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

19 Pages Posted: 26 Oct 2020

See all articles by Tatiana Ruzhentsova

Tatiana Ruzhentsova

The Federal Service on Customers' Rights Protection and Human Well-being Surveillance - Gabrichevsky Research Institute for Epidemiology and Microbiology

Pavel Chukhliaev

The Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing - Clinical Research Department

Daria Khavkina

The Federal Service on Customers' Rights Protection and Human Well-being Surveillance - Gabrichevsky Research Institute for Epidemiology and Microbiology

Alexander Garbuzov

The Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing - Clinical Research Department

Rodion Oseshnyuk

Medical Center "Eco-safety"

Tatyana Soluyanova

Medical Center "Group of companies "MEDSI" JSC

Irina Shestakova

Medical Center "Group of companies "MEDSI" JSC

Adel Vafin

Medical Center "Group of companies "MEDSI" JSC

Elena Petrovna Dmitrikova

Budgetary Institution of Healthcare of Moscow region "Clinical Hospital of Zhukovsky" - Clinical Pharmacology Department

Dzhavanshir Mustafaev

Medical center "Neuroprofi" LLC

Tatyana Domostroeva

Medical center "Neuroprofi" LLC

Maria Otpushchennikova

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 67 named after L.А. Vorokhobov of the Moscow City Healthcare Department”

Konstantin Pokrovsky

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 67 named after L.А. Vorokhobov of the Moscow City Healthcare Department”

Тatyana Markova

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 52 of the Moscow City Healthcare Department”

Elena Kaplun

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 52 of the Moscow City Healthcare Department”

Diana Petina

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 52 of the Moscow City Healthcare Department”

Marina Rusanova

State Budgetary Healthcare Institution of Moscow city "Infectious Clinical Hospital No. 1 of the Moscow City Healthcare Department"

Dmitriy Bistritskiy

State Budgetary Healthcare Institution of Moscow city "Infectious Clinical Hospital No. 1 of the Moscow City Healthcare Department"

Natalia Kostina

Budgetary Healthcare Institution of the Voronezh region “Voronezh Regional Clinical Hospital No. 1”

Viсtoria Lesina

Budgetary Healthcare Institution of the Voronezh region “Voronezh Regional Clinical Hospital No. 1”

Sergey Scherbak

St. Petersburg State Budgetary Healthcare Institution "City Hospital No. 40 of the Kurortny District"

Alina Agafina

St. Petersburg State Budgetary Healthcare Institution "City Hospital No. 40 of the Kurortny District"

Yury Brook

Federal State Budgetary Institution “National Medical and Surgical Center named after N.I. Pirogov" of the Ministry of Health of the Russian Federation

Oleg Bronov

Federal State Budgetary Institution “National Medical and Surgical Center named after N.I. Pirogov" of the Ministry of Health of the Russian Federation

Evgeny Shults

Federal State Autonomous Institution “N.N. Burdenko National Medical Research Centr of Neurosurgery” of the Ministry of Health of the Russian Federation

Mikhail Samsonov

R-Pharm Group of Companies

Emilia Krasavina

R-Pharm Group of Companies

Arkadi Zintchenko

R-Pharm Group of Companies

Maria Nikolskaya

R-Pharm Group of Companies

Victoria Razzhivina

R-Pharm Group of Companies

Olga Filon

R-Pharm Group of Companies

More...

Abstract

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 co-primary 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.

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.

Trial Registration: The trial is registered on ClinicalTrials.gov, identifier: NCT04501783.

Funding: Funded by R-Pharm Group of Companies

Declaration of Interests: ENK, MYS, MVN, VAR, AVZ, and OVF were employees of R-Pharm Group of Companies during the study and received compensation as part of their employment. All other authors declare no competing interests.

Ethics Approval Statement: The trial protocol was approved by the Russian Ministry of Health (MoH) (permission #201 dated by May 20, 202010), including Central Ethics Council, and by the appropriate local ethics committees at each center. Enrollment in this trial was done on the10 trial sites in Russia, including hospitals and outpatient sites. All of the patients provided written informed consent (IC) before the enrollment.

Keywords: coronavirus disease, COVID-19, SARS-CoV-2 virus, favipiravir, phase 3 study

Suggested Citation

Ruzhentsova, Tatiana and Chukhliaev, Pavel and Khavkina, Daria and Garbuzov, Alexander and Oseshnyuk, Rodion and Soluyanova, Tatyana and Shestakova, Irina and Vafin, Adel and Dmitrikova, Elena Petrovna and Mustafaev, Dzhavanshir and Domostroeva, Tatyana and Otpushchennikova, Maria and Pokrovsky, Konstantin and Markova, Тatyana and Kaplun, Elena and Petina, Diana and Rusanova, Marina and Bistritskiy, Dmitriy and Kostina, Natalia and Lesina, Viсtoria and Scherbak, Sergey and Agafina, Alina and Brook, Yury and Bronov, Oleg and Shults, Evgeny and Samsonov, Mikhail and Krasavina, Emilia and Zintchenko, Arkadi and Nikolskaya, Maria and Razzhivina, Victoria and Filon, Olga, Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19. Available at SSRN: https://ssrn.com/abstract=3696907 or http://dx.doi.org/10.2139/ssrn.3696907

Tatiana Ruzhentsova

The Federal Service on Customers' Rights Protection and Human Well-being Surveillance - Gabrichevsky Research Institute for Epidemiology and Microbiology ( email )

Moscow, Admirala Makarova Str., 10
Moscow, 125212
+74954521816 (Phone)
+74954521830 (Fax)

Pavel Chukhliaev

The Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing - Clinical Research Department ( email )

Daria Khavkina

The Federal Service on Customers' Rights Protection and Human Well-being Surveillance - Gabrichevsky Research Institute for Epidemiology and Microbiology ( email )

Moscow, Admirala Makarova Str., 10
Moscow, 125212
+7-495-452-18-16 (Phone)

HOME PAGE: http://www.gabrich.ru

Alexander Garbuzov

The Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing - Clinical Research Department ( email )

Rodion Oseshnyuk

Medical Center "Eco-safety" ( email )

Tatyana Soluyanova

Medical Center "Group of companies "MEDSI" JSC ( email )

Irina Shestakova

Medical Center "Group of companies "MEDSI" JSC ( email )

Adel Vafin

Medical Center "Group of companies "MEDSI" JSC ( email )

Elena Petrovna Dmitrikova

Budgetary Institution of Healthcare of Moscow region "Clinical Hospital of Zhukovsky" - Clinical Pharmacology Department ( email )

Dzhavanshir Mustafaev

Medical center "Neuroprofi" LLC ( email )

Tatyana Domostroeva

Medical center "Neuroprofi" LLC ( email )

Maria Otpushchennikova

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 67 named after L.А. Vorokhobov of the Moscow City Healthcare Department” ( email )

Konstantin Pokrovsky

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 67 named after L.А. Vorokhobov of the Moscow City Healthcare Department” ( email )

Тatyana Markova

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 52 of the Moscow City Healthcare Department” ( email )

Elena Kaplun

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 52 of the Moscow City Healthcare Department” ( email )

Diana Petina

State Budgetary Institution of Healthcare of Moscow city “City Clinical Hospital No. 52 of the Moscow City Healthcare Department” ( email )

Marina Rusanova

State Budgetary Healthcare Institution of Moscow city "Infectious Clinical Hospital No. 1 of the Moscow City Healthcare Department" ( email )

Dmitriy Bistritskiy

State Budgetary Healthcare Institution of Moscow city "Infectious Clinical Hospital No. 1 of the Moscow City Healthcare Department" ( email )

Natalia Kostina

Budgetary Healthcare Institution of the Voronezh region “Voronezh Regional Clinical Hospital No. 1” ( email )

Viсtoria Lesina

Budgetary Healthcare Institution of the Voronezh region “Voronezh Regional Clinical Hospital No. 1” ( email )

Sergey Scherbak

St. Petersburg State Budgetary Healthcare Institution "City Hospital No. 40 of the Kurortny District" ( email )

Alina Agafina

St. Petersburg State Budgetary Healthcare Institution "City Hospital No. 40 of the Kurortny District" ( email )

Yury Brook

Federal State Budgetary Institution “National Medical and Surgical Center named after N.I. Pirogov" of the Ministry of Health of the Russian Federation ( email )

Oleg Bronov

Federal State Budgetary Institution “National Medical and Surgical Center named after N.I. Pirogov" of the Ministry of Health of the Russian Federation ( email )

Evgeny Shults

Federal State Autonomous Institution “N.N. Burdenko National Medical Research Centr of Neurosurgery” of the Ministry of Health of the Russian Federation ( email )

Mikhail Samsonov

R-Pharm Group of Companies ( email )

Russia

Emilia Krasavina

R-Pharm Group of Companies ( email )

Russia

Arkadi Zintchenko

R-Pharm Group of Companies ( email )

Russia

Maria Nikolskaya

R-Pharm Group of Companies ( email )

Russia

Victoria Razzhivina

R-Pharm Group of Companies ( email )

Russia

Olga Filon (Contact Author)

R-Pharm Group of Companies ( email )

Russia

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