ABSTRACT
Background: No antiviral drug has been proven effective for the treatment of patients with moderate-to-severe coronavirus disease 2019 (COVID-19). Favipiravir and hydroxychloroquine were introduced as potential antiviral agents to treat patients with COVID-19.Methods: We conducted an investigator-initiated, multicentre, open-label, randomised trial involving hospitalised patients with confirmed moderate-to-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at nine hospitals in Saudi Arabia. Eligible patients were adult with moderate-to-severe COVID-19 defined as oxygen saturation (Sao2) of 94% or less while breathing ambient air or significant clinical symptoms with chest X-ray changes requiring hospital admission. Randomisation was in a 1:1 ratio to receive standard care (control group) or standard care plus favipiravir and hydroxychloroquine. The favipiravir loading dose was 1800 mg twice daily on day 1, then 800mg twice daily for nine days and hydroxychloroquine as 400mg twice daily, followed by 200mg twice daily for days 2-5. The primary outcome was time to clinical improvement of two points (from the status at randomisation) on a seven-category ordinal scale or live discharge from the hospital within 14 days. Analyses were done in an intention-to-treat population of patients to assess the primary and secondary endpoints. The trial is registered at ClinicalTrials.gov (NCT04392973).Findings: From May 2020 to Jan 2021, 254 patients were enrolled; 129 were assigned to standard of care and 125 patients to the combination of favipiravir and hydroxychloroquine. The mean age was 52·65 ±13·06 years, 59·4% were men, and 229 (90·15%) required supplemental oxygen at randomisation (with or without non-invasive ventilation). The time to clinical improvement was not significantly different between the two groups; median of 9 days (95%CI: 8, 12) in the treatment group and 7 days (95%CI: 6, 10) in the control group (HR:0·845; 95% CI 0·617 to 1·157; p-value = 0·29). The median duration of hospitalisation among patients discharged on or before day 14 was 9 days (95%CI: 8, 12) for the treatment group and 8 days (95%CI: 7, 10) for the control group with a p-value of 0·42. The 28-day mortality was not significantly different between the two groups, 9 (7·63%) in the treatment group vs 13 (10·32%) in the control group; p-value=0·45. The most prevalent adverse events were headache, elevation in ALT, and the prolonged QTc interval in the treatment group.Interpretation: The combination of favipiravir and hydroxychloroquine did not result in a statistically significant clinical benefit in patients with moderate-to-severe COVID-19. No new safety signals were recognised for both medications.Trial Registration: This trial is registered with ClinicalTrials.gov, Identifier: NCT04392973, May 19, 2020.Funding Statement: King Abdullah International Medical Research Center, Saudi Arabia.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This trial was approved by the Saudi Food and Drug Authority (SFDA). Ethical approval was obtained from the Institutional Review Board (IRB) at the Ministry of National Guard-Health Affairs (MNGHA) and Ministry of Health (MOH). The trial was overseen by an independent data and safety monitoring board (DSMB). The trial was done according to the Declaration of Helsinki principles and the International Conference on Harmonization-Good Clinical Practice guidelines.