Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial

Abstract

Background: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients.

Methods: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544).

Results: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC₅₀) of 5.48 μM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 μM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group.

Conclusions: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.

Keywords: COVID-19; baloxavir marboxil; favipiravir; pharmacokinetics; the half-maximal effective concentration (EC(50)).

Graphical abstract

Figure 1

Overview of the Clinical Study. BAL: baloxavir marboxil; FAV: favipiravir; ARB: arbidol; LOP/RIT: lopinavir/ritonavir; DAR/COB: darunavir/cobicistat.

Figure 2

Cumulative negative conversion rates of subjects by Day 14. The x-axis represents the time (days) since trial initiation. The y-axis represents cumulative negative conversion rat.

Figure 3

Changes in Ct values since trial initiation. The x-axis represents the time (days) since trial initiation. The y-axis represents ΔCt value (38 minus the RT-PCR Ct value, with 38 being the Ct cutoff value for positivity). Each line represents one patient. Patients are coded according to clinical classification of COVID-19, with red line representing critical cases, blue line representing severe cases, and gold line representing moderate cases. Clinical classifications were made from discharge diagnosis.