Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial

Chen et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.683296

Sep 2021

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Very late stage (9 days from symptom onset) RCT with 116 favipiravir patients and 120 arbidol patients in China, showing no significant difference in clinical recovery (relief of fever and cough, respiratory frequency ≤24 times/min, and oxygen saturation ≥98%), however the time to resolution of fever and cough was significantly lower with favipiravir. ChiCTR2000030254.

Potential risks of favipiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-5.

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risk of ICU admission, 3.4% higher, RR 1.03, p = 1.00, treatment 2 of 116 (1.7%), control 2 of 120 (1.7%).

risk of respiratory failure, 74.1% lower, RR 0.26, p = 0.37, treatment 1 of 116 (0.9%), control 4 of 120 (3.3%), NNT 40.

risk of oxygen therapy, 19.5% lower, RR 0.80, p = 0.42, treatment 21 of 116 (18.1%), control 27 of 120 (22.5%), NNT 23.

risk of progression to dyspnea, 70.4% lower, RR 0.30, p = 0.03, treatment 4 of 116 (3.4%), control 14 of 120 (11.7%), NNT 12.

risk of dyspnea, 10.3% lower, RR 0.90, p = 0.84, treatment 13 of 116 (11.2%), control 15 of 120 (12.5%), NNT 77.

risk of no recovery, 19.7% lower, RR 0.80, p = 0.15, treatment 45 of 116 (38.8%), control 58 of 120 (48.3%), NNT 10, day 7, primary outcome.

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1. Zhirnov et al., Favipiravir: the hidden threat of mutagenic action, Journal of microbiology, epidemiology and immunobiology, doi:10.36233/0372-9311-114.elpub.ru, doi.org.

2. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

3. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

4. Shum, C., An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses, The University of Hong Kong, PhD Thesis, hub.hku.hk/handle/10722/344396.hku.hk.

5. Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.sciencedirect.com, doi.org.

Chen et al., 2 Sep 2021, Randomized Controlled Trial, China, peer-reviewed, 14 authors, average treatment delay 9.0 days, this trial compares with another treatment - results may be better when compared to placebo.

This Paper Favipiravir All

Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial

Chang Chen, Yi Zhang, Jianying Huang, Ping Yin, Zhenshun Cheng, Jianyuan Wu, Song Chen, Yongxi Zhang, Bo Chen, Mengxin Lu, Yongwen Luo, Lingao Ju, Jingyi Zhang, Xinghuan Wang

Frontiers in Pharmacology, doi:10.3389/fphar.2021.683296

Background: In addition to supportive therapy, antiviral therapy is an effective treatment for coronavirus disease 2019 . Objective: To compare the efficacy and safety of favipiravir and umifenovir (Arbidol) to treat COVID-19 patients. Methods: We conducted a prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19. Enrolled patients with initial symptoms within 12 days were randomly assigned in a 1:1 ratio to receive conventional therapy plus Arbidol (200 mg*3/day) or favipiravir (1600 mg*2/first day followed by 600 mg*2/day) for 7 days. The primary outcome was the clinical recovery rate at day 7 of drug administration (relief for pyrexia and cough, respiratory frequency ≤24 times/min; oxygen saturation ≥98%). Latency to relief for pyrexia and cough and the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV)/mechanical ventilation (MV) were the secondary outcomes. Safety data were collected for 17 days. Results: A total of 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive favipiravir (116 assessed), and 120 patients were assigned to receive Arbidol (120 assessed). The clinical recovery rate at day 7 of drug administration did not significantly differ between the favipiravir group (71/116) and Arbidol group (62/120) (p 0.1396, difference in recovery rate: 0.0954; 95% CI: −0.0305∼0.2213). Favipiravir contributed to relief for both pyrexia (difference: 1.70 days, p < 0.0001) and cough (difference: 1.75 days, p < 0.0001). No difference was observed in the

ETHICS STATEMENT The studies involving human participants were reviewed and approved by The study was approved by the Institutional Ethics Committee (No. 2020040). The patients/participants provided their written informed consent to participate in this study. AUTHOR CONTRIBUTIONS CC, YiZ, JH, and PY contributed equally to this paper. CC, JH, JW, and XW conceived and designed the study. CC, YiZ, JH, PY, ZC, JW, and YoZ contributed to patient recruitment, data collection, data analysis and data interpretation. CC, YiZ, JH, PY, SC, BC, ML, YL, and LJ wrote the first draft of the manuscript. CC, JH, and XW provided administrative, technical, or material support. JH and XW supervised the study. CC, YiZ, JH, JW, YoZ, BC, JZ, and XW contributed to the critical revision of the manuscript for important intellectual content. All authors reviewed and approved the final version of the manuscript. FUNDING This work was supported by the National Key Research and Development Program of China (2020YFC0844400). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2021.683296/ full#supplementary-material Conflict of Interest: Author YZ is employed by the company Euler..

References

Dong, Hu, Gao, Discovering Drugs to Treat Coronavirus Disease 2019 (COVID-19), Drug Discov. Ther, doi:10.5582/ddt.2020.01012

Du, Chen, Favipiravir: Pharmacokinetics and Concerns about Clinical Trials for 2019-nCoV Infection, Clin. Pharmacol. Ther, doi:10.1002/cpt.1844

Furuta, Takahashi, Fukuda, Kuno, Kamiyama et al., In Vitro and In Vivo Activities of Anti-influenza Virus Compound T-705, Antimicrob. Agents Chemother, doi:10.1128/aac.46.4.977-981.2002

Goldhill, Te, Velthuis, Fletcher, Langat et al., The Mechanism of Resistance to Favipiravir in Influenza, Proc. Natl. Acad. Sci. U S A, doi:10.1073/pnas.1811345115

Guan, Ni, Hu, Liang, Ou et al., Clinical Characteristics of Coronavirus Disease 2019 in China, N. Engl. J. Med, doi:10.1056/NEJMoa2002032

Hulseberg, Fénéant, Szymańska-De Wijs, Kessler, Nelson et al., Arbidol and Other Low-Molecular-Weight Drugs that Inhibit Lassa and Ebola Viruses, J. Virol, doi:10.1128/JVI.02185-18

Leneva, Burtseva, Yatsyshina, Fedyakina, Kirillova et al., Virus Susceptibility and Clinical Effectiveness Frontiers in Pharmacology | www.frontiersin

Leneva, Falynskova, Makhmudova, Poromov, Yatsyshina et al., Umifenovir Susceptibility Monitoring and Characterization of Influenza Viruses Isolated during ARBITR Clinical Study, J. Med. Virol, doi:10.1002/jmv.25358

Li, Guan, Wu, Wang, Zhou et al., Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia, N. Engl. J. Med, doi:10.1056/NEJMoa2001316

Mentre, Taburet, Guedj, Anglaret, Keita et al., Dose Regimen of Favipiravir for Ebola Virus Disease, Lancet Infect. Dis, doi:10.1016/S1473-3099(14)71047-3

Nojomi, Yassin, Keyvani, Makiani, Roham et al., Effect of Arbidol (Umifenovir) on COVID-19: a Randomized Controlled Trial, BMC Infect. Dis, doi:10.26442/00403660.2019.03.000127

Roser, Ritchie, Ortiz-Ospina, Coronavirus Disease (COVID-19)-Statistics and Research

Shi, Xiong, He, Deng, Li et al., Antiviral Activity of Arbidol against Influenza A Virus, Respiratory Syncytial Virus, Rhinovirus, coxsackie Virus and Adenovirus In Vitro and In Vivo, Arch. Virol, doi:10.1007/s00705-007-0974-5

Wang, Hu, Hu, Zhu, Liu et al., Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China, JAMA, doi:10.1001/jama.2020.1585

Who, Coronavirus Disease

Xu, Chen, Yuan, Yi, Ding et al., Clinical Efficacy of Arbidol in Patients with 2019 Novel Coronavirus-Infected Pneumonia: A Retrospective Cohort Study, doi:https://ssrn.com/abstract=3542148%20or%20doi:%2010.2139/ssrn.3542148

Zhang, Wang, Peng, Peng, Zhang et al., Potential of Arbidol for post-exposure Prophylaxis of COVID-19 Transmission: a Preliminary Report of a Retrospective Cohort Study, Curr. Med. Sci, doi:10.1007/s11596-020-2203-3

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Late treatment
is less effective

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