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) was conducted 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; n=55), favipiravir plus lopinavir-ritonavir placebo (n=56), lopinavir-ritonavir plus favipiravir placebo (n=55), or both placebos (n=58). At these doses, no treatment significantly reduced viral load in the primary analysis. Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir trough and peak drug levels at day 7 were significantly lower in the combination arm than the favipiravir monotherapy arm. While a cytochromeP450 mediated drug–drug interaction is not expected between favipiravir and lopinavir/ritonavir, the authors suggest possible explanations include lower favipiravir absorption associated with the gastrointestinal effects of lopinavir-ritonavir, or more unreported missed doses in the combination arm.