Randomized controlled trial of favipiravir, hydroxychloroquine, and standard care in patients with mild/moderate COVID-19 disease

Manaf AlQahtani, Nitya Kumar, Dhuha Aljawder, Abdulkarim Abdulrahman, Mohammed Wael Mohamed, Fatema Alnashaba, Mohammed Abu Fayyad, Faisal Alshaikh, Fatima Alsahaf, Sawsan Saeed, Amal Almahroos, Zainab Abdulrahim, Sameer Otoom, Stephen L Atkin, Manaf AlQahtani, Nitya Kumar, Dhuha Aljawder, Abdulkarim Abdulrahman, Mohammed Wael Mohamed, Fatema Alnashaba, Mohammed Abu Fayyad, Faisal Alshaikh, Fatima Alsahaf, Sawsan Saeed, Amal Almahroos, Zainab Abdulrahim, Sameer Otoom, Stephen L Atkin

Abstract

Favipiravir has antiviral activity against influenza, West Nile virus, and yellow fever virus and against flaviviruses. The objective of this pilot study was to compare three arms: favipiravir; hydroxychloroquine; standard care (no specific SARS-CoV-2 treatment) only, in symptomatic patients infected by SARS-CoV-2 in an open-labelled randomized clinical trial. The trial was registered with Bahrain National Taskforce for Combatting COVID-19 on the 7th of May 2020 (registration code: NCT04387760). 150 symptomatic patients with COVID-19 disease were randomized into one of three arms: favipiravir, hydroxychloroquine, or standard care only. The primary outcome was the clinical scale at the end of study follow up (day 14 or on discharge/death) based on a points scale. The secondary outcomes were viral clearance, biochemical parameter changes and mortality at 30-days. Baseline characteristics did not differ between groups. The proportion of patients who achieved a clinical scale < 2 did not differ between groups. The favipiravir-treated and hydroxychloroquine-treated group showed increased viral clearance (OR, 95%CI 2.38, 0.83-6.78, OR, 95%CI 2.15, 0.78-5.92, respectively) compared to standard care, but this was not significant. The biochemical profile did not differ between groups, except for the platelet count (P < 0.03) and uric acid (P < 0.004) that were higher with favipiravir-treatment. Primary or secondary outcome measures did not differ between favipiravir, hydroxychloroquine, and standard therapy for mild to moderate COVID-19 disease; therefore, whilst favipiravir therapy appeared safe with a trend to increased viral clearance, there was no superior therapeutic utility.Clinical trials registration. NCT04387760. Registration date: 07/05/2020.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Flow chart of patient participation in the clinical trial.
Figure 2
Figure 2
Odds of achieving a clinical scale score 

Figure 3

The median length of hospital…

Figure 3

The median length of hospital stay (Table 3) was not significantly higher (6…

Figure 3
The median length of hospital stay (Table 3) was not significantly higher (6 days) for both HCQ and Favipiravir groups, compared to patients on standard care (7 days).
Figure 3
Figure 3
The median length of hospital stay (Table 3) was not significantly higher (6 days) for both HCQ and Favipiravir groups, compared to patients on standard care (7 days).

References

    1. Coronavirus Update (Live): 46,432,714 Cases and 1,200,927 Deaths from COVID-19 Virus Pandemic-Worldometer, .
    1. Mehrotra DV, et al. Clinical endpoints for evaluating efficacy in COVID-19 vaccine trials. Ann. Intern. Med. 2021;174:221–228. doi: 10.7326/m20-6169.
    1. Beigel JH, et al. Remdesivir for the treatment of Covid-19-preliminary report. N. Engl. J. Med. 2020 doi: 10.1056/NEJMoa2007764.
    1. Mehta N, Mazer-Amirshahi M, Alkindi N, Pourmand A. Pharmacotherapy in COVID-19; A narrative review for emergency providers. Am. J. Emerg. Med. 2020;38:1488–1493. doi: 10.1016/j.ajem.2020.04.035.
    1. Gautret P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents. 2020;56:105949. doi: 10.1016/j.ijantimicag.2020.105949.
    1. Geleris J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N. Engl. J. Med. 2020;382:2411–2418. doi: 10.1056/NEJMoa2012410.
    1. Tang W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomised controlled trial. BMJ. 2020;369:m1849. doi: 10.1136/bmj.m1849.
    1. Mitjà O, et al. A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19. N. Engl. J. Med. 2021;384:417–427. doi: 10.1056/NEJMoa2021801.
    1. Echeverría-Esnal D, et al. Azithromycin in the treatment of COVID-19: A review. Expert Rev. Anti Infect. Ther. 2021;19:147–163. doi: 10.1080/14787210.2020.1813024.
    1. AlQahtani M, et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. Sci. Rep. 2021;11:9927. doi: 10.1038/s41598-021-89444-5.
    1. Gavriatopoulou M, et al. Emerging treatment strategies for COVID-19 infection. Clin. Exp. Med. 2021;21:167–179. doi: 10.1007/s10238-020-00671-y.
    1. Sreekanth RO, Lai W-F. Tackling COVID-19 using remdesivir and favipiravir as therapeutic options. Chembiochem Eur. J. Chem. Biol. 2021;22:939–948. doi: 10.1002/cbic.202000595.
    1. Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res. 2018;153:85–94. doi: 10.1016/j.antiviral.2018.03.003.
    1. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19) Drug Discover. Therap. 2020;14:58–60. doi: 10.5582/ddt.2020.01012.
    1. Cai Q, et al. Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering (Beijing) 2020;6:1192–1198. doi: 10.1016/j.eng.2020.03.007.
    1. Corman VM, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020 doi: 10.2807/1560-7917.Es.2020.25.3.2000045.
    1. Vincent JL, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: Results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit. Care Med. 1998;26:1793–1800. doi: 10.1097/00003246-199811000-00016.
    1. Shah M, et al. Safety and efficacy of ozone therapy in mild to moderate COVID-19 patients: A phase 1/11 randomized control trial (SEOT study) Int. Immunopharmacol. 2021;91:107301. doi: 10.1016/j.intimp.2020.107301.
    1. Gautret P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med. Infect. Dis. 2020;34:101663. doi: 10.1016/j.tmaid.2020.101663.
    1. Birkett MA, Day SJ. Internal pilot studies for estimating sample size. Stat. Med. 1994;13:2455–2463. doi: 10.1002/sim.4780132309.
    1. Udwadia ZF, et al. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int. J. Infect. Dis. 2021;103:62–71. doi: 10.1016/j.ijid.2020.11.142.
    1. Hassanipour S, et al. The efficacy and safety of Favipiravir in treatment of COVID-19: A systematic review and meta-analysis of clinical trials. Sci. Rep. 2021;11:1–11. doi: 10.1038/s41598-021-90551-6.
    1. Vicenzi M, et al. The liaison between respiratory failure and high blood pressure: Evidence from COVID-19 patients. Eur. Respir. J. 2020 doi: 10.1183/13993003.01157-2020.
    1. Yaylaci S, et al. The effects of favipiravir on hematological parameters of covıd-19 patients. Rev. Assoc Med. Bras (1992) 2020;66(2):65–70. doi: 10.1590/1806-9282.66.S2.65.
    1. Mishima E, Anzai N, Miyazaki M, Abe T. Uric acid elevation by favipiravir, an antiviral drug. Tohoku J. Exp. Med. 2020;251:87–90. doi: 10.1620/tjem.251.87.
    1. Murohashi K, et al. Outcome of early-stage combination treatment with favipiravir and methylprednisolone for severe COVID-19 pneumonia: A report of 11 cases. Respir. Investig. 2020;58:430–434. doi: 10.1016/j.resinv.2020.08.001.
    1. Yao X, et al. In Vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Clin. Infect. Dis. 2020;71:732–739. doi: 10.1093/cid/ciaa237.
    1. Geleris J, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N. Engl. J. Med. 2020;382:2411–2418. doi: 10.1056/NEJMoa2012410.
    1. Ghazy RM, et al. A systematic review and meta-analysis on chloroquine and hydroxychloroquine as monotherapy or combined with azithromycin in COVID-19 treatment. Sci. Rep. 2020;10:1–18. doi: 10.1038/s41598-020-77748-x.
    1. Rao SN, Manissero D, Steele VR, Pareja J. A systematic review of the clinical utility of cycle threshold values in the context of COVID-19. Infect. Dis. Ther. 2020;9:573–586. doi: 10.1007/s40121-020-00324-3.
    1. Néant N, et al. (2021) Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort. Proc. Natl. Acad. Sci. USA. 2021;118:1008. doi: 10.1073/pnas.2017962118.

Source: PubMed

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