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0 0.5 1 1.5 2+ 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) Lowe et al., PLOS Medicine, February 2022 Favors favipiravir Favors control

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.
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).
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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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