N.; DUPONT, A.; ALFAIATE, T.; LESCURE, F.-X.; RAFFI, F.; GOEHRINGER, F.; KIMMOUN, A.; JAUREGUIBERRY, S.; REIGNIER, J.; NSEIR, S.; DANION, F.; CLERE-JEHL, R.; BOUILLER, K.; NAVELLOU, J.-C.; TOLSMA, V.; CABIE, A.; DUBOST, C.; COURJON, J.; LEROY, S.; MOOTIEN, J.; GACI, R.; MOURVILLIER, B.; FAURE, E.; POURCHER, V.; GALLIEN, S.; LAUNAY, O.; LACOMBE, K.; LANOIX, J.-P.; MAKINSON, A.; MARTIN-BLONDEL, G.; BOUADMA, L.; BOTELHO-NEVERS, e.; GAGNEUX-BRUNON, A.; EPAULA,
title: An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19 - Final results from the DisCoVeRy trial
date: 2022-02-21
journal: nan
DOI: 10.1101/2022.02.16.22271064
sha: 0697d3edd70aafd2c631733774902aacdfc84446
doc_id: 898942
cord_uid: up0e0pi0

Objectives We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-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-beta-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-beta-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-beta-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

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.

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/ritonavircontaining arms and for the hydroxychloroquine arm, which were stopped prematurely.

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 The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.

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.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. ; https://doi.org/10.1101/2022.02. 16 .22271064 doi: medRxiv preprint

Worldwide research efforts against SARS-CoV-2 initially focused on repurposed drugs that showed broad-spectrum antiviral activity against coronaviruses (1, 2) . Lopinavir/ritonavir (3, 4) , type I interferon (IFN) (5-7), hydroxychloroquine (8) (9) (10) , and remdesivir (11) were among the first investigational treatments to be tested on the basis of their in vitro activity against SARS-CoV-2.

The DisCoVeRy trial is a European randomized controlled trial evaluating the clinical and the virological efficacy, as well as the safety, of lopinavir/ritonavir, lopinavir/ritonavir plus IFNβ-1a, hydroxychloroquine, and remdesivir as compared with standard of care in adults hospitalized for COVID- 19 (12) . As an add-on trial to the international Solidarity trial sponsored by the World Health Organization (WHO), it has contributed to data acquisition on in-hospital mortality, need for mechanical ventilation and time to hospital discharge. Interim analyses of these variables concluded to futility, leading to discontinuation of three treatment arms while inclusions continued in the remdesivir arm (13) . The DisCoVeRy trial was designed to further document clinical outcomes, virological kinetics, treatment pharmacokinetics and related safety data. We report here the final results for the lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine arms, after completion of the data monitoring. Preliminary results were previously published (14) .

Results for the remdesivir arm have been presented separately (15) .

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. 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). Written informed consent was obtained from all included participants or their legal representative, when unable to consent. The trial was conducted in accordance with the Declaration of Helsinki and national laws and regulations and declared on the clinicatrials.gov registry (NCT 04315948) and on the European Clinical Trials Database (2020-000936-23).

Eligible participants were adults (≥ 18-year-old) hospitalized with a PCR-positive (< 72 hours) SARS-CoV-2 infection and pulmonary rales or crackles with a peripheral oxygen . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) saturation ≤ 94% or requiring supplemental oxygen. Inclusion and exclusion criteria are presented in the Supplementary Appendix.

Participants were randomly assigned to treatment arms in a 1:1 Hospitalized, on non-invasive ventilation or high flow oxygen devices; 6. Hospitalized, on invasive mechanical ventilation or ECMO; 7. Death.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) cell quantification was below 500 cells/reaction, the quality of the sample was considered too low to be measured. We computed a normalized SARS-CoV-2 load by dividing the viral load by the number of cells. All viral loads strictly below 1 log 10 RNA copies/10 000 cells were considered under the limit of detection and were reported as negative.

Plasma concentrations of lopinavir, ritonavir and hydroxychloroquine were determined using liquid chromatography coupled with tandem mass spectrometry (19, 20) . The limits of quantification were 30 ng/mL for lopinavir and ritonavir, and 10 ng/mL for hydroxychloroquine.

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%. At the time of the trial design, there was a significant uncertainty with these assumptions. We powered the study for an odds ratio of 1.5 (an odds ratio higher than 1 indicates superiority of the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. experimental treatment over the control for each ordinal scale category), with 90% power and using an overall two-sided type I error rate of 0.05. Adjusting for multiplicity of 4 pairwise comparisons with the control arm in a 5-arm setting, the two-sided false positive error rate would be 0.0125. We determined that the inclusion of 620 patients in each treatment arm was required.

An independent data safety and monitoring board ( 

Between March 22 nd and June 29 th 2020, 603 participants were randomized across 30 sites in 

The distribution of the 7-point ordinal scale at day 15 is presented in Figure 1 and Table 2 . 

There was no significant difference between any of the treatment and control arms on the 7point ordinal scale at day 29 ( Figure 1 and Table 2 ). The time to improvement of 2 categories . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. No other significant difference was observed for other secondary outcomes (Table 2 and Supplementary Figures S2-S4 ).

The slope of the decrease of the viral loads in NPS over time was not significantly affected by any of the investigational treatments ( Figure 2 ). No significant difference in the proportion of participants with detectable viral loads at each sampling time was observed in the NPS nor in the LRT specimens (Supplementary Table S2 and S3). 

The safety analysis included 589 participants (control, n=149; lopinavir/ritonavir, n=147;

lopinavir/ritonavir plus IFN-β-1a, n=145; hydroxychloroquine, n=148). Safety outcomes are presented in Table 3 . Among 2524 reported AEs, 570 were graded 3 or 4 in 243 patients and mostly reported in lopinavir/ritonavir-containing arms (Table 3) .

A total of 856 SAEs were reported in 282 participants; 189 (22.1%) were related to the investigational drug according to investigator's judgment (lopinavir/ritonavir arm, n=54

lopinavir/ritonavir plus IFN-β-1a arm, n=89; hydroxychloroquine arm, n=46). A significantly greater number of patients experienced at least one SAE in the lopinavir/ritonavir-containing arms than in the control arm ( Table 3 ). The most frequently reported SAEs were acute . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 

In patients admitted to hospital with COVID-19, lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine were not associated with clinical improvement at day 15 and day 29, nor reduction in viral shedding, and generated significantly more SAEs in lopinavir/ritonavir-containing arms. These findings do not support the use of these investigational treatments for patients hospitalized with COVID-19.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Reported numbers refer to the proportion of patients with the corresponding level in each group. L/r, Lopinavir/ritonavir; L/r + IFN, Lopinavir/ritonavir + interferon ß-1a; HCQ, Hydroxychloroquine.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. 

L/r, Lopinavir/ritonavir (blue line); L/r + IFN, Lopinavir/ritonavir + interferon ß-1a (yellow line);

HCQ, Hydroxychloroquine (red line); control (black line).

LSMD, least-square mean difference; 95%CI, 95% confidence interval.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. Table 3 . Summary of adverse events according treatment group in the modified intention to treat population.

In the "Overall" column, numbers refer to number of events and number of patients. In other columns, number refer to number of patients (%).

Some patients had more than a single SAE. Analyses were performed on the modified Intention-to-treat population. SAE, Serious Adverse Event. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 21, 2022. 

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It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)