Early Treatment of Favipiravir in COVID-19 Patients Without Pneumonia: A Multicentre, Open-Labelled, Randomized Control Study

DOI record: { "DOI": "10.1101/2022.06.06.22275902", "URL": "http://dx.doi.org/10.1101/2022.06.06.22275902", "abstract": "<jats:title>Abstract</jats:title><jats:p>We investigated Favipiravir (FPV) efficacy in mild cases of COVID-19 without pneumonia and its effects towards viral clearance, clinical condition, and risk of COVID-19 pneumonia development. PCR-confirmed SARS-CoV-2-infected patients without pneumonia were enrolled (2:1) within 10 days of symptomatic onset into FPV and control arms. The former received 1800 mg FPV twice-daily (BID) on Day 1 and 800 mg BID 5-14 days thereafter until negative viral detection, while the latter received supportive care only. The primary endpoint was time to clinical improvement, which was defined by a reduced National Early Warning Score (NEWS) or score of ≤1. 62 patients (41 female) comprised the FPV arm (median age: 32 years, median BMI: 22 kg/m²) and 31 patients (19 female) comprised the control arm (median age: 28 years, median BMI: 22 kg/m². The median time to sustained clinical improvement by NEWS was 2 vs 14 days for FPV and control arms respectively (adjusted hazard ratio (aHR) of 2.77, 95% CI 1.57-4.88, <jats:italic>P</jats:italic> &lt;0.001). The FPV arm also had significantly higher likelihoods of clinical improvement within 14 days after enrolment by NEWS (79% vs 32% respectively, <jats:italic>P</jats:italic> &lt;0.001), particularly female patients (aOR 6.35, 95% CI 1.49-27.07, <jats:italic>P</jats:italic> &lt;0.001). 8 (12.9%) and 7 (22.6%) patients in FPV and control arms developed mild pneumonia at a median (range) 6.5 (1-13) and 7 (1-13) days after treatment, respectively (<jats:italic>P</jats:italic> = 0.316); all recovered well without complications. We can conclude that early treatment of FPV in symptomatic COVID-19 patients without pneumonia was associated with faster clinical improvement.</jats:p>", "accepted": { "date-parts": [ [ 2022, 6, 8 ] ] }, "author": [ { "ORCID": "http://orcid.org/0000-0003-1486-5550", "affiliation": [], "authenticated-orcid": false, "family": "Sirijatuphat", "given": "Rujipas", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0003-2583-9390", "affiliation": [], "authenticated-orcid": false, "family": "Manosuthi", "given": "Weerawat", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-4785-2716", "affiliation": [], "authenticated-orcid": false, "family": "Niyomnaitham", "given": "Suvimol", "sequence": "additional" }, { "affiliation": [], "family": "Owen", "given": "Andrew", "sequence": "additional" }, { "affiliation": [], "family": "Copeland", "given": "Katherine K.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-3811-0267", "affiliation": [], "authenticated-orcid": false, "family": "Charoenpong", "given": "Lantharita", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-1150-2597", "affiliation": [], "authenticated-orcid": false, "family": "Rattanasompattikul", "given": "Manoch", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-7555-1056", "affiliation": [], "authenticated-orcid": false, "family": "Mahasirimongkol", "given": "Surakameth", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-0140-4600", "affiliation": [], "authenticated-orcid": false, "family": "Chokephaibulkit", "given": "Kulkanya", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2022, 6, 8 ] ], "date-time": "2022-06-08T15:00:11Z", "timestamp": 1654700411000 }, "deposited": { "date-parts": [ [ 2022, 6, 10 ] ], "date-time": "2022-06-10T09:46:15Z", "timestamp": 1654854375000 }, "group-title": "Pharmacology and Therapeutics", "indexed": { "date-parts": [ [ 2024, 3, 28 ] ], "date-time": "2024-03-28T04:35:24Z", "timestamp": 1711600524335 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 1, "issued": { "date-parts": [ [ 2022, 6, 8 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2022.06.06.22275902", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2022, 6, 8 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2022, 6, 8 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "key": "2022061002451014000_2022.06.06.22275902v1.1", "unstructured": "Organization WH. 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Available from: https://covid19.who.int/" }, { "DOI": "10.35772/ghm.2020.01031", "article-title": "Coronavirus disease 2019 (COVID-19): research progress and clinical practice", "doi-asserted-by": "crossref", "first-page": "78", "issue": "2", "journal-title": "Glob Health Med", "key": "2022061002451014000_2022.06.06.22275902v1.2", "volume": "2", "year": "2020" }, { "DOI": "10.1016/j.jinf.2021.01.015", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.3" }, { "article-title": "Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study", "first-page": "1192", "issue": "10", "journal-title": "Engineering (Beijing)", "key": "2022061002451014000_2022.06.06.22275902v1.4", "volume": "6", "year": "2020" }, { "DOI": "10.1371/journal.pntd.0008806", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.5" }, { "DOI": "10.1016/j.ijid.2020.10.069", "article-title": "Role of favipiravir in the treatment of COVID-19", "doi-asserted-by": "crossref", "first-page": "501", "journal-title": "Int J Infect Dis", "key": "2022061002451014000_2022.06.06.22275902v1.6", "volume": "102", "year": "2021" }, { "DOI": "10.1371/journal.pone.0249090", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.7" }, { "DOI": "10.1128/AAC.01897-20", "doi-asserted-by": "crossref", "key": "2022061002451014000_2022.06.06.22275902v1.8", "unstructured": "Doi Y , Hibino M , Hase R , et al. A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19. Antimicrob Agents Chemother. 2020 Nov 17;64(12)." }, { "DOI": "10.1016/j.ijid.2020.11.142", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.9" }, { "DOI": "10.1038/s41591-021-01283-z", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.10" }, { "key": "2022061002451014000_2022.06.06.22275902v1.11", "unstructured": "Eroglu E , Toprak C. Overview of favipiravir and remdesivir treatment for COVID-19. International Journal of Pharmaceutical Sciences and Research. 2021:1950–1957." }, { "DOI": "10.1007/s40495-020-00226-5", "article-title": "Pipeline Pharmacological Therapies in Clinical Trial for COVID-19 Pandemic: a Recent Update", "doi-asserted-by": "crossref", "first-page": "228", "issue": "5", "journal-title": "Curr Pharmacol Rep", "key": "2022061002451014000_2022.06.06.22275902v1.12", "volume": "6", "year": "2020" }, { "DOI": "10.1186/s12879-021-06164-x", "article-title": "Favipiravir for the treatment of patients with COVID-19: a systematic review and meta-analysis", "doi-asserted-by": "crossref", "first-page": "489", "issue": "1", "journal-title": "BMC Infect Dis", "key": "2022061002451014000_2022.06.06.22275902v1.13", "volume": "21", "year": "2021" }, { "article-title": "Evaluating the Treatment with Favipiravir in Patients Infected by COVID-19", "first-page": "87", "issue": "3", "journal-title": "A Systematic Review and Meta-analysis International Journal of Scientific Research in Dental and Medical Sciences", "key": "2022061002451014000_2022.06.06.22275902v1.14", "volume": "2", "year": "2020" }, { "DOI": "10.1007/s42399-021-00824-4", "article-title": "Tocilizumab, Remdesivir, Favipiravir, and Dexamethasone Repurposed for COVID-19: a Comprehensive Clinical and Pharmacovigilant Reassessment", "doi-asserted-by": "crossref", "first-page": "919", "issue": "4", "journal-title": "SN Compr Clin Med", "key": "2022061002451014000_2022.06.06.22275902v1.15", "volume": "3", "year": "2021" }, { "DOI": "10.1002/jmv.26397", "article-title": "Comparative analysis of antiviral efficacy of FDA-approved drugs against SARS-CoV-2 in human lung cells", "doi-asserted-by": "crossref", "first-page": "1403", "issue": "3", "journal-title": "J Med Virol", "key": "2022061002451014000_2022.06.06.22275902v1.16", "volume": "93", "year": "2021" }, { "DOI": "10.1002/cbic.202000595", "article-title": "Tackling COVID-19 Using Remdesivir and Favipiravir as Therapeutic Options", "doi-asserted-by": "crossref", "first-page": "939", "issue": "6", "journal-title": "Chembiochem", "key": "2022061002451014000_2022.06.06.22275902v1.17", "volume": "22", "year": "2021" }, { "DOI": "10.1186/s12985-020-01412-z", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.18" }, { "DOI": "10.1056/NEJMoa2116846", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.19" }, { "DOI": "10.1056/NEJMoa2116044", "article-title": "Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients", "doi-asserted-by": "crossref", "first-page": "509", "issue": "6", "journal-title": "New England Journal of Medicine", "key": "2022061002451014000_2022.06.06.22275902v1.20", "volume": "386", "year": "2022" }, { "DOI": "10.1056/NEJMc2201612", "article-title": "Molnupiravir for Covid-19 in Nonhospitalized Patients", "doi-asserted-by": "crossref", "first-page": "e32", "issue": "13", "journal-title": "New England Journal of Medicine", "key": "2022061002451014000_2022.06.06.22275902v1.21", "volume": "386", "year": "2022" }, { "DOI": "10.1136/bmj.o443", "doi-asserted-by": "crossref", "key": "2022061002451014000_2022.06.06.22275902v1.22", "unstructured": "Brophy JM . Molnupiravir’s authorisation was premature. British Medical Journal Publishing Group; 2022." }, { "article-title": "Favipiravir in COVID-19", "first-page": "143", "issue": "2", "journal-title": "International Journal of Progressive Sciences and Technologies", "key": "2022061002451014000_2022.06.06.22275902v1.23", "volume": "19", "year": "2020" }, { "DOI": "10.2183/pjab.93.027", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.24" }, { "DOI": "10.1016/j.mjafi.2020.08.004", "article-title": "Favipiravir: A new and emerging antiviral option in COVID-19", "doi-asserted-by": "crossref", "first-page": "370", "issue": "4", "journal-title": "Med J Armed Forces India", "key": "2022061002451014000_2022.06.06.22275902v1.25", "volume": "76", "year": "2020" }, { "DOI": "10.1038/s41422-020-0282-0", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.26" }, { "DOI": "10.1093/cid/ciaa1176", "article-title": "AVIFAVIR for Treatment of Patients With Moderate Coronavirus Disease 2019 (COVID-19): Interim Results of a Phase II/III Multicenter Randomized Clinical Trial", "doi-asserted-by": "crossref", "first-page": "531", "issue": "3", "journal-title": "Clin Infect Dis", "key": "2022061002451014000_2022.06.06.22275902v1.27", "volume": "73", "year": "2021" }, { "DOI": "10.14740/jem645", "article-title": "Favipiravir: A Possible Pharmaceutical Treatment for COVID-19", "doi-asserted-by": "crossref", "first-page": "33", "issue": "2", "journal-title": "Journal of Endocrinology & Metabolism", "key": "2022061002451014000_2022.06.06.22275902v1.28", "volume": "10", "year": "2020" }, { "DOI": "10.1093/cid/ciac312", "doi-asserted-by": "crossref", "key": "2022061002451014000_2022.06.06.22275902v1.29", "unstructured": "Holubar M , Subramanian A , Purington N , et al. Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial. Clin Infect Dis. 2022 Apr 21." }, { "DOI": "10.3390/v14040670", "doi-asserted-by": "crossref", "key": "2022061002451014000_2022.06.06.22275902v1.30", "unstructured": "Shinada K , Sato T , Moriyama S , et al. Longitudinal Analysis of Neutralizing Potency against SARS-CoV-2 in the Recovered Patients after Treatment with or without Favipiravir. Viruses. 2022 Mar 24;14(4)." }, { "DOI": "10.1007/s10096-021-04307-1", "article-title": "Effectiveness of favipiravir in COVID-19: a live systematic review", "doi-asserted-by": "crossref", "first-page": "2575", "issue": "12", "journal-title": "Eur J Clin Microbiol Infect Dis", "key": "2022061002451014000_2022.06.06.22275902v1.31", "volume": "40", "year": "2021" }, { "DOI": "10.1136/bmj.m2980", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.32" }, { "DOI": "10.1038/s41598-021-90551-6", "article-title": "The efficacy and safety of Favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials", "doi-asserted-by": "crossref", "first-page": "11022", "issue": "1", "journal-title": "Sci Rep", "key": "2022061002451014000_2022.06.06.22275902v1.33", "volume": "11", "year": "2021" }, { "DOI": "10.1016/S2055-6640(20)30016-9", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.34" }, { "key": "2022061002451014000_2022.06.06.22275902v1.35", "unstructured": "Fujifilm Toyama Chemical Co. L. Notice of The New Drug Application Approval of “AVIGAN® Tablet 200mg” in Japan for the Anti-influenza Virus Drug 2014. Available from: https://www.cdc.gov.tw/File/Get/ht8jUiB_MI-aKnlwstwzvw" }, { "DOI": "10.1515/abm-2020-0016", "doi-asserted-by": "crossref", "key": "2022061002451014000_2022.06.06.22275902v1.36", "unstructured": "Prasithsirikul W , Pongpirul K , Sakornsakolpat P , et al. Adjunctive favipiravir for severe COVID-19: a retrospective observational study of the first 41 patients in Thailand. Asian Biomedicine. 2020;14(3)." }, { "DOI": "10.1371/journal.pntd.0001342", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.37" }, { "DOI": "10.1016/j.antiviral.2014.02.014", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.38" }, { "DOI": "10.1128/AAC.00356-07", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.39" }, { "DOI": "10.1093/cid/ciw571", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.40" }, { "DOI": "10.1097/JCMA.0000000000000318", "article-title": "Potential therapeutic agents against COVID-19: What we know so far", "doi-asserted-by": "crossref", "first-page": "534", "issue": "6", "journal-title": "J Chin Med Assoc", "key": "2022061002451014000_2022.06.06.22275902v1.41", "volume": "83", "year": "2020" }, { "DOI": "10.1128/JVI.02346-12", "doi-asserted-by": "publisher", "key": "2022061002451014000_2022.06.06.22275902v1.42" }, { "DOI": "10.1126/scitranslmed.abb5883", "doi-asserted-by": "crossref", "key": "2022061002451014000_2022.06.06.22275902v1.43", "unstructured": "Sheahan TP , Sims AC , Zhou S , et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020 Apr 29;12(541)." }, { "article-title": "Assessement of outcomes following implementation of antiviral treatment guidelines for COVID-19 during the first wave in Thailand", "first-page": "572", "issue": "4", "journal-title": "Southeast Asian Journal of Tropical Medicine and Public Health", "key": "2022061002451014000_2022.06.06.22275902v1.44", "volume": "52", "year": "2021" }, { "DOI": "10.1016/j.jiac.2021.04.013", "article-title": "Early favipiravir treatment was associated with early defervescence in non-severe COVID-19 patients", "doi-asserted-by": "crossref", "first-page": "1051", "issue": "7", "journal-title": "Journal of Infection and Chemotherapy", "key": "2022061002451014000_2022.06.06.22275902v1.45", "volume": "27", "year": "2021" }, { "DOI": "10.1055/a-1296-7935", "article-title": "Favipiravir and COVID-19: A Simplified Summary", "doi-asserted-by": "crossref", "first-page": "166", "issue": "3", "journal-title": "Drug Res (Stuttg)", "key": "2022061002451014000_2022.06.06.22275902v1.46", "volume": "71", "year": "2021" }, { "DOI": "10.3949/ccjm.87a.ccc030", "doi-asserted-by": "crossref", "key": "2022061002451014000_2022.06.06.22275902v1.47", "unstructured": "Srinivas P , Sacha G , Koval C. Antivirals for COVID-19. Cleaveland Clinical Journal of Medicine. 2020." }, { "key": "2022061002451014000_2022.06.06.22275902v1.48", "unstructured": "Medical Research Foundation T. Thai Clinical Trials Registry 2021. Available from: https://thaiclinicaltrials.org/" }, { "key": "2022061002451014000_2022.06.06.22275902v1.49", "unstructured": "Health Do. National Early Warning Score: National Clinical Guideline No. 1 2013." }, { "DOI": "10.4103/ijp.ijp_998_20", "article-title": "Systematic review and meta-analysis of effectiveness and safety of favipiravir in the management of novel coronavirus (COVID-19) patients", "doi-asserted-by": "crossref", "first-page": "414", "issue": "5", "journal-title": "Indian J Pharmacol", "key": "2022061002451014000_2022.06.06.22275902v1.50", "volume": "52", "year": "2020" }, { "DOI": "10.7883/yoken.JJID.2020.827", "article-title": "Nasopharyngeal SARS-CoV-2 Viral Load Response among COVID-19 Patients Receiving Favipiravir", "doi-asserted-by": "crossref", "first-page": "416", "issue": "5", "journal-title": "Jpn J Infect Dis", "key": "2022061002451014000_2022.06.06.22275902v1.51", "volume": "74", "year": "2021" }, { "DOI": "10.1080/14787210.2022.2012155", "article-title": "Evaluation of favipiravir in the treatment of COVID-19 based on the real-world", "doi-asserted-by": "crossref", "first-page": "555", "issue": "4", "journal-title": "Expert Rev Anti Infect Ther", "key": "2022061002451014000_2022.06.06.22275902v1.52", "volume": "20", "year": "2022" }, { "DOI": "10.1126/scitranslmed.abl7430", "article-title": "A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus", "doi-asserted-by": "crossref", "first-page": "eabl7430", "issue": "628", "journal-title": "Sci Transl Med", "key": "2022061002451014000_2022.06.06.22275902v1.53", "volume": "14", "year": "2022" }, { "DOI": "10.1016/S1473-3099(21)00485-0", "article-title": "Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial", "doi-asserted-by": "crossref", "first-page": "209", "issue": "2", "journal-title": "Lancet Infect Dis", "key": "2022061002451014000_2022.06.06.22275902v1.54", "volume": "22", "year": "2022" }, { "key": "2022061002451014000_2022.06.06.22275902v1.55", "unstructured": "Chuah CH , Chow TS , Hor CP , et al. Efficacy of Early Treatment with Favipiravir on Disease Progression among High Risk COVID-19 Patients: A Randomized, Open-Label Clinical Trial. Clin Infect Dis. 2021 Nov 19." }, { "key": "2022061002451014000_2022.06.06.22275902v1.56", "unstructured": "35 generic manufacturers sign agreements with MPP to produce low-cost, generic versions of Pfizer’s oral COVID-19 treatment nirmatrelvir in combination with ritonavir for supply in 95 low-and middle-income countries [Internet]. Medicines Patent Pool; 2022. Available from: https://medicinespatentpool.org/news-publications-post/35-generic-manufacturers-sign-agreements-with-mpp-to-produce-low-cost-generic-versions-of-pfizers-oral-covid-19-treatment-nirmatrelvir-in-combination-with-ritonavir-for-supply-in-95-low-and" }, { "key": "2022061002451014000_2022.06.06.22275902v1.57", "unstructured": "27 generic manufacturers sign agreements with MPP to produce low-cost versions of COVID-19 antiviral medication molnupiravir for supply in 105 low-and-middle-income countries [Internet]. Medicines Patent Pool; 2022. Available from: https://medicinespatentpool.org/news-publications-post/27-generic-manufacturers-sign-agreements-with-mpp-to-produce-molnupiravir" }, { "DOI": "10.1093/jac/dkab135", "article-title": "Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5’-triphosphate exposure to support posology for SARS-CoV-2", "doi-asserted-by": "crossref", "first-page": "2121", "issue": "8", "journal-title": "J Antimicrob Chemother", "key": "2022061002451014000_2022.06.06.22275902v1.58", "volume": "76", "year": "2021" } ], "reference-count": 58, "references-count": 58, "relation": {}, "resource": { "primary": { "URL": "http://medrxiv.org/lookup/doi/10.1101/2022.06.06.22275902" } }, "score": 1, "short-title": [], "source": "Crossref", "subtitle": [], "subtype": "preprint", "title": "Early Treatment of Favipiravir in COVID-19 Patients Without Pneumonia: A Multicentre, Open-Labelled, Randomized Control Study", "type": "posted-content" }