Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19

Ruzhentsova et al., SSRN, doi:10.2139/ssrn.3696907

Oct 2020

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RCT 168 patients, 112 receiving favipiravir and 56 SOC, showing shorter time to clinical improvement and faster viral clearance with favipiravir.

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

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risk of hospitalization, 6.0% lower, RR 0.94, p = 0.49, treatment 3 of 112 (2.7%), control 2 of 56 (3.6%), adjusted per study.

risk of mechanical ventilation, 150.0% higher, RR 2.50, p = 1.00, treatment 1 of 112 (0.9%), control 0 of 56 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).

risk of ICU admission, 51.0% higher, RR 1.51, p = 0.63, treatment 3 of 112 (2.7%), control 1 of 56 (1.8%), adjusted per study.

HR for time to clinical improvement, 38.7% lower, HR 0.61, p = 0.007, treatment 112, control 56, inverted to make HR<1 favor treatment.

risk of no viral clearance, 21.9% lower, RR 0.78, p = 0.16, treatment 112, control 56, inverted to make RR<1 favor treatment, day 5 mid-recovery.

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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.

Ruzhentsova et al., 26 Oct 2020, Randomized Controlled Trial, Russia, preprint, 31 authors, study period 23 May, 2020 - 30 June, 2020, average treatment delay 3.55 days.

This Paper Favipiravir All

Phase 3 Trial of Coronavir (Favipiravir) in patients with mild to moderate COVID-19

Tatiana A Ruzhentsova, Pavel V Chukhliaev, Daria A Khavkina, Alexander A Garbuzov, Rodion A Oseshnyuk, Tatyana N Soluyanova, Irina V Shestakova, Adel Yu Vafin, Elena P Dmitrikova, Dzhavanshir M Mustafaev, Tatiana N Domostroeva, Maria V Otpushchennikova, Konstantin A Pokrovskiy, Тatyana N Markova, Elena A Kaplun, Diana V Petina, Marina G Rusanova, Dmitriy A Bistritskiy, Natalia E Kostina, Viсtoria S Lesina, Sergey G Scherbak, Alina S Agafina, Yury F Brook, Oleg Y Bronov, Evgeny I Shults, Mikhail Y Samsonov, Emilia N Krasavina, Arkadiy V Zintchenko, Maria V Nikolskaya, Viсtoria A Razzhivina, Olga V Filon

Background Favipiravir is an antiviral drug, an inhibitor of RNA dependent RNA polymerase that is preliminarily effective against SARS-CoV-2 virus. The aim of this study was to evaluate the efficacy and safety of favipiravir for treatment of mild to moderate coronavirus disease (COVID-19). Methods We conducted an open-labeled, randomized, active-controlled multicenter trial of an oral dosage form of favipiravir in out-and hospitalized patients with mild to moderate COVID-19. The study was organized in 10 clinical centers in Russia. Eligible patients had laboratory confirmed by PCR test infection of SARS-CoV-2 and were aged 18-60 years. Patients were randomly assigned (in a 2:1 ratio) to receive either favipiravir (1800 mg BID on day 1, followed by 800 mg BID for up to 9 days), or standard of care (SOC) treatment (umifenovir + intranasal interferon alpha-2b, or hydroxychloroquine) for up to 10 days. Randomization was performed using a web-response system after stratification by COVID-19 severity, age and CT severity at enrollment. The coprimary outcomes were the time to clinical improvement and the time to viral clearance. An efficacy analysis was performed in intent-to-treat population. The safety population included all participants who received at least one dose of favipiravir or SOC. The trial is registered on ClinicalTrials.gov, identifier: NCT04501783. Findings Between May 23, 2020, and June 30, 2020, 190 patients were assessed for eligibility, of whom 168 were randomly assigned to receive either favipiravir (n = 112), or SOC (n = 56). The median time to clinical improvement was 6.0 (IQR 4•0; 9•3) days in favipiravir group and 10.0 (IQR 5•0; 21•0) days in SOC group; the median difference was 4 days (HR 1•63; 95% CI 1•14-2•34, p = 0•007). The statistically significant difference in the median time to viral clearance was observed only in the hospitalized cohort of patients: 3•0 (IQR 3•0; 3•0) vs. 5•0 (IQR 4•5; 5•5), respectively (HR 2•11; 95% CI 1•04-4•31; p = 0•038). However, the rate of viral elimination on Day 5 in the favipiravir group was significantly higher in the whole population: 81•2% vs. 67•9% respectively (RR 1•22; 05% CI 1•00-1•48; p = 0.022). The rate of clinical improvement on Day 7 in the favipiravir group was 1.5-fold higher compared to SOC: 52•7% vs. 35•8% (RR 1•50; 95% CI 1•02-2•22; p = 0•020). Favipiravir was well tolerated: most of the adverse events (AE) were mild. Any AEs were reported in 74•1% of patients in the favipiravir group vs. 60•0% in the SOC group. Among the most common adverse reactions was asymptomatic hyperuricemia, transient elevation of ALT & AST, and gastrointestinal disorders (diarrhea, nausea, abdominal pain). Interpretation Favipiravir was superior to SOC in shortening the time to clinical improvement in patients with mild to moderate COVID-19.

Favipiravir 3) and decreased oxygen saturation due to COVID-19 progression (gr. 3). § The difference was statistically significant (р < 0•0001). Table 3 : Adverse events of any cause that occurred in 5% or more patients in the Astreated population

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