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All Studies   Meta Analysis    Recent:   

Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19

Lowe et al., PLOS Medicine, doi:10.1371/journal.pmed.1004120 (date from preprint), FLARE, NCT04499677
Feb 2022  
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ICU admission -202% Improvement Relative Risk Hospitalization -202% Viral clearance 28% primary Favipiravir  FLARE  EARLY TREATMENT  DB RCT Is early treatment with favipiravir beneficial for COVID-19? Double-blind RCT 119 patients in the United Kingdom (Oct 2020 - Nov 2021) Improved viral clearance with favipiravir (p=0.03) c19early.org Lowe et al., PLOS Medicine, February 2022 Favorsfavipiravir Favorscontrol 0 0.5 1 1.5 2+
240 patient RCT comparing favipiravir, favipiravir + LPV/r, LPV/r, and placebo, showing improved viral clearance with favipiravir. Efficacy was lower in the combined favipiravir + LPV/r arm, where plasma levels of favipiravir were lower. Favipiravir 1800mg twice daily on day 1 followed by 400mg four times daily on days 2-7.
risk of ICU admission, 201.7% higher, RR 3.02, p = 0.50, treatment 1 of 59 (1.7%), control 0 of 60 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of hospitalization, 201.7% higher, RR 3.02, p = 0.50, treatment 1 of 59 (1.7%), control 0 of 60 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of no viral clearance, 28.4% lower, RR 0.72, p = 0.03, treatment 29 of 54 (53.7%), control 38 of 52 (73.1%), NNT 5.2, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, day 5, primary outcome.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Lowe et al., 15 Feb 2022, Double Blind Randomized Controlled Trial, placebo-controlled, United Kingdom, peer-reviewed, 18 authors, study period 6 October, 2020 - 4 November, 2021, trial NCT04499677 (history) (FLARE). Contact: d.lowe@ucl.ac.uk.
This PaperFavipiravirAll
Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19
David M Lowe, Li-An K. Brown, Kashfia Chowdhury, Stephanie Davey, Philip Yee, Felicia Ikeji, Amalia Ndoutoumou, Divya Shah, Alexander Lennon, Abhulya Rai, Akosua A Agyeman, Anna Checkley, Nicola Longley, Hakim-Moulay Dehbi, Nick Freemantle, Judith Breuer, Joseph F Standing
PLOS Medicine, doi:10.1371/journal.pmed.1004120
Background Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory when administered early. Methods and findings We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 × 2 factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by 400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. The primary outcome
Author summary Why was this study done? � The FLARE trial aimed to discover whether existing oral antiviral drugs could reduce the viral load of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus if given soon after symptoms started.
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{ 'indexed': { 'date-parts': [[2022, 10, 20]], 'date-time': '2022-10-20T05:13:45Z', 'timestamp': 1666242825324}, 'reference-count': 35, 'publisher': 'Public Library of Science (PLoS)', 'issue': '10', 'license': [ { 'start': { 'date-parts': [[2022, 10, 19]], 'date-time': '2022-10-19T00:00:00Z', 'timestamp': 1666137600000}, 'content-version': 'am', 'delay-in-days': 0, 'URL': 'http://creativecommons.org/licenses/by/4.0/'}], 'funder': [ { 'DOI': '10.13039/100012357', 'name': 'LifeArc', 'doi-asserted-by': 'publisher', 'award': ['COVID0005']}, { 'DOI': '10.13039/501100000265', 'name': 'Medical Research Council', 'doi-asserted-by': 'publisher', 'award': ['MR/M008665/']}, { 'DOI': '10.13039/501100000265', 'name': 'Medical Research Council', 'doi-asserted-by': 'publisher', 'award': ['MR/W015560/1']}], 'content-domain': {'domain': ['www.plosmedicine.org'], 'crossmark-restriction': False}, 'abstract': '<jats:sec id="sec001">\n' '<jats:title>Background</jats:title>\n' '<jats:p>Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but ' 'currently available agents are expensive. Favipiravir is routinely used in many countries, ' 'but efficacy is unproven. Antiviral combinations have not been systematically studied. We ' 'aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both ' 'agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory ' 'when administered early.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec002">\n' '<jats:title>Methods and findings</jats:title>\n' '<jats:p>We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 × 2 ' 'factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of ' 'symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a ' 'centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by ' '400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on ' 'Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus ' 'lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. ' 'The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. ' 'Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the ' 'favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo, and ' 'placebo-only arms, we recruited 61, 59, 60, and 60 participants and analysed 55, 56, 55, and ' '58 participants, respectively, who provided viral load measures at Day 1 and Day 5. In the ' 'primary analysis, the mean viral load in the favipiravir+placebo arm had changed by −0.57 ' 'log<jats:sub>10</jats:sub> (95% CI −1.21 to 0.07, <jats:italic>p</jats:italic> = 0.08) and in ' 'the lopinavir-ritonavir+placebo arm by −0.18 log<jats:sub>10</jats:sub> (95% CI −0.82 to ' '0.46, <jats:italic>p</jats:italic> = 0.58) compared to the placebo arm at Day 5. There was no ' 'significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient ' 'term: 0.59 log<jats:sub>10</jats:sub>, 95% CI −0.32 to 1.50, <jats:italic>p</jats:italic> = ' '0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm ' 'compared to placebo only (46.3% versus 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; ' '<jats:italic>p</jats:italic> = 0.03). Adverse events were observed more frequently with ' 'lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower ' 'in the combination arm than the favipiravir monotherapy arm, possibly due to poor absorption. ' 'The major limitation was that the study population was relatively young and healthy compared ' 'to those most affected by the COVID-19 pandemic.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec003">\n' '<jats:title>Conclusions</jats:title>\n' '<jats:p>At the current doses, no treatment significantly reduced viral load in the primary ' 'analysis. Favipiravir requires further evaluation with consideration of dose escalation. ' 'Lopinavir-ritonavir administration was associated with lower plasma favipiravir ' 'concentrations.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec004">\n' '<jats:title>Trial registration</jats:title>\n' '<jats:p>Clinicaltrials.gov <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ' 'ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT04499677" ' 'xlink:type="simple">NCT04499677</jats:ext-link></jats:p>\n' '<jats:p>EudraCT: 2020-002106-68</jats:p>\n' '</jats:sec>', 'DOI': '10.1371/journal.pmed.1004120', 'type': 'journal-article', 'created': { 'date-parts': [[2022, 10, 19]], 'date-time': '2022-10-19T17:42:13Z', 'timestamp': 1666201333000}, 'page': 'e1004120', 'update-policy': 'http://dx.doi.org/10.1371/journal.pmed.corrections_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 ' '× 2 factorial placebo-controlled trial of early antiviral therapy 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'journal-title': 'Trials'}, { 'key': 'pmed.1004120.ref021', 'doi-asserted-by': 'crossref', 'first-page': '113046', 'DOI': '10.1016/j.jim.2021.113046', 'article-title': 'Validation of a combined ELISA to detect IgG, IgA and IgM antibody ' 'responses to SARS-CoV-2 in mild or moderate non-hospitalised patients', 'volume': '494', 'author': 'AM Cook', 'year': '2021', 'journal-title': 'J Immunol Methods'}, { 'key': 'pmed.1004120.ref022', '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', 'author': 'WA, 2nd Fischer', 'year': '2021', 'journal-title': 'Sci Transl Med'}, { 'key': 'pmed.1004120.ref023', 'doi-asserted-by': 'crossref', 'first-page': 'e0005389', 'DOI': '10.1371/journal.pntd.0005389', 'article-title': 'Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI ' 'trial reveals concentrations lower than targeted', 'volume': '11', 'author': 'TH Nguyen', 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Treatment with Favipiravir on Disease Progression ' 'among High Risk COVID-19 Patients: A Randomized, Open-Label Clinical ' 'Trial', 'author': 'CH Chuah', 'year': '2021', 'journal-title': 'Clin Infect Dis'}, { 'key': 'pmed.1004120.ref033', 'doi-asserted-by': 'crossref', 'first-page': '22640', 'DOI': '10.1038/s41598-021-02097-2', 'article-title': 'Saliva is superior over nasopharyngeal swab for detecting SARS-CoV2 in ' 'COVID-19 patients', 'volume': '11', 'author': 'GT Beyene', 'year': '2021', 'journal-title': 'Sci Rep'}, { 'key': 'pmed.1004120.ref034', 'article-title': 'Performance of nasopharyngeal swab and saliva in detecting Delta and ' 'Omicron SARS-CoV-2 variants', 'author': 'T Ursic', 'year': '2022', 'journal-title': 'J Med Virol'}, { 'key': 'pmed.1004120.ref035', 'doi-asserted-by': 'crossref', 'first-page': '83', 'DOI': '10.1016/j.ijid.2021.02.009', 'article-title': 'Saliva is a reliable and accessible source for the detection of ' 'SARS-CoV-2', 'volume': '105', 'author': 'LA Herrera', 'year': '2021', 'journal-title': 'Int J Infect Dis'}], 'container-title': 'PLOS Medicine', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://dx.plos.org/10.1371/journal.pmed.1004120', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 10, 19]], 'date-time': '2022-10-19T17:42:53Z', 'timestamp': 1666201373000}, 'score': 1, 'resource': {'primary': {'URL': 'https://dx.plos.org/10.1371/journal.pmed.1004120'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 10, 19]]}, 'references-count': 35, 'journal-issue': {'issue': '10', 'published-online': {'date-parts': [[2022, 10, 19]]}}, 'URL': 'http://dx.doi.org/10.1371/journal.pmed.1004120', 'relation': {}, 'ISSN': ['1549-1676'], 'subject': ['General Medicine'], 'container-title-short': 'PLoS Med', 'published': {'date-parts': [[2022, 10, 19]]}}
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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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