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.
| Original language | English |
|---|---|
| Pages (from-to) | 1826-1837 |
| Number of pages | 12 |
| Journal | Clinical Microbiology and Infection |
| Volume | 27 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2021 |
Keywords
- COVID-19
- Hydroxychloroquine
- Interferon β-1a
- Lopinavir/ritonavir
- Randomized controlled trial
- SARS-CoV-2
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In: Clinical Microbiology and Infection, Vol. 27, No. 12, 12.2021, p. 1826-1837.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - 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
AU - Ader, Florence
AU - Peiffer-Smadja, Nathan
AU - Poissy, Julien
AU - Bouscambert-Duchamp, Maude
AU - Belhadi, Drifa
AU - Diallo, Alpha
AU - Delmas, Christelle
AU - Saillard, Juliette
AU - Dechanet, Aline
AU - Mercier, Noémie
AU - Dupont, Axelle
AU - Alfaiate, Toni
AU - Lescure, François Xavier
AU - Raffi, François
AU - Goehringer, François
AU - Kimmoun, Antoine
AU - Jaureguiberry, Stéphane
AU - Reignier, Jean
AU - Nseir, Saad
AU - Danion, François
AU - Clere-Jehl, Raphael
AU - Bouiller, Kévin
AU - Navellou, Jean Christophe
AU - Tolsma, Violaine
AU - Cabié, André
AU - Dubost, Clément
AU - Courjon, Johan
AU - Leroy, Sylvie
AU - Mootien, Joy
AU - Gaci, Rostane
AU - Mourvillier, Bruno
AU - Faure, Emmanuel
AU - Pourcher, Valérie
AU - Gallien, Sébastien
AU - Launay, Odile
AU - Lacombe, Karine
AU - Lanoix, Jean Philippe
AU - Makinson, Alain
AU - Martin-Blondel, Guillaume
AU - Bouadma, Lila
AU - Botelho-Nevers, Elisabeth
AU - Gagneux-Brunon, Amandine
AU - Epaulard, Olivier
AU - Piroth, Lionel
AU - Wallet, Florent
AU - Richard, Jean Christophe
AU - Reuter, Jean
AU - Staub, Thérèse
AU - Lina, Bruno
AU - Noret, Marion
AU - DisCoVeRy study group
AU - Alexandre, Myriam
N1 - Funding Information: FR 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. FG reports grants from BioMerieux, personal fees and non-financial support from Gilead , non-financial support from Corevio , outside the submitted work. GP 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. KL 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 the conduct of the study. YY has nothing to disclose. He has been a board member receiving consultancy fees from ABBVIE, BMS, Gilead, MSD, J&J, Pfizer, and ViiV Healthcare; however, all these activities have been stopped in the 3 past years. FL reports personal fees from Gilead, personal fees and non-financial support from MSD , non-financial support from Astellas , and non-financial support from Eulmedica , outside the submitted work. AK reports personal fees from Baxter, personal fees from Aspen, and personal fees from Aguettant, outside the submitted work. SN reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomérieux, and personal fees from BioRad, outside the submitted work. FD reports personal fees from Gilead, outside the submitted work. JN reports non-financial support from MSD France, non-financial support from GILEAD Sciences and personal fees from PASCALEO, outside the submitted work. JM reports non-financial support from GILEAD, outside the submitted work. AM reports personal fees from MSD, personal fees from GILEAD, personal fees from JANSSEN and personal fees from Viiv Healthcare, outside the submitted work. MH reports grants from Fonds Erasme—COVID—Université Libre de Bruxelles, grants from Belgian health Care Knowledge Centre, during the conduct of the study, personal fees from Gilead advisory board on education on invasive fungal infections, personal fees from Pfizer: moderator for session on Isavuconazole, outside the submitted work. DC reports personal fees from Gilead, grants and personal fees from Janssen, outside the submitted work. CB reports personal fees from Da Volterra and personal fees from Mylan Pharmaceuticals, outside the submitted work. FM reports grants from Sanofi and grants and personal fees from Da Volterra, outside the submitted work. All other authors have nothing to disclose. The study was founded by Programme Hospitalier de Recherche Clinique (PHRC-20-0351) (Ministry of Health), from the DIM One Health Île-de-France (R20117HD), and from REACTing, a French multidisciplinary collaborative network working on emerging infectious diseases. The funding sources had no role in the analysis of the data or in the decision of publication. Funding Information: FR 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. FG reports grants from BioMerieux, personal fees and non-financial support from Gilead, non-financial support from Corevio, outside the submitted work. GP 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. KL 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 the conduct of the study. YY has nothing to disclose. He has been a board member receiving consultancy fees from ABBVIE, BMS, Gilead, MSD, J&J, Pfizer, and ViiV Healthcare; however, all these activities have been stopped in the 3 past years. FL reports personal fees from Gilead, personal fees and non-financial support from MSD, non-financial support from Astellas, and non-financial support from Eulmedica, outside the submitted work. AK reports personal fees from Baxter, personal fees from Aspen, and personal fees from Aguettant, outside the submitted work. SN reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biom?rieux, and personal fees from BioRad, outside the submitted work. FD reports personal fees from Gilead, outside the submitted work. JN reports non-financial support from MSD France, non-financial support from GILEAD Sciences and personal fees from PASCALEO, outside the submitted work. JM reports non-financial support from GILEAD, outside the submitted work. AM reports personal fees from MSD, personal fees from GILEAD, personal fees from JANSSEN and personal fees from Viiv Healthcare, outside the submitted work. MH reports grants from Fonds Erasme?COVID?Universit? Libre de Bruxelles, grants from Belgian health Care Knowledge Centre, during the conduct of the study, personal fees from Gilead advisory board on education on invasive fungal infections, personal fees from Pfizer: moderator for session on Isavuconazole, outside the submitted work. DC reports personal fees from Gilead, grants and personal fees from Janssen, outside the submitted work. CB reports personal fees from Da Volterra and personal fees from Mylan Pharmaceuticals, outside the submitted work. FM reports grants from Sanofi and grants and personal fees from Da Volterra, outside the submitted work. All other authors have nothing to disclose. The study was founded by Programme Hospitalier de Recherche Clinique (PHRC-20-0351) (Ministry of Health), from the DIM One Health ?le-de-France (R20117HD), and from REACTing, a French multidisciplinary collaborative network working on emerging infectious diseases. The funding sources had no role in the analysis of the data or in the decision of publication. Publisher Copyright: © 2021 European Society of Clinical Microbiology and Infectious Diseases
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - COVID-19
KW - Hydroxychloroquine
KW - Interferon β-1a
KW - Lopinavir/ritonavir
KW - Randomized controlled trial
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85107640220&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/34048876
U2 - 10.1016/j.cmi.2021.05.020
DO - 10.1016/j.cmi.2021.05.020
M3 - Article
C2 - 34048876
AN - SCOPUS:85107640220
SN - 1198-743X
VL - 27
SP - 1826
EP - 1837
JO - Clinical Microbiology and Infection
JF - Clinical Microbiology and Infection
IS - 12
ER -