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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

Ader et al., medRxiv, doi:10.1101/2022.02.16.22271064
Oct 2020  
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Mortality, day 90 -15% Improvement Relative Risk Mortality, day 28 10% Viral clearance 24% HCQ  Ader et al.  LATE TREATMENT  RCT Is late treatment with HCQ beneficial for COVID-19? RCT 299 patients in multiple countries (March - June 2020) Trial underpowered to detect differences Ader et al., medRxiv, October 2020 FavorsHCQ Favorscontrol 0 0.5 1 1.5 2+
HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now with p < 0.00000000001 from 411 studies, recognized in 46 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments.
Early terminated very late stage (95% on oxygen at baseline) DISCOVERY trial. 4% more patients were on ventilation at baseline in the HCQ group. This preprint presents more recent results than the earlier journal article.
This study is excluded in the after exclusion results of meta analysis: very late stage, >50% on oxygen/ventilation at baseline.
risk of death, 15.3% higher, RR 1.15, p = 0.70, treatment 11 of 150 (7.3%), control 13 of 149 (8.7%), adjusted per study, odds ratio converted to relative risk, day 90.
risk of death, 10.1% lower, RR 0.90, p = 0.75, treatment 15 of 150 (10.0%), control 13 of 149 (8.7%), adjusted per study, odds ratio converted to relative risk, day 28.
risk of no viral clearance, 23.8% lower, RR 0.76, p = 0.68, treatment 4 of 83 (4.8%), control 5 of 81 (6.2%), NNT 74, odds ratio converted to relative risk, Table S2, day 29.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Ader et al., 6 Oct 2020, Randomized Controlled Trial, multiple countries, preprint, baseline oxygen required 95.4%, 59 authors, study period 22 March, 2020 - 29 June, 2020, average treatment delay 9.0 days. Contact:
This PaperHCQAll
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
M.D Florence Ader, Nathan Peiffer-Smadja, Julien Poissy, Maude Bouscambert-Duchamp, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Noémie Mercier, Axelle Dupont, Toni Alfaiate, François-Xavier Lescure, François Raffi, François Goehringer, Antoine Kimmoun, Stéphane Jaureguiberry, Jean Reignier, Saad Nseir, François Danion, Raphael Clere-Jehl, Kévin Bouiller, Jean-Christophe Navellou, Violaine Tolsma, André Cabie, Clément Dubost, Johan Courjon, Sylvie Leroy, Joy Mootien, Rostane Gaci, Bruno Mourvillier, Emmanuel Faure, Valérie Pourcher, Sébastien Gallien, Odile Launay, Karine Lacombe, Jean-Philippe Lanoix, Alain Makinson, Guillaume Martin-Blondel, Lila Bouadma, Elisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Olivier Epaulard, Lionel Piroth, Florent Wallet, Jean-Christophe Richard, Jean Reuter, Thérèse Staub, Bruno Lina, Marion Noret, Claire Andrejak, Minh Patrick Lê, Gilles Peytavin, Maya Hites, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentre
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.
Authors contribution Writing -Original Draft: FA, CB; Writing -Review & Editing: NPS, JP, MBD, DB, ADi, MH, MPL, GP, DC, YY, FM; Conceptualization: FA, NPS, JP, MBD, GP, BL, DC, YY, FM; Investigation: FA, NPS, JP, MBD, Adi, NM, FXL, FR, FG, AK, SJ, JR, SN, FD, RCJ, KB, JCN, VT, AC, CDu, JC, SL, JM, RG, BM, EF, VP, SG, OL, KL, JPL, AM, GMB, LB, ÉBN, AGB, OE, LP, FW, JCR, JR, TS, MH, CA, MPL, GP; Methodology: FA, NPS, JP, MBD, DC, CB, FM; Data curation: ADi, ADe, NM, ADu, TA; Formal Analysis: DB, ADu, DC, CB, FM Project Administration: FA, CD, FM; Funding Acquisition: FA, CDe, JS, DC, YY, FM. Declaration of interests F.R. reports personal fees from Gilead Sciences, personal fees from MSD, personal fees from Pfizer, personal fees from TheraTechnologies, personal fees from ViiV Healthcare, outside the submitted work. F.G. reports grants from BioMerieux, personal fees and non-financial support from Gilead, non-financial support from Corevio, outside the submitted work. G.P. reports grants and personal fees from Gilead Sciences, grants and personal fees from Merck, grants and personal fees from ViiV Healthcare, grants and personal fees from TheraTechnologies, outside the submitted work. K.L. 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..
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While preliminary results were previously published, we present here the final ' 'results, following completion of the data monitoring.\n' 'Methods\n' 'We conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled ' 'trial (DisCoVeRy), add-on trial to Solidarity (<jats:ext-link ' 'xmlns:xlink="" ext-link-type="clintrialgov" ' 'xlink:href="NCT04315948">NCT04315948</jats:ext-link>, 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.\n' 'Results\n' '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. \n' 'Conclusion\n' '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.</jats:p>', 'DOI': '10.1101/2022.02.16.22271064', 'type': 'posted-content', 'created': {'date-parts': [[2022, 2, 21]], 'date-time': '2022-02-21T21:00:20Z', 'timestamp': 1645477220000}, 'source': 'Crossref', 'is-referenced-by-count': 0, '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'], 'prefix': '10.1101', 'author': [ {'given': 'Florence', 'family': 'ADER', 'sequence': 'first', 'affiliation': []}, {'given': 'Nathan', 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Late treatment
is less effective
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