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

Abstract

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 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.

Conclusions: 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.

Trial registration: Clinicaltrials.gov NCT04499677 EudraCT: 2020-002106-68.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: DML has received personal fees from Gilead for an educational video on COVID-19 in immunodeficiency and from Merck for a roundtable discussion on risk of COVID-19 in immunosuppressed patients. DML also holds research grants from Blood Cancer UK, Bristol Myers Squibb and the British Society for Antimicrobial Chemotherapy, all outside the current work. NF has received funding from Gedeon Richter, Abbott Singapore, Galderma, ALK, AstraZeneca, Ipsen, Vertex, Novo Nordisk, Aimmune, Allergan and Novartis, all outside the current work. JB holds research funding from GSK, Wellcome Trust, UKRI, Rosetrees Foundation and the John Black Foundation, all outside the current work. All other authors declare no conflict of interest.

Figures

Fig 1. CONSORT diagram for the FLARE trial.

* SARS-CoV-2 vaccination was an exclusion in the earlier part of the trial. FU, follow-up; IMP, investigational medicinal product; ITT, intention-to-treat LPV/r, lopinavir-ritonavir; SAE, serious adverse event; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Fig 2

Mean log10 SARS-CoV-2 viral load at baseline (Day 1) and Day 5 per treatment arm in (A) the full ITT population and (B) the mITT population, excluding participants with negative viral load at baseline and Day 5. ITT, intention-to-treat; LPV/r, lopinavir-ritonavir; mITT, modified intention-to-treat; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Fig 3

Mean log10 SARS-CoV-2 viral load at baseline (Day 1) and Day 5 per treatment arm in (A) participants with baseline viral load below or equal to the median level for the entire cohort and (B) participants with baseline viral load above the median level for the entire cohort. LPV/r, lopinavir-ritonavir; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; VL, viral load.

Fig 4

Plasma favipiravir concentration in the combination favipiravir+lopinavir-ritonavir (LPV/r) arm and the favipiravir+placebo arm on Day 7 (A) pre-dose (trough) and (B) 30–60 minutes post-dose (peak). Boxes represent IQR and whiskers represent 1.5*IQR. EC50: half maximal effective concentration. EC90, 90% maximal effective concentration. IQR, interquartile range.