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Interim Results of a Phase II/III Multicenter Randomized Clinical Trial of

AVIFAVIR in Hospitalized Patients with COVID-19

Andrey A. Ivashchenko1, Kirill A. Dmitriev2, Natalia V. Vostokova3, Valeria N. Azarova3,

Andrew A. Blinow4, Alina N. Egorova3, Ivan G. Gordeev5, Alexey P. Ilin6, Ruben N.
Karapetian7, Dmitry V. Kravchenko6, Nikita V. Lomakin8, Elena A. Merkulova3, Natalia A.
Papazova9, Elena P. Pavlikova10, Nikolay P. Savchuk11, Elena N. Simakina12, Tagir A.
Sitdekov2, Elena A. Smolyarchuk13, Elena G. Tikhomolova14, Elena V. Yakubova4, Alexandre
V. Ivachtchenko11

Affiliations:
1
ChemRar High-Tech Center, Khimki, Moscow region, Russian Federation
2
Russian Direct Investment Fund, Moscow, Russian Federation
3
IPHARMA LLC, Skolkovo Innovative Centre, Moscow, Russian Federation
4
Chromis LLC, Skolkovo Innovative Centre, Moscow, Russian Federation
5
City Clinical Hospital n.a. O.M. Filatov, Moscow, Russian Federation
6
Department of Chemistry and Technology, Chemical Diversity Research Institute, Khimki, Moscow region
7
Department of Biology, Chemical Diversity Research Institute, Khimki, Moscow region, Russian Federation
8
Central Clinical Hospital with Polyclinic, Moscow, Russian Federation
9
Department of finished dosage forms, Chemical Diversity Research Institute, Khimki, Moscow region, Russian
Federation
10
Moscow State University n.a. M. V. Lomonosov, Moscow, Russian Federation
11
Chemical Diversity Research Institute, Khimki, Moscow region, Russian Federation
12
Clinical Hospital No.1, Smolensk, Russian Federation
13
First Moscow State Medical University n.a. I.M. Sechenov, Moscow, Russian Federation
14
Infectious clinical hospital No. 2, Nizhny Novgorod, Russian Federation

Correspondence:
Alexandre V. Ivachtchenko e-mail: [email protected];
Natalia V. Vostokova e-mail: [email protected]

Keywords. AVIFAVIR, favipiravir, COVID-19, SARS-CoV-2

medRxiv preprint doi: https://doi.org/10.1101/2020.07.26.20154724.this version posted August 4, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

ABSTRACT
In May 2020 the Russian Ministry of Health granted fast-track marketing authorization to RNA
polymerase inhibitor AVIFAVIR (favipiravir) for the treatment of COVID-19 patients. In the
pilot stage of Phase II/III clinical trial, AVIFAVIR enabled SARS-CoV-2 viral clearance in
62.5% of patients within 4 days, and was safe and well-tolerated.

INTRODUCTION
The pandemic of the novel coronavirus infection (COVID-19) represents an unprecedented
disaster for healthcare providers and economy worldwide. The urgent requirement for the
effective treatments has sparked an intense effort on the part of the pharmaceutical industry and
shifted drug development to a new scale of commitment and collaboration.
On May 29, 2020 the Russian Ministry of Health (MoH) granted fast-track marketing
authorization to AVIFAVIR (favipiravir) for the treatment of COVID-19 patients. The drug was
developed and brought to market within a period of only two months, a feat made possible by the
highly concerted and coordinated efforts of regulator, industry, and health professionals. The
marketing authorization makes AVIFAVIR the only oral drug approved for treatment of
moderate to severe COVID-19 to date.
Favipiravir is an RNA-dependent RNA polymerase inhibitor marketed in Japan (Avigan)
[1] and China (Favilavir) as a second-line treatment of novel or re-emerging influenza outbreaks.
Earlier this year it was reported to demonstrate antiviral activity against SARS-CoV-2 in Vero
E6 cells (EC50, 61.88 μM , CC50 > 400 μM, SI > 6.46) and to provide shorter viral clearance time
in patients with COVID-19 [2]. A non-randomized study conducted in China demonstrated a
median viral clearance time of 4 days, versus a period of 11 days for lopinavir/ritonavir (p <
0.001) [3]. The World Health Organization (WHO) also listed Favipiravir as a candidate
experimental treatment (broad spectrum antiviral) [4].
In the attempt of establishing COVID-19 treatment in the Russian Federation, in March
2020, the Russian Direct Investment Fund and ChemRar Group organized a joint venture aimed
at research, development, manufacturing, and marketing of favipiravir under the brand name
AVIFAVIR. The API synthesis and the final drug product manufacturing were performed at the
Good Manufacturing Practice facility of Chemical Diversity Research Institute.
medRxiv preprint doi: https://doi.org/10.1101/2020.07.26.20154724.this version posted August 4, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

METHODS

Study design and participants

The pilot stage of the adaptive, multicenter, open label, randomized, Phase II/III clinical trial of
AVIFAVIR versus standard of care (SOC) in hospitalized patients with moderate to severe
COVID-19 pneumonia was conducted by IPHARMA CRO in April and May 2020 at six
Russian clinical sites based at infectious hospitals in Moscow, Smolensk, and Nizhniy Novgorod
(ClinicalTrials.gov Identifier: NCT04434248). The Independent Data Monitoring Committee
(IDMC) was introduced to review the results of the interim analysis.
The objective of the pilot stage of the clinical study was to conduct a preliminary
assessment of the efficacy and safety of AVIFAVIR, and to select the optimal dosing regimen
for further evaluation in moderately ill SARS-CoV-2 virus-infected patients at the pivotal stage.
The study design was based on WHO R&D Blueprint recommendations for clinical trials of
therapeutics for COVID-19 [5].
Upon signing the informed consent form and screening, 60 eligible patients with
pneumonia associated with PCR confirmed COVID-19 were randomized at a 1:1:1 ratio to
receive either AVIFAVIR 1600 mg BID on Day 1 followed by 600 mg BID on Days 2-14
(1600/600 mg), or AVIFAVIR 1800 mg BID on Day 1 followed by 800 mg BID on Days 2-14
(1800/800 mg), or SOC. Each treatment group comprised 20 patients and all randomized patients
constituted safety and intent-to-treat (ITT) analysis sets.
In the 40 AVIFAVIR-treated patients, the drug was administered for a mean period of 11
days, with antibiotics (30%) and anticoagulants (35%) as concomitant medications for COVID-
19. SOC was assigned in the control group according to the recommended treatment schemes
presented in the Russian MoH interim guidelines for treatment of COVID-19 [6]. Patients
received hydroxychloroquine (65%), chloroquine (10%), lopinavir/ritonavir (5%), or no
etiological treatment (20%), with antibiotics (40%) and anticoagulants (20%) as concomitant
medications for COVID-19.
The AVIFAVIR and control groups were generally comparable in demographic and
baseline characteristics. 36.7% of patients (22/60) had risk factors for severe disease (age 60 and
older and/or concurrent chronic conditions). At baseline, 73.3% of patients (44/60) were on
ambient air (Score 3 on the WHO Ordinal Scale for Clinical Improvement) and 26.7% of
patients (16/60) required supplemental oxygen via mask or nasal cannula (Score 4). Mean
disease duration was 7 days from the start of the first symptoms. Most common symptoms were
body temperature above 37.5oC (95.0%), cough (83.3%), weakness (70.0%), anosmia (35.0%),
chest tightness (30.0%), and dyspnea (28.3%).
medRxiv preprint doi: https://doi.org/10.1101/2020.07.26.20154724.this version posted August 4, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

The study assessments included daily vital signs, SpO2 and WHO Ordinal Scale for
Clinical Improvement; PCR for SARS-CoV-2 virus detection in nasopharyngeal/oropharyngeal
swabs at baseline and on Days 5, 10, and 15; chest computed tomography (CT) scan at baseline
and on Day 15; physical examination, complete blood count with differential, biochemistry, C-
reactive protein, urinalysis, and electrocardiogram at baseline and on Days 5 and 15. If not
discharged from the hospital earlier, the patients attended follow-up visits on Day 22 and
Day 29. All patients were followed until Day 29.

RESULTS
Interim efficacy and safety results
The primary efficacy endpoint at the pilot stage was the elimination of SARS-CoV-2 by Day 10
(defined as two negative PCR tests with at least a 24-hour interval). The “go-no-go” decision to
start Phase III was based on the exact single-stage Phase II assessment at one-sided α=0.05 and
80% power [7]. Thirteen or more responders out of 18 treated patients would have been
sufficient to demonstrate that the effect of the viral clearance in 80% of patients by Day 10 is
plausible, and that the efficacy is greater than the presumably non-effective level of 50%.
On Day 5 (i.e. 4 days after treatment was started), the viral clearance was achieved in
62.5% of patients (25/40) on AVIFAVIR (similar proportions on both dosage levels) and in
30.0% of patients (6/20) on SOC (p=0.018). By Day 10 (i.e. 9 days after treatment was started)
the viral clearance was achieved in 90.0% of patients (36/40) on AVIFAVIR (similar proportions
on both dosage levels) and in 80.0% of patients (16/20) on SOC (p=0.221).
The median time to body temperature normalization (< 37oC) was 2 days (IQR 1-3) in the
AVIFAVIR groups and 4 days (IQR 1-8) in the SOC group (p=0.007). By Day 15, chest CT
scans improved in 82.5% of patients (33/40) on AVIFAVIR and 75.0% of patients (15/20) on
SOC (p=0.494).
Adverse drug reactions to AVIFAVIR were reported in 17.5% of patients (7/40)
including diarrhea, nausea, vomiting, chest pain and an increase in liver transaminase levels
(ALT and AST). The adverse drug reactions were mild to moderate and caused early
discontinuation of the study drug in 5.0% of patients (2/40).
During the pilot stage of the study, 2 patients on AVIFAVIR 1600/600 mg were moved
to ICU and received mechanical ventilation, 1 of them died due to deterioration of the disease.
Both patients had concurrent chronic conditions that increased the risk of severe disease.
By the time of the interim analysis 80.0% of patients (32/40) from the AVIFAVIR group
and 90.0% of patients (18/20) from the SOC group were discharged from hospital after
improvement in their condition.
medRxiv preprint doi: https://doi.org/10.1101/2020.07.26.20154724.this version posted August 4, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

Dose-response analysis
Two AVIFAVIR regiments (1600/600 mg and 1800/800 mg) demonstrated similar results in
most efficacy and safety endpoint assessments. The median loading dose of AVIFAVIR was
43.9 mg/kg (IQR 40.0-47.1) in patients with confirmed negative PCR on Day 5, and 39.1 mg/kg
(IQR 35.6-43.9) in patients with positive PCR on Day 5. The confirmed SARS-CoV-2 virus
elimination on Day 5 on AVIFAVIR < 43 mg/kg was achieved in 47.3% of patients (9/19) and
on AVIFAVIR ≥ 43 mg/kg was achieved in 80.0% of patients (16/20) (р=0.0362). No dose-
dependent toxicity was observed in the study.
Thus, 3 weight-based AVIFAVIR dosing regimens were suggested for the pivotal stage of the
study. The recommended duration of AVIFAVIR treatment was 10 days, although it can be
reduced based on laboratory-confirmed viral clearance.

CONCLUSIONS
At the pilot stage of the Phase II/III open label, randomized clinical trial in the Russian
Federation, AVIFAVIR therapy demonstrated rapid antiviral response against SARS-CoV-2.
62.5% of AVIFAVIR-treated patients (25/40) achieved viral clearance within 4 days after
initiation of therapy, which was significantly higher than in the SOC group (p=0.018). There
were no new safety concerns related to AVIFAVIR as all adverse reactions were mild to
moderate in severity and were consistent with those reported previously for AVIGAN [1, 8].
Dose-dependent efficacy pattern was identified and will be studied further. The results of the
pivotal stage of the study are expected in July 2020.
The fast-track marketing authorization granted by the Russian MoH makes AVIFAVIR
the only approved oral drug for treatment of moderate to severe COVID-19 to date.
medRxiv preprint doi: https://doi.org/10.1101/2020.07.26.20154724.this version posted August 4, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

Acknowledgements. The authors thank the co-investigators MD Oksana Y. Shaydyuk of City

Clinical Hospital n.a. O.M. Filatov (Moscow, Russia); MD, PhD Dmitry A. Garkavi and MD
Anna V. Bushmanova of First Moscow State Medical University n.a. I.M. Sechenov (Moscow,
Russia); MD, PhD Anton V. Potapenko and MD Anna G. Sorokina, Moscow State University
n.a. M. V. Lomonosov (Moscow, Russia); MD PhD Olga S. Rozinkova of Clinical hospital No.1
(Smolensk, Russia); MD, PhD Veronika S. Vasilieva, MD Ekaterina E. Shokhina, MD Natalia
O. Simonova, and MD Valery A. Luybinskiy of Central Clinical Hospital with Polyclinic
(Moscow, Russia) as well as Independent Data Monitoring Committee, including MD, PhD,
Professor Alexey V. Kravchenko of Central Research Institute of Epidemiology (Moscow,
Russia), MD, PhD, Professor, Russian Academy of Sciences Professor Kirill A. Zykov of
Moscow State Medical Dental University n.a. A.I. Yevdokimov (Moscow, Russia) and MD,
PhD, Professor Vladimir V. Rafalskiy of Immanuel Kant Baltic Federal University (Kaliningrad,
Russia).

Financial support. This project is supported financially by the Russian Direct Investment Fund,
the Ministry of Industry and Trade of the Russian Federation and The Skolkovo Innovation
Center.

Potential conflicts of interest. None declared.

Authors’ contributions. EPP, NVL, EAS, IGG, ENS, EGT were Principal Investigators
responsible for patients’ recruitment, study treatment, and data collection in compliance with the
Protocol and ICH GCP. AAI, KAD and TAS conceived this project, proposed a variant of its
organization and controlled the progress of its implementation. NVV, VNA and ANE developed
a clinical trial protocol, worked on the statistical aspects of the study and the analysis of the
results. EAM, AAB and EVY organized clinical trials and collection of the results. RNK
developed a preclinical study design and organized its implementation. API, DVK developed the
technology and organized the production of the substance. NAP has developed the composition
and technology for the production of AVIFAVIR tablets. NPS studied and analyzed a possible
market for AVIFAVIR. AVI carried out scientific management of the project and edited Rapid
communication.
medRxiv preprint doi: https://doi.org/10.1101/2020.07.26.20154724.this version posted August 4, 2020. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-ND 4.0 International license .