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

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

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.