Various Combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, High-Dose Oseltamivir, and Hydroxychloroquine for the Treatment of COVID-19: A Randomized Controlled Trial (FIGHT-COVID-19 Study)

Abstract

Background: Monotherapy with Remdesivir, Favipiravir, Lopinavir-Ritonavir, or Hydroxychloroquine has been evaluated for the treatment of coronavirus disease 2019 (Covid-19). No antiviral agents have yet been shown to be efficacious in terms of viral clearance and reduction of death in moderate to severe Covid-19 in randomized controlled trials.Methods: We conducted an open-label, randomized, controlled trial of various oral combinations of Favipiravir, Lopinavir-Ritonavir, Darunavir-Ritonavir, high-dose Oseltamivir, and Hydroxychloroquine in adults who were hospitalized with Covid-19. Ninety patients were randomly assigned to receive either 1) high-dose Oseltamivir and Hydroxychloroquine, 2) Lopinavir-Ritonavir and high-dose Oseltamivir, or 3) Darunavir- Ritonavir, high-dose Oseltamivir, and Hydroxychloroquine, compared to thirty voluntary quarantine patients without antiviral agent for mild Covid-19. In addition, two hundred patients were randomly assigned to receive 1) high-dose Oseltamivir and Lopinavir- Ritonavir, 2) Favipiravir and Lopinavir-Ritonavir, 3) high-dose Oseltamivir and Darunavir-Ritonavir, or 4) Favipiravir and Darunavir-Ritonavir and Hydroxychloroquine for moderate to severe Covid-19.Results: A total of 320 patients were enrolled. Those mild Covid-19 patients who received high-dose Oseltamivir and Hydroxychloroquine had a better median time for negative Polymerase Chain Reaction test (PCR) for SARS-CoV-2 than who were voluntarily quarantined without antiviral agent (ITT: 7.5 days (IQR, 4 to 25) versus 11.5 days (IQR, 8 to 18) (P=0.02), LOCF: 7.5 days (IQR, 4.5 to 14) versus 10 days (IQR, 6.5 to18.5) (P=0.01), and PP 8 days (IQR, 4 to 15) versus 9 days (IQR, 6 to17) (P=0.01).For moderate to severe Covid-19 patients, Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine had a better median time to negative PCR for SARS-CoV-2 than who received high-dose Oseltamivir plus Lopinavir-Ritonavir (ITT: 10 days (IQR, 5.5 to 13) versus 12 days (IQR, 7 to 15) (P=0.15), LOCF: 10 days (IQR, 5to 13) versus 11 days (IQR, 6 to 15) (P=0.005), and PP 10 days (IQR, 5 to 13) versus 9.5 days (IQR, 5 to15) (P=0.003). In moderate to severe Covid -19, The Kaplan–Meier estimates of mortality were 16.0% with high-dose Oseltamivir plus Lopinavir-Ritonavir compared to 4.0% with Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine (P=0.04), and more patient deaths with high-dose Oseltamivir plus Lopinavir-Ritonavir, and Favipiravir plus Lopinavir-Ritonavir, compared to Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine ( P=0.04).Conclusions: High-dose Oseltamivir and Hydroxychloroquine were superior to voluntary quarantine without antiviral agent in terms of viral clearance in mild Covid -19. Favipiravir plus Darunavir-Ritonavir plus Hydroxychloroquine were superior to other antiviral agent combinations in terms viral clearance and death in moderate to severe Covid -19. Clinical Trial Registration Details: ClinicalTrials.gov number NCT04303299.Funding Information: Department of Medical Services of Ministry of Public Health, Health System Research Institute of Ministry of Public Health, and The Office of the National Broadcasting and Telecommunications Commission Institute of Thailand. Declaration of Interests: All authors declare no conflicts of interest, no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: The trial protocol was approved by the institutional review board at each site and the centralized institutional review board of the Ethics Committee of the Ministry of Public Health, Thailand. There were independent data and safety monitoring boards. Written informed consent was obtained from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent.