Favipiravir, lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19

Abstract

Background: Early antiviral treatment is effective for 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 SARS-CoV-2 viral load trajectory when administered early. Methods: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2x2 factorial, double-blind trial of outpatients with early COVID-19 (within 7 days of symptom onset) at two sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1800mg twice daily on Day 1 followed by 400mg four times daily on Days 2-7) plus lopinavir-ritonavir (400mg/100mg twice daily on Day 1, followed by 200mg/50mg four times daily on Days 2-7); 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. ClinicalTrials.gov: NCT04499677. Findings: 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 decreased 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) more than in 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% vs 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. Interpretation: 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.

Care for adults with COVID ‐19: living guidelines from the National COVID ‐19 Clinical Evidence Taskforce

“…66 Findings from an additional fourteen studies support the conclusion that hydroxychloroquine provides no benefit for patients with COVID-19 but increases the incidence of adverse events. 13,[67][68][69][70][71][72][73][74][75][76][77][78][79] Recommendations against several other treatments have subsequently been made, primarily on the basis of the findings of the RECOVERY trial: convalescent plasma (fifteen studies, 16 122 participants [80][81][82][83][84][85][86][87][88][89][90][91][92][93][94] ), lopinavir/ritonavir (nine studies, 9389 participants 20,68,78,[95][96][97][98][99][100], colchicine (eight studies, 17 782 participants [101][102][103][104][105][106][107]…”

Japanese rapid/living recommendations on drug management for COVID‐19: updated guidelines (July 2022)

“…There were 11 RCTs 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 with adopted evidence. Point estimates were not expected to have a clinically meaningful effect on clinical improvement at 28 days (an increase of 14 per 1,000).…”

Learning and confirming in publicly funded antiviral trials

“…Perhaps now is the time to start considering a similar approach for antivirals. The modest effect on viral load by favipiravir in early COVID-19 7 predicted favipiravir's phase 3 failure, 9 and retrospective studies highlight the relationship between viral load and clinical outcome. 10 …”

“…The rapid setup and roll-out of high-quality clinical learning studies is perfectly possible in an emergency setting: Khoo and colleagues opened recruitment to AGILE CST-2 in November, 2020. The double-blind, 2 × 2 factorial FLARE trial 7 investigating favipiravir with or without lopinavir–ritonavir for the treatment of patients with COVID-19 opened recruitment in September, 2020, without UK Research and Innovation funding or Urgent Public Health badging. But, in both cases, these high-quality trials requiring 180 patients (AGILE CST-2) or 240 patients (FLARE) took more than 1 year to recruit.…”