Favipiravir and Hydroxychloroquine Combination Therapy in Patients with Moderate to Severe COVID-19 (FACCT Trial): An Open-Label, Multicenter, Randomized, Controlled Trial

Abstract

Introduction: Antiviral drugs have shown limited effectiveness in treating patients with coronavirus disease 2019 (COVID-19). We aimed to assess the effects of a favipiravir and hydroxychloroquine combination on treating moderate-to-severe COVID-19 patients.

Methods: An investigator-initiated, multicenter, open-label, randomized trial at nine hospitals. Eligible patients were adults with moderate-to-severe COVID-19 defined as oxygen saturation (SaO2) of ≤ 94% while breathing ambient air or significant clinical symptoms with chest x-ray changes requiring hospital admission. Randomization was in a 1:1 ratio to receive standard care (control group) or standard care plus favipiravir and hydroxychloroquine. The primary outcome was time to clinical improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital within 14 days. Analyses were done in an intention-to-treat population.

Results: From May 2020 to Jan 2021, 254 patients were enrolled; 129 were assigned to standard of care and 125 to the treatment. The mean age was 52 (± 13) years, and 103 (41%) were women. At randomization, six patients were on invasive mechanical ventilation, 229 (90.15%) were requiring supplemental oxygen only (with or without non-invasive ventilation), and 19 (7.48%) were receiving neither. The time to clinical improvement was not significantly different between the groups: median of 9 days in the treatment group and 7 days in the control group (HR: 0.845; 95% CI 0.617-1.157; p-value = 0.29). The 28-day mortality was not significantly different between the groups (7.63% treatment) vs. (10.32% control); p-value = 0.45. The most prevalent adverse events were headache, elevation in ALT, and the prolonged QTc interval in the treatment group.

Conclusion: The combination of favipiravir and hydroxychloroquine did not result in a statistically significant clinical benefit in patients with moderate-to-severe COVID-19.

Clinical trial registration: ClinicalTrials.gov (NCT04392973).

Keywords: COVID-19; Favipiravir; Hydroxychloroquine; Moderate-to-severe; SARS-CoV-2.

© 2021. The Author(s).

Figures

Fig. 1

Trial profile

Fig. 2

A–C Kaplan-Meier estimates of cumulative recoveries. Time to clinical improvement in the intention-to-treat population (A) and the number of patients without clinical improvement were still included in the number at risk. The hospital discharge curves are cumulative incidence curves of alive hospital discharge (B). All the patients were followed up daily to discharge or 14 days after randomization. A patient was considered discharged from the hospital once discharged from the index hospitalization. Transferring to another hospital is not considered alive hospital discharge; rehospitalizations were not considered in this analysis, and deaths before day 14 were excluded. The survival curves are survival function (Kaplan-Meier) curves with a p-value calculated by the log-rank test. (C) Time to death in the intention-to-treat population. Patients were followed up for death until day 28 following randomization using in-hospital records and phone follow-up. Data on patients who died on or before day 28 were censored at day 28. Nine patients had unknown vital status at 28 days. There was no difference between the treatment and control groups in clinical improvement, time to discharge, or survival

Fig. 3

Time to clinical improvement according to subgroups