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Clinical Trial
. 2020 May 30;395(10238):1695-1704.
doi: 10.1016/S0140-6736(20)31042-4. Epub 2020 May 10.

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

Ivan Fan-Ngai Hung  1 , Kwok-Cheung Lung  2 , Eugene Yuk-Keung Tso  3 , Raymond Liu  4 , Tom Wai-Hin Chung  5 , Man-Yee Chu  6 , Yuk-Yung Ng  7 , Jenny Lo  4 , Jacky Chan  8 , Anthony Raymond Tam  9 , Hoi-Ping Shum  10 , Veronica Chan  3 , Alan Ka-Lun Wu  11 , Kit-Man Sin  7 , Wai-Shing Leung  8 , Wai-Lam Law  6 , David Christopher Lung  12 , Simon Sin  13 , Pauline Yeung  13 , Cyril Chik-Yan Yip  5 , Ricky Ruiqi Zhang  1 , Agnes Yim-Fong Fung  14 , Erica Yuen-Wing Yan  14 , Kit-Hang Leung  14 , Jonathan Daniel Ip  14 , Allen Wing-Ho Chu  14 , Wan-Mui Chan  14 , Anthony Chin-Ki Ng  14 , Rodney Lee  11 , Kitty Fung  15 , Alwin Yeung  4 , Tak-Chiu Wu  6 , Johnny Wai-Man Chan  6 , Wing-Wah Yan  10 , Wai-Ming Chan  13 , Jasper Fuk-Woo Chan  14 , Albert Kwok-Wai Lie  9 , Owen Tak-Yin Tsang  8 , Vincent Chi-Chung Cheng  5 , Tak-Lun Que  16 , Chak-Sing Lau  9 , Kwok-Hung Chan  14 , Kelvin Kai-Wang To  14 , Kwok-Yung Yuen  17
Affiliations
Clinical Trial

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

Ivan Fan-Ngai Hung et al. Lancet. .

Abstract

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.

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Figures

Figure 1
Figure 1
Trial profile
Figure 2
Figure 2
Outcomes over time (A) National early warning score 2; (B) nasopharyngeal swab viral load; (C) posterior oropharyngeal saliva viral load; (D) throat swab viral load; (E) stool viral load; and (F) serum IL-6 cytokine concentration (first 60 recruited patients). Data points are medians and error bars are IQRs.
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