key: cord-0965343-nq3aacnr authors: Ivashchenko, Andrey A; Dmitriev, Kirill A; Vostokova, Natalia V; Azarova, Valeria N; Blinow, Andrew A; Egorova, Alina N; Gordeev, Ivan G; Ilin, Alexey P; Karapetian, Ruben N; Kravchenko, Dmitry V; Lomakin, Nikita V; Merkulova, Elena A; Papazova, Natalia A; Pavlikova, Elena P; Savchuk, Nikolay P; Simakina, Elena N; Sitdekov, Tagir A; Smolyarchuk, Elena A; Tikhomolova, Elena G; Yakubova, Elena V; Ivachtchenko, Alexandre V title: AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial date: 2020-08-09 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa1176 sha: d900189f938c3d82e3c472e8152f803914ef42f1 doc_id: 965343 cord_uid: nq3aacnr 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. The pandemic of the novel coronavirus infection 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. Repositioning of antiviral drugs that could be effective against SARS-CoV-2 is one of the common strategies in the fight against COVID-19. In May 2020, remdesivir received conditional approval from U.S. Food and Drug Administration for the treatment of hospitalized patients with severe COVID-19. However, there are still limited data on its efficacy and safety and limitations of the intravenous route of administration [1] . Thus, the development of the effective oral antiviral agents for use at earlier stages of the disease is still warranted. Favipiravir is an RNA-dependent RNA polymerase inhibitor marketed in Japan (Avigan) and China (Favilavir) as a second-line treatment of novel or re-emerging influenza outbreaks [2] . Earlier this year it was reported to demonstrate antiviral activity against SARS-CoV-2 in Vero E6 cells (EC 50 , 61.88 μM , CC 50 > 400 μM, SI > 6.46) and to provide shorter viral clearance time in patients with COVID-19 [3] . 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) [4] . The World Health Organization (WHO) also listed Favipiravir as a candidate experimental treatment (broad spectrum antiviral) [5] . Favipiravir under brand name AVIFAVIR was resynthesized and developed in Russia by the joint venture of Russian Direct Investment Fund and ChemRar Group. Following preclinical tests, a Phase II/III clinical trial of AVIFAVIR in patients with COVID-19 was initiated. This brief report provides the interim results of the study from 60 patients enrolled in the pilot stage (Phase II). at screening), were able to administrate the drug orally and willing to use adequate contraception during the study and 3 months after its completion. The patients 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 according to the Russian guidelines for treatment of COVID-19 [7] . During the study, patients in all groups were allowed to use pathogenetic and symptomatic treatment; patients in the AVIFAVIR groups were not allowed to use other antivirals or antimalarial drugs. The objective of the pilot stage of the study was to preliminary assess the efficacy and safety of AVIFAVIR, and to select the optimal dosing regimen for further evaluation at the pivotal stage The "go-no-go" decision to start the pivotal stage of the study was based on the exact singlestage Phase II assessment at one-sided α=0.05 and 80% power [8] . 13/18 (72.2%) or more patients would have been sufficient to demonstrate that the viral clearance in 80% of patients by Day 10 was plausible, and that the response was greater than the presumably non-effective level of 50%. The secondary endpoints that were assessed during the interim analysis were the rate of viral clearance by Day 5, time to normalization of clinical symptoms (i.e. body temperature), changes on CT scan by Day 15, and incidence and severity of adverse events related to the study drug. Upon signing the informed consent form and confirmed eligibility criteria, 60 patients hospitalized with COVID-19 pneumonia were randomized into three treatment groups: AVIFAVIR 1600/600 mg, The AVIFAVIR and control groups were generally comparable in demographic and baseline characteristics. 28/60 (46.7%) had risk factors for severe disease (i.e. age 60 and older and/or concurrent chronic conditions); 45/60 (75.0%) were on ambient air (Score 3 on WHO-OSCI) and 15/60 (25.0%) required supplemental oxygen via mask or nasal cannula (Score 4 on WHO-OSCI); 15/60 (25.0%) had body temperature > 38 o C, and 42/60 (70.0%) had CRP > 10 mg/L. Mean disease duration at baseline was 6.7 days from the start of the symptoms. In the AVIFAVIR groups, the study drug was administered for a mean period of 10.9 ± 2.8 days. In the SOC group, hydroxychloroquine or chloroquine was administered to 15/20 (75.0%) patients, lopinavir/ritonavir was used in 1/20 (5%) patient, and 4/20 (20%) patients did not receive control group (p<0.05). The median loading dose of AVIFAVIR given to responders was 43.9 mg/kg (IQR 40.0-47.1), and to those with positive PCR on Day 5, it was 39.1 mg/kg (IQR 35. 6-43.9 ). 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 [2, 9] . No increasing toxicity was observed in patients who received higher doses of AVIFAVIR. Based on this observation, it was decided to introduce a weight-based dosing regimen of AVIFAVIR in the pivotal stage of the study with the target loading dose of ≥ 44 mg/kg and the treatment duration of up to 10 days. While clinical effects of AVIFAVIR will be further studied in the pivotal stage of the study, the pilot data demonstrates proof of concept and high treatment potential of the drug in moderately ill patients. It also suggests that the administration of AVIFAVIR to patients with signs of respiratory distress and cytokine storm should be considered only as part of the combination therapy that includes anti-inflammatory agents with proven efficacy against COVID-19. Based on the interim results of the Phase II/III clinical trial, the Russian Ministry of Health granted a conditional marketing authorization to AVIFAVIR, which makes it the only approved oral drug for treatment of moderate COVID-19 to date. reports patent application 2020116521 pending. A.V.I. reports patents 2020116521 and 2020117666 pending. A.A.I. reports patent Application RU No. 2020116521 pending, a patent Application RU No. 2020117666 pending, a patent Copyright Application RU No has a patent Application RU No. 2020116521 pending, a patent Application RU No. 2020117666 pending, a patent Copyright Application RU No. 2020724142 pending, and a patent Copyright Application RU No. 2020724139 pending and are founders of IPHARMA LLC, which conducted clinical trials of Avifavir and is one of the founders of Chromis LLC. N.A.P. reports patent Application RU No. 2020116521 pending. T.S. is the Deputy CEO of Russian Direct Investment Fund (RDIF) which is an investor of Chromis LLC Available Evidence and Ongoing Clinical Trials of Remdesivir: Could It Be a Promising Therapeutic Option for COVID-19? Report on the Deliberation Results. Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau. Ministry of Health, Labour and Welfare Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (2020) WHO R&D Blueprint COVID 19 Experimental Treatments. COVID Classification of treatment types WHO R&D Blueprint novel Coronavirus COVID-19 Therapeutic Trial Synopsis Interim guidelines. Prevention, diagnostics and treatment of a new coronavirus infection (COVID-19), MOH of the Russian Federation Sample size tables for exact single-stage phase II designs A review of the safety of favipiravir -a potential treatment in the COVID-19 pandemic Elimination of SARS-CoV-2 in nasopharyngeal and/or oropharyngeal swabs of patients treated with AVIFAVIR or SOC on Day 5 and Day 10 of the study treatment. B. Time to normal body temperature in patients treated with AVIFAVIR or SOC A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t