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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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.

Potential risks include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-5.

Important missing comments or errors? Let us know.

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

1. Zhirnov et al., Favipiravir: the hidden threat of mutagenic action, Journal of microbiology, epidemiology and immunobiology, doi:10.36233/0372-9311-114.elpub.ru, doi.org.

2. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

3. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

4. Shum, C., An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses, The University of Hong Kong, PhD Thesis, hub.hku.hk/handle/10722/344396.hku.hk.

5. Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.sciencedirect.com, doi.org.

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 Paper Favipiravir All

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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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.\n' '\n' '\n' 'Methods and findings\n' '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 ' 'log10 (95% CI −1.21 to 0.07, p = 0.08) and in ' 'the lopinavir-ritonavir+placebo arm by −0.18 log10 (95% CI −0.82 to ' '0.46, p = 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 log10, 95% CI −0.32 to 1.50, p = ' '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; ' 'p = 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.\n' '\n' '\n' 'Conclusions\n' 'At the current doses, no treatment significantly reduced viral load in the primary ' 'analysis. Favipiravir requires further evaluation with consideration of dose escalation. 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'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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