Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial
Open accessPreprint — published as 10.3389/fphar.2021.683296
Abstract
Background: No clinically proven effective antiviral strategy exists for the epidemic Coronavirus Disease 2019 (COVID-19). Methods: We conducted a prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19. Patients were randomly assigned in a 1:1 ratio to receive conventional therapy plus Umifenovir (Arbidol) (200mg*3/day) or Favipiravir (1600mg*2/first day followed by 600mg*2/day) for 10 days. The primary outcome was clinical recovery rate of Day 7. Latency to relief for pyrexia and cough, the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV) were the secondary outcomes. Safety data were collected for 17 days. Results: 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive Favipiravir (116 assessed), and 120 to receive Arbidol (120 assessed). Clinical recovery rate of Day 7 does not significantly differ between Favipiravir group (71/116) and Arbidol group (62/120) (P=0.1396, difference of recovery rate: 0.0954; 95% CI: -0.0305 to 0.2213). Favipiravir led to shorter latencies 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 of AOT or NMV rate (both P>0.05). The most frequently observed Favipiravir-associated adverse event was raised serum uric acid (16/116, OR: 5.52, P=0.0014). Conclusions: Among patients with COVID-19, Favipiravir, compared to Arbidol, did not significantly improve the clinically recovery rate at Day 7. Favipiravir significantly improved the latency to relief for pyrexia and cough. Adverse effects caused Favipiravir are mild and manageable. This trial is registered with Chictr.org.cn (ChiCTR2000030254).
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“The subgroup effect is consistent with evidence from other meta-analyses.36”
From Drug treatments for covid-19: living systematic review and network meta-analysis (2020) · cites this paper as [36]
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Yousefi, B., Valizadeh, S., Ghaffari, H., Vahedi, A., Karbalaei, M., & Eslami, M. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29785 · Cited by 118 · see citing works
“In a randomized clinical trial, Chen et al. (2020) showed that in patients with moderate COVID‐19 who were untreated with antiviral drugs, favipiravir increased clinical recovery over 7 days and reduced fever, cough, and respiratory problems, it was therefore used as an effective drug in these…”
BackgroundRad, A. S., Ardjmand, M., Esfahani, M. R., & Khodashenas, B. (2020) · Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy · doi:10.1016/j.saa.2020.119082 · Cited by 115 · see citing works
COVID-19: A review of the proposed pharmacological treatments
Lam, S., Lombardi, A. M., & Ouanounou, A. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173451 · Cited by 132 · see citing works
“Furthermore, high levels of IL-6 were found to be the main cause of cytokine storm (Zhang et al., 2020; S. Zhang et al., 2020).”
InfluentialRNA‐dependent RNA polymerase of SARS‐CoV‐2 as a therapeutic target
Wang, Y., Anirudhan, V., Du, R., Cui, Q., & Rong, L. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26264 · Cited by 117 · see citing works
“(ChiCTR2000030254), FPV showed superior efficacy to treat moderate COVID‐19 pneumonia as compared with Arbidol (umifenovir, a membrane fusion inhibitor).(73) In a small‐scale non‐randomized controlled study at The Third People's Hospital of Shenzhen”
BackgroundA review of potential suggested drugs for coronavirus disease (COVID-19) treatment
Tarighi, P., Eftekhari, S., Chizari, M., Sabernavaei, M., Jafari, D., & Mirzabeigi, P. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.173890 · Cited by 125 · see citing works
Structural Basis of SARS-CoV-2 Polymerase Inhibition by Favipiravir
Peng, Q., Peng, R., Yuan, B., Wang, M., Zhao, J., Fu, L., Qi, J., & Shi, Y. (2021) · The Innovation · doi:10.1016/j.xinn.2021.100080 · Cited by 101 · see citing works
“Given the better record of Favipiravir than Remdesivir with regard to side effects, 28,29 itmayrepresentabetteroptionforclinicaltreatmentof SARS-CoV-2 infections, as well as a panel of other human-infecting RNA viruses.”
Treatment Options for COVID-19: A Review
Ali, M. J., Hanif, M., Haider, M. A., Ahmed, M. U., Sundas, F., Hirani, A., Khan, I. A., Anis, K., & Karim, A. H. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00480 · Cited by 108 · see citing works
Covid-19: what treatments are being investigated?
Mahase, E. (2020) · BMJ · doi:10.1136/bmj.m1252 · Cited by 108 · see citing works
The impact of sofosbuvir/daclatasvir or ribavirin in patients with severe COVID-19
Eslami, G., Mousaviasl, S., Radmanesh, E., Jelvay, S., Bitaraf, S., Simmons, B., Wentzel, H., Hill, A. M., Sadeghı, A., Freeman, J. A., et al. (2020) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkaa331 · Cited by 112 · see citing works
Current Strategies of Antiviral Drug Discovery for COVID-19
Mei, M., & Tan, X. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.671263 · Cited by 110 · see citing works
Huang, D., Yu, H., Wang, T., Yang, H., Yao, R., & Liang, Z.-A. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26256 · Cited by 100 · see citing works
An update on COVID-19: SARS-CoV-2 variants, antiviral drugs, and vaccines
Hillary, V. E., & Ceasar, S. A. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e13952 · Cited by 112 · see citing works
“In February 2020, China investigated the use of favipiravir for the treatment of SARS-CoV-2 infection by providing 1600 mg for the first day (every 12 h), followed by 600 mg for 10 days (every 12 h), and observed a significant difference between hosts with mild fever and cold [64].”
Jin, Y., Zhan, Q., Peng, Z., Ren, X., Yin, X., Cai, L., Yuan, Y., Yue, J., Zhang, X., Yang, Q., et al. (2020) · Military Medical Research · doi:10.1186/s40779-020-00270-8 · Cited by 118 · see citing works
Self-citationGe, Y., Tian, T., Huang, S., Wan, F., Li, J., Li, S., Wang, X., Yang, H., Hong, L., Wu, N., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00568-6 · Cited by 300 · see citing works
“24 In particular, the inhibitory activities against SARS-CoV-2 replication of favipiravir at 30 μ M, CVL218 at 3.5 μ M and a combination of both were measured in Vero E6 cells (Methods).”
BackgroundInfluentialSelf-citationTargeting Proteases for Treating COVID-19
Luan, B., Huynh, T., Cheng, X. M., Lan, G., & Wang, H. (2020) · Journal of Proteome Research · doi:10.1021/acs.jproteome.0c00430 · Cited by 108 · see citing works
Fighting COVID-19: A quick review of diagnoses, therapies, and vaccines
Shih, H., Wu, C.-J., Tu, Y., & Chi, C. (2020) · Biomedical Journal · doi:10.1016/j.bj.2020.05.021 · Cited by 110 · see citing works
“[46] Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al.”
COVID-19 and the Kidneys: An Update
Benedetti, C., Waldman, M. A., Zaza, G., Riella, L. V., & Cravedi, P. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00423 · Cited by 142 · see citing works
Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials
Vegivinti, C. T. R., Evanson, K. W., Lyons, H., Akosman, I., Barrett, A., Hardy, N. J., Kane, B., Keesari, P. R., Pulakurthi, Y. S., Sheffels, E., et al. (2022) · BMC Infectious Diseases · doi:10.1186/s12879-022-07068-0 · Cited by 119 · see citing works
“Antiviral treatments compared in the included studies were umifenovir (Arbidol) [25, 29, 31, 47], baloxavir marboxil [30], enisamium [50], Table 1 Search terms Search terms Database Search date Number of results (Lopinavir OR Ritonavir OR Remdesivir OR Ribavirin OR Arbidol OR Favipiravir OR Sofosbuvir OR Daclatasvir)…”
Emerging Therapeutic Approaches to Combat COVID-19: Present Status and Future Perspectives
Vivekanandhan, K., Poornima, S., Barabadi, H., Arumugam, V., Raj, D. D. R. D. P., Manikandan, S., Subbaiya, R., Anand, K., Pandi, B., Chandrasekaran, B., et al. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.604447 · Cited by 58 · see citing works
Uric Acid Elevation by Favipiravir, an Antiviral Drug.
Mishima, E., Anzai, N., Miyazaki, M., et al. (2020) · Tohoku journal of experimental medicine · doi:10.1620/tjem.251.87 · Cited by 90
“Thus, favipiravir can also increase blood uric acid levels in COVID-19 patients; however, these studies did not show data about the detailed uric acid levels.”
BackgroundInfluentialCOVID-19 Pandemic: Epidemiology, Etiology, Conventional and Non-Conventional Therapies
Rauf, A., Abu‐Izneid, T., Olatunde, A., Khalil, A. A., Alhumaydhi, F. A., Tufail, T., Shariati, M. A., Ребезов, М. Б., Almarhoon, Z. M., Mabkhot, Y. N., et al. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17218155 · Cited by 130 · see citing works
“However, a non-significant improvement was seen in clinical recovery rate observed at day 7 in both groups [143].”
BackgroundImmune Therapy, or Antiviral Therapy, or Both for COVID-19: A Systematic Review
Cantini, F., Goletti, D., Petrone, L., Fard, S. N., Niccoli, L., & Foti, R. (2020) · Drugs · doi:10.1007/s40265-020-01421-w · Cited by 111 · see citing works
Wang, X., & Guan, Y. (2020) · Medicinal Research Reviews · doi:10.1002/med.21728 · Cited by 93 · see citing works
Self-citationEmerging pharmacological therapies for ARDS: COVID-19 and beyond
Horie, S., McNicholas, B., Rezoagli, E., Pham, T. O., Curley, G., McAuley, D. F., O’Kane, C. M., Nichol, A., dos Santos, C. C., Rocco, P. R. M., et al. (2020) · Intensive Care Medicine · doi:10.1007/s00134-020-06141-z · Cited by 94 · see citing works
“Umifenovir (arbidol) Inhibits viral interaction and binding with host cells via ACE2 Retrospective analysis showed that arbidol treatment (n = 16) in comparison with lopinavir/ritonavir treatment (n = 36) reduced viral load in SARS-CoV-2 patients [69] No benefit over favipiravir in openlabel trial [70] 1.”
BackgroundMethodResultInfluentialAn overview on nanoparticle-based strategies to fight viral infections with a focus on COVID-19
Yasamineh, S., Kalajahi, H. G., Yasamineh, P., Yazdani, Y., Gholizadeh, O., Tabatabaie, R., Afkhami, H., Davodabadi, F., farkhad, A. K., Pahlevan, D., et al. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01625-0 · Cited by 102 · see citing works
“Tulbah AS, Lee W‑H. Physicochemical Characteristics and In Vitro Toxic‑ ity/Anti‑SARS‑CoV‑2 Activity of Favipiravir Solid Lipid Nanoparticles (SLNs).”
BackgroundInfluentialFavipiravir and COVID-19: A Simplified Summary
Ghasemnejad‐Berenji, M., & Pashapour, S. (2020) · Drug Research · doi:10.1055/a-1296-7935 · Cited by 102 · see citing works
“In addition another multicenter, open-labelled clinical trial reported that in moderate COVID-19 patients untreated with antiviral previously, favipiravir can be considered as a preferred treatment because of the higher clinical recovery rate of day 7 and more effectively reduced incidence of fever, cough besides some…”
BackgroundIdentification of SARS-CoV-2 entry inhibitors among already approved drugs
Yang, L., Pei, R., Li, H., et al. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00556-6 · Cited by 81
Self-citationJuul, S., Nielsen, E. E., Feinberg, J. B., Siddiqui, F., Kamp, C. B., Barot, E., Nielsen, N., Bentzer, P., Veroniki, A. A., Thabane, L., et al. (2020) · PLoS Medicine · doi:10.1371/journal.pmed.1003293 · Cited by 85 · see citing works
Nanocarrier vaccines for SARS-CoV-2
Machhi, J., Shahjin, F., Das, S., Patel, M., Abdelmoaty, M. M., Cohen, J. D., Singh, P., Baldi, A., Bajwa, N., Kumar, R., et al. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.01.002 · Cited by 80 · see citing works
“The drug acts by inhibiting cell membrane-SARS-CoV-2 envelope fusion [57].”
Natural history of COVID-19 and current knowledge on treatment therapeutic options
dos Santos, W. G. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110493 · Cited by 222 · see citing works
“However, it was shown that patients treated with umifenovir demonstrated inferior outcome in clinical recovery rate and less improvement in symptoms like fever and cough, when compared to favipiravir [160].”
Battagello, D. S., Dragunas, G., Klein, M., Ayub, A. L. P., Velloso, F. J., & Correa, R. G. (2020) · Clinical Science · doi:10.1042/cs20200904 · Cited by 87 · see citing works
Minimum costs to manufacture new treatments for COVID-19
Hill, A. M., Wang, J., Levi, J., Heath, K., & Fortunak, J. (2020) · Journal of Virus Eradication · doi:10.1016/s2055-6640(20)30018-2 · Cited by 81 · see citing works
Favipiravir in Therapy of Viral Infections
Łagocka, R., Dziedziejko, V., Kłos, P., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10020273 · Cited by 75
“Treatment of COVID-19 patients Day 1: 3200 mg (1600 mg twice a day) Day 2–10: 1200 mg (600 mg twice a day) [26]”
BackgroundMethodInfluentialClinical efficacy of antivirals against novel coronavirus (COVID-19): A review
Jomah, S., Asdaq, S. M. B., & Al‐Yamani, M. (2020) · Journal of Infection and Public Health · doi:10.1016/j.jiph.2020.07.013 · Cited by 93 · see citing works
Savi, C. D., Hughes, D. L., & Kværnø, L. (2020) · Organic Process Research & Development · doi:10.1021/acs.oprd.0c00233 · Cited by 99 · see citing works
The COVID-19 Vaccines: Recent Development, Challenges and Prospects
Yan, Y., Pang, Y. X., Lyu, Z., Wang, R., Wu, X., You, C., Zhao, H., Manickam, S., Lester, E. H., Wu, T., et al. (2021) · Vaccines · doi:10.3390/vaccines9040349 · Cited by 82 · see citing works
Potential therapeutic targets and promising drugs for combating SARS‐CoV‐2
Zhou, H., Fang, Y., Xu, T., Ni, W., Shen, A., & Meng, X. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15092 · Cited by 76 · see citing works
“prospective, multicentre, open-label, randomized superiority trial (ChiCTR200030254) has come to the similar conclusion that favipiravir (1600 mg/time/bid on the first day; 600 mg/time/bid from the second day to the end of treatment) should be regarded as one of the most promising candidate drugs for combating SARS-Co…”
BackgroundCutaneous sıde‐effects of the potential COVID‐19 drugs
Türsen, Ü., Türsen, B., & Lotti, T. (2020) · Dermatologic Therapy · doi:10.1111/dth.13476 · Cited by 70 · see citing works
“There are no reports on the skin reaction of umifenovir.(16)”
BackgroundBhavana, V., Thakor, P., Singh, S. B., & Mehra, N. K. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118336 · Cited by 83 · see citing works
“Favipiravir showed significant relief in cough and pyrexia after 7 days treatments [43].”
Remdesivir in Coronavirus Disease 2019 (COVID-19) treatment: a review of evidence
Lin, H., Cho, S., Aravamudan, V. M., Sanda, H., Palraj, R., Molton, J. S., & Venkatachalam, I. (2021) · Infection · doi:10.1007/s15010-020-01557-7 · Cited by 98 · see citing works
“Duration of febrile illness and cough, however, was significantly shorter in the favipiravir group [31].”
BackgroundInfluentialLiu, W. Y., Zhou, P., Chen, K., Ye, Z., Liu, F., Li, X., He, N., Wu, Z., Zhang, Q., Gong, X., et al. (2020) · Canadian Medical Association Journal · doi:10.1503/cmaj.200647 · Cited by 84 · see citing works
Self-citationCutaneous manifestations in hospitalized patients diagnosed as COVID ‐19
Aşkın, Ö., Altunkalem, R. N., Altınışık, D. D., Uzunçakmak, T. K., Türsen, Ü., & Kutlubay, Z. (2020) · Dermatologic Therapy · doi:10.1111/dth.13896 · Cited by 73 · see citing works
Research Progress of Coronavirus Based on Bibliometric Analysis
Zhai, F., Zhai, Y., Cong, C., Song, T., Xiang, R., Feng, T., Liang, Z., Zeng, Y., Yang, J., Yang, J., et al. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17113766 · Cited by 70 · see citing works
Andrew, M., & Jayaraman, G. (2021) · Carbohydrate Research · doi:10.1016/j.carres.2021.108326 · Cited by 80 · see citing works
“Currently, the repurposing of antivirals [5,6] has been the possible strategy to prevent the mild and moderate COVID-19 cases [7, 8].”
Padhi, A. K., Seal, A., Khan, J. M., Ahamed, M., & Tripathi, T. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173836 · Cited by 81 · see citing works
“Arbidol has been shown to be superior to the antiviral favipiravir, which did not improve the clinical recovery rate at day 7 compared to that in the arbidol group (Chen et al., 2020).”
Varghese, P. M., Tsolaki, A. G., Yasmin, H., Shastri, A., Ferluga, J., Vatish, M., Madan, T., & Kishore, U. (2020) · Immunobiology · doi:10.1016/j.imbio.2020.152008 · Cited by 82 · see citing works
Effectiveness of favipiravir in COVID-19: a live systematic review
Özlüşen, B., Kozan, Ş., Akcan, R. E., et al. (2021) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-021-04307-1 · Cited by 77 · see citing works
- Authors
- Chen, C., Zhang, Y., Huang, J., Yin, P., Cheng, Z., Wu, J., Chen, S., Zhang, Y., Chen, B., Lu, M., Luo, Y., Ju, L., Zhang, J., & Wang, X.
- Affiliations
- Zhongnan Hospital of Wuhan University (CN)
- Peking University (CN)
- Huazhong University of Science and Technology (CN)
- Hubei Zhongshan Hospital (CN)
- Corresponding author
- Wang, Xinghuan
- ORCID
- Venue
- Frontiers in Pharmacology
- Publisher
- openRxiv
- Published
- 2020-03-20
- Volume
- 12
- Pages
- 683296-683296
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC8443786
- OpenAlex
- W3197627421
- Cited by
- 852
- References
- 12
- Citations by year
- 2026: 2 · 2025: 18 · 2024: 32 · 2023: 54 · 2022: 136 · 2021: 231 · 2020: 379
- FWCI
- 36.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- medRxiv (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Capital Medical University
- Huazhong University of Science and Technology
- Tongji University
- Wuhan University
- Wuhan University of Science and Technology
- Shanghai University of Traditional Chinese Medicine
- Longhua Hospital Shanghai University of Traditional Chinese Medicine
- Science and Technology Department of Hubei Province
- National Key Research and Development Program of China (2020YFC0844400)
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Keywords
- favipiravir, umifenovir, arbidol, COVID-19 pandemic, antiviral therapy, clinical recovery, non-invasive ventilation, mechanical ventilation, serum uric acid, drug safety, SARS-CoV-2, adults, randomized trial comparison, adverse events
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