Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial

Shenoy et al., medRxiv, doi:10.1101/2021.11.08.21265884, NCT04529499, Nov 2021

https://c19early.org/shenoy.html

Late stage RCT with 353 hospitalized patients, showing no significant differences with favipiravir treatment overall, however a trend towards benefit was seen within patients treated relatively early, including a statistically significant shorter time to discharge with treatment.

Potential risks of favipiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-6.

Important missing comments or errors? Let us know.

risk of death, 29.5% higher, RR 1.29, p = 0.54, treatment 14 of 175 (8.0%), control 11 of 178 (6.2%), day 28.

risk of mechanical ventilation, 33.0% higher, RR 1.33, p = 0.54, treatment 17 of 175 (9.7%), control 13 of 178 (7.3%).

risk of ICU admission, 1.7% higher, RR 1.02, p = 0.54, treatment 20 of 175 (11.4%), control 20 of 178 (11.2%).

time to resolution of hypoxia, 1.0% higher, HR 1.01, p = 0.94, treatment 157, control 158, inverted to make HR<1 favor treatment, primary outcome.

time to hospital discharge, 5.7% lower, HR 0.94, p = 0.60, treatment 175, control 178, inverted to make HR<1 favor treatment.

time to resolution of hypoxia, 17.4% lower, HR 0.83, p = 0.29, treatment 157, control 158, inverted to make HR<1 favor treatment, earlier treatment subgroup, primary outcome.

time to hospital discharge, 32.0% lower, HR 0.68, p = 0.01, treatment 175, control 178, inverted to make HR<1 favor treatment, earlier treatment subgroup.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

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.

6. Cenikli et al., Does Favipiravir interact with DNA? Design of electrochemical DNA nanobiosensor to investigate the interaction between DNA and Favipiravir used in the treatment of COVID-19, Talanta, doi:10.1016/j.talanta.2025.128084.sciencedirect.com, doi.org.

Shenoy et al., 9 Nov 2021, Double Blind Randomized Controlled Trial, Kuwait, preprint, 8 authors, study period 22 August, 2020 - 27 January, 2021, average treatment delay 6.3 days, trial NCT04529499 (history).

This Paper Favipiravir All

Favipiravir In Adults with Moderate to Severe COVID-19: A Phase 3 Multicentre, Randomized, Double-Blinded, Placebo-Controlled Trial

Srinivas Shenoy, Sagar Munjal, Sarah Al Youha, Mohammad Alghounaim, Sulaiman Almazeedi, Yousef Alshamali, Richard H Kaszynski, Salman Al-Sabah

doi:10.1101/2021.11.08.21265884

Aim: To assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 . Methods: In this randomized, double-blind, multicenter, phase 3 trial, adults (21-80 years) with real-time reverse transcriptase polymerase chain reaction (rRT-PCR) confirmed SARS-CoV-2 infection and presenting with moderate to severe COVID-19 and requiring hospitalization were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) (FPV) plus standard supportive care (SoC) versus placebo plus SoC (placebo). The primary endpoint was time to resolution of hypoxia. Results: In total, 353 patients were randomized to receive either FPV or placebo (175 and 178 in the FPV and placebo groups, respectively). Overall, 76% of the patients (240/315, 78% in FPV vs. 75% in placebo group) reached resolution of hypoxia on or before day 28. The median time to resolution of hypoxia was 7 days in the FPV group and 8 days in the placebo group. Treatment effect was not significant [Hazard ratio (HR) (95% CI): 0.991 (0.767, 1.280) (p=0.94)]. Patients in the lower NEWS-2 clinical risk subgroup were more likely to achieve shorter time to resolution of hypoxia with the median time to resolution of hypoxia of 6 days in FPV and 7 days in placebo group [HR (95% CI): 1.21 (0.847, 1.731) (p=0.29)]; shorter time to hospital discharge with a median time to discharge of 8 and 10 days in the FPV and placebo group, respectively [HR (95% CI): 1.47 (1.081, 1.997) (p=0.014)]; and shorter time to improvement by 1-point improvement over baseline in WHO 10-point clinical status score with the median time to improvement by 1-point from baseline of 6 and 7 days in the FPV and placebo group, respectively [HR (95% CI): 1.16 (0.830, 1.624) (p=0.38)] than higher NEWS-2 clinical risk subgroup. Treatment emergent adverse event (TEAEs) were experienced by 62/334 (19%) patients [35/168 (21%) patients in FPV and 27/166 (16%) in placebo group]. Hyperuricaemia/increased blood uric acid was reported in 9 (3%)/2 (1%) patients [8 (5%)/1(1%) patients in FPV and 1 (1%)/1(1%) in placebo group] ,which were of mild intensity and transient. Overall, 36 serious adverse events (SAEs) were reported, 20 in FPV and 16 in placebo group. Client Confidential Conclusion: The trial did not find favipiravir to be effective in moderate to severe, hospitalized COVID-19 patients; favourable clinical trends were observed in patients with lower NEWS-2 risk when early administration of favipiravir could be achieved.

Conflict of Interest Drs. Srinivas Shenoy and Sagar Munjal are paid employees of Dr. Reddy's Laboratories and didn't receive any additional compensation for this study. Dr Salman Al-Sabah was the Principal Investigator and National Co-Ordinator (Kuwait) for the trial, while Drs. Sarah Al Youha, Mohammad Alghounaim, Sulaiman Almazeedi and Yousef Alshamali were sub-Investigators. The Investigators and sub-investigators are employees of various public sector hospitals in the State of Kuwait and did not receive any financial compensation for this study. Dr Richard H Kaczynski is a consultant to Fujifilm Toyoma Chemical Co. Ltd. and Chief Medical Officer of AiPharma. He contributed significantly to study design and did not receive any additional compensation for this study.

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DOI record: { "DOI": "10.1101/2021.11.08.21265884", "URL": "http://dx.doi.org/10.1101/2021.11.08.21265884", "abstract": "ABSTRACTAimTo assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 (COVID-19).MethodsIn this randomized, double-blind, multicenter, phase 3 trial, adults (21-80 years) with real-time reverse transcriptase polymerase chain reaction (rRT-PCR) confirmed SARS-CoV-2 infection and presenting with moderate to severe COVID-19 and requiring hospitalization were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) (FPV) plus standard supportive care (SoC) versus placebo plus SoC (placebo). The primary endpoint was time to resolution of hypoxia.ResultsIn total, 353 patients were randomized to receive either FPV or placebo (175 and 178 in the FPV and placebo groups, respectively). Overall, 76% of the patients (240/315, 78% in FPV vs. 75% in placebo group) reached resolution of hypoxia on or before day 28. The median time to resolution of hypoxia was 7 days in the FPV group and 8 days in the placebo group. Treatment effect was not significant [Hazard ratio (HR) (95% CI): 0.991 (0.767, 1.280) (p=0.94)].Patients in the lower NEWS-2 clinical risk subgroup were more likely to achieve shorter time to resolution of hypoxia with the median time to resolution of hypoxia of 6 days in FPV and 7 days in placebo group [HR (95% CI): 1.21 (0.847, 1.731) (p=0.29)]; shorter time to hospital discharge with a median time to discharge of 8 and 10 days in the FPV and placebo group, respectively [HR (95% CI): 1.47 (1.081, 1.997) (p=0.014)]; and shorter time to improvement by 1-point improvement over baseline in WHO 10-point clinical status score with the median time to improvement by 1-point from baseline of 6 and 7 days in the FPV and placebo group, respectively [HR (95% CI): 1.16 (0.830, 1.624) (p=0.38)] than higher NEWS-2 clinical risk subgroup.Treatment emergent adverse event (TEAEs) were experienced by 62/334 (19%) patients [35/168 (21%) patients in FPV and 27/166 (16%) in placebo group]. Hyperuricaemia/increased blood uric acid was reported in 9 (3%)/2 (1%) patients [8 (5%)/1(1%) patients in FPV and 1 (1%)/1(1%) in placebo group], which were of mild intensity and transient. Overall, 36 serious adverse events (SAEs) were reported, 20 in FPV and 16 in placebo group.ConclusionThe trial did not find favipiravir to be effective in moderate to severe, hospitalized COVID-19 patients; favourable clinical trends were observed in patients with lower NEWS-2 risk when early administration of favipiravir could be achieved.", "accepted": { "date-parts": [ [ 2021, 11, 9 ] ] }, "author": [ { "ORCID": "http://orcid.org/0000-0002-0147-7148", "affiliation": [], "authenticated-orcid": false, "family": "Shenoy", "given": "Srinivas", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0001-5387-720X", "affiliation": [], "authenticated-orcid": false, "family": "Munjal", "given": "Sagar", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-1900-0150", "affiliation": [], "authenticated-orcid": false, "family": "Youha", "given": "Sarah Al", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-0665-3761", "affiliation": [], "authenticated-orcid": false, "family": "Alghounaim", "given": "Mohammad", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-0686-0664", "affiliation": [], "authenticated-orcid": false, "family": "Almazeedi", "given": "Sulaiman", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-1948-1559", "affiliation": [], "authenticated-orcid": false, "family": "Alshamali", "given": "Yousef", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-1459-7085", "affiliation": [], "authenticated-orcid": false, "family": "Kaszynski", "given": "Richard H", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-8081-8544", "affiliation": [], "authenticated-orcid": false, "family": "Al-Sabah", "given": "Salman", "sequence": "additional" }, { "affiliation": [], "name": "Kuwait Clinical Trial Group", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2021, 11, 9 ] ], "date-time": "2021-11-09T19:15:15Z", "timestamp": 1636485315000 }, "deposited": { "date-parts": [ [ 2021, 11, 12 ] ], "date-time": "2021-11-12T06:45:21Z", "timestamp": 1636699521000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2024, 3, 28 ] ], "date-time": "2024-03-28T04:44:52Z", "timestamp": 1711601092600 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 4, "issued": { "date-parts": [ [ 2021, 11, 9 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2021.11.08.21265884", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2021, 11, 9 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2021, 11, 9 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "DOI": "10.1016/j.ijsu.2020.04.001", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.1" }, { "DOI": "10.1016/j.addr.2020.12.011", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.2" }, { "DOI": "10.1016/S2213-2600(21)00129-6", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.3" }, { "DOI": "10.1038/d41586-021-01696-3", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.4" }, { "DOI": "10.1056/NEJMoa2023184", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.5" }, { "DOI": "10.2183/pjab.93.027", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.6" }, { "DOI": "10.1016/j.antiviral.2014.01.012", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.7" }, { "DOI": "10.1016/j.antiviral.2013.09.015", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.8" }, { "DOI": "10.1038/s41422-020-0282-0", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.9" }, { "DOI": "10.1016/j.antiviral.2014.02.014", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.10" }, { "key": "2021111122450686000_2021.11.08.21265884v1.11", "unstructured": "Favipiravir Observational Study Interim Report 3. 2021;:6." }, { "DOI": "10.3390/jcm10020273", "doi-asserted-by": "publisher", "key": "2021111122450686000_2021.11.08.21265884v1.12" }, { "key": "2021111122450686000_2021.11.08.21265884v1.13", "unstructured": "National Early Warning Score (NEWS) 2. 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Late treatment
is less effective

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