Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.
Adult
Betacoronavirus
COVID-19
Coronavirus Infections
/ drug therapy
Drug Combinations
Drug Therapy, Combination
Female
Hong Kong
Hospitalization
Humans
Interferon beta-1b
/ therapeutic use
Lopinavir
/ therapeutic use
Male
Middle Aged
Pandemics
Pneumonia, Viral
/ drug therapy
Ribavirin
/ therapeutic use
Ritonavir
/ therapeutic use
SARS-CoV-2
COVID-19 Drug Treatment
Journal
Lancet (London, England)
ISSN: 1474-547X
Titre abrégé: Lancet
Pays: England
ID NLM: 2985213R
Informations de publication
Date de publication:
30 05 2020
30 05 2020
Historique:
received:
03
04
2020
revised:
21
04
2020
accepted:
23
04
2020
pubmed:
14
5
2020
medline:
3
6
2020
entrez:
14
5
2020
Statut:
ppublish
Résumé
Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir-ritonavir, and ribavirin for treating patients with COVID-19. This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688. Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3-7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5-11]) than the control group (12 days [8-15]; hazard ratio 4·37 [95% CI 1·86-10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir-ritonavir because of biochemical hepatitis. No patients died during the study. Early triple antiviral therapy was safe and superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted. The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.
Sections du résumé
BACKGROUND
Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir-ritonavir, and ribavirin for treating patients with COVID-19.
METHODS
This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.
FINDINGS
Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3-7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5-11]) than the control group (12 days [8-15]; hazard ratio 4·37 [95% CI 1·86-10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir-ritonavir because of biochemical hepatitis. No patients died during the study.
INTERPRETATION
Early triple antiviral therapy was safe and superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.
FUNDING
The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.
Identifiants
pubmed: 32401715
pii: S0140-6736(20)31042-4
doi: 10.1016/S0140-6736(20)31042-4
pmc: PMC7211500
pii:
doi:
Substances chimiques
Drug Combinations
0
lopinavir-ritonavir drug combination
0
Interferon beta-1b
145155-23-3
Lopinavir
2494G1JF75
Ribavirin
49717AWG6K
Ritonavir
O3J8G9O825
Banques de données
ClinicalTrials.gov
['NCT04276688']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1695-1704Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Références
Lancet. 2020 Feb 15;395(10223):514-523
pubmed: 31986261
Drug Discov Ther. 2020;14(1):58-60
pubmed: 32147628
Zhonghua Bing Li Xue Za Zhi. 2020 May 8;49(5):411-417
pubmed: 32172546
Cell Res. 2020 Mar;30(3):269-271
pubmed: 32020029
J Infect Dis. 2015 Dec 15;212(12):1904-13
pubmed: 26198719
J Infect. 2020 Jul;81(1):e1-e5
pubmed: 32171872
Clin Infect Dis. 2020 Mar 26;:
pubmed: 32215622
Clin Infect Dis. 2020 Apr 15;70(9):1837-1844
pubmed: 31925415
Antimicrob Agents Chemother. 2014 Aug;58(8):4875-84
pubmed: 24841269
Lancet Infect Dis. 2020 May;20(5):565-574
pubmed: 32213337
N Engl J Med. 2018 Sep 6;379(10):913-923
pubmed: 30184455
Fibrogenesis Tissue Repair. 2011 Aug 02;4:18
pubmed: 21810214
J Clin Virol. 2004 Sep;31(1):69-75
pubmed: 15288617
Int J Antimicrob Agents. 2020 Jul;56(1):105949
pubmed: 32205204
Lancet Infect Dis. 2014 Dec;14(12):1259-70
pubmed: 25213733
N Engl J Med. 2020 May 7;382(19):1787-1799
pubmed: 32187464
J Infect Dis. 2015 Jan 1;211(1):80-90
pubmed: 25030060
Clin Infect Dis. 2020 Apr 09;:
pubmed: 32270184
J Infect. 2004 Nov;49(4):262-73
pubmed: 15474623
Thorax. 2004 Mar;59(3):252-6
pubmed: 14985565
Antiviral Res. 2019 Jul;167:45-67
pubmed: 30974127
Chest. 2017 May;151(5):1069-1080
pubmed: 27884765
Nat Rev Drug Discov. 2020 Mar;19(3):149-150
pubmed: 32127666
mBio. 2018 Mar 6;9(2):
pubmed: 29511076
J Infect Public Health. 2016 May-Jun;9(3):227-30
pubmed: 27095301
J Infect. 2013 Dec;67(6):606-16
pubmed: 24096239
Nat Commun. 2020 Jan 10;11(1):222
pubmed: 31924756
Emerg Infect Dis. 2004 Apr;10(4):581-6
pubmed: 15200845
Crit Care. 2020 Mar 16;24(1):91
pubmed: 32178711