Optimal Dose and Safety of Intravenous Favipiravir in Hospitalized Patients With COVID-19: A Dose-Escalating, Randomized Controlled Phase Ib Study.

AGILE (NCT04746183) is a Phase Ib/IIa platform, evaluating candidates to treat COVID-19. Candidate Specific Trial 6 evaluated the safety and optimal dose of a novel intravenous formulation of favipiravir in a dose-escalating, open-label, randomized, controlled, Bayesian adaptive Phase Ib trial. Hospitalized adults with PCR-confirmed SARS-CoV-2 infection, within 14 days of symptomatic COVID-19 were randomized 2:1 in groups of 6 (n = 4 favipiravir, n = 2 standard of care) to ascending doses of intravenous favipiravir twice daily (b.i.d.) for 7 days or standard of care. Clinical data, safety evaluations, virology and pharmacokinetic samples were collected. The primary outcome was safety. Secondary outcomes included clinical, pharmacokinetic and virological endpoints. Twenty-four participants enrolled between September 10, 2022 and November 1, 2023 [10/24 female; median age 74 years (range 52-93)]. Favipiravir was well tolerated despite a high background rate of unrelated adverse events. No dose limiting toxicities were observed, with a model-predicted dose limiting toxicity risk of 16.8% and probability of unacceptable toxicity of 2.7% at the highest dose level. No serious adverse events were deemed related to favipiravir but an expected association with asymptomatic, transient hyperuricemia was observed. Favipiravir exposures increased disproportionally to dose with significant accumulation in plasma, but with marked variability between participants within each cohort. This novel formulation of favipiravir was safe at sustained high doses that reached pre-specified pharmacokinetic targets in a study group with frailty and complex health profiles. We consider doses up to 2,400 mg b.i.d. to be safe for further evaluation.