Optimal dose and safety of intravenous favipiravir in hospitalized patients with SARS-COV-2: A phase I, open-label, dose-escalating, randomized controlled study

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Optimal dose and safety of intravenous favipiravir in hospitalized patients with SARS-COV-2: A phase I, open-label, dose-escalating, randomized controlled study

Tim Rowland^1,2, Richard FitzGerald^2,3, Laura Else³, Elizabeth Challenger³, Laura Dickinson³, Lauren Walker^2,3, Colin Hale², Rebecca Lyon², Karim Dhamani⁴, Margaret Irwin⁴, Yvanne Enever⁴, Michelle Tetlow³, Orod Osanlou⁵, Helen Reynolds³, Justin Chiong³, Henry Pertinez⁶, Andrew Owen⁶, Geoff Saunders⁷, Gareth Griffiths⁷, Saye Khoo³ and Tom Fletcher¹

¹Liverpool School of Tropical Medicine; ²NIHR Liverpool Clinical Research Facility; ³Centre for Experimental Therapeutics (TherEx), Department of Pharmacology and Therapeutics, Institute of Integrative, Systems and Molecular Biology, University of Liverpool; ⁴PHARMExcel; ⁵Bangor University; ⁶Centre of Excellence for Long-acting Therapeutics (CELT), University of Liverpool; ⁷Southampton Clinical Trials Unit, University of Southampton

Background: AGILE is a phase Ib/IIa platform for rapidly evaluating candidate therapeutics for the treatment of COVID-19. In this trial (NCT04746183), we evaluated the safety and optimal dose of a novel intravenous (IV) formulation of favipiravir (FVP) in hospitalized participants with SARS-CoV-2.

Materials and methods: CST-6 was a dose-escalating, open-label, randomized, controlled Bayesian adaptive phase Ib trial carried out at the NIHR Liverpool Clinical Research Facility. Participants (hospitalized adults with PCR-confirmed SARS-CoV-2 infection within 14 days of onset of symptomatic COVID-19) were randomized 2:1 in groups of six participants (n = 4 FVP, n = 2 SoC) to 600, 1200, 1800 and 2400 mg doses of IV FVP twice daily for 7 days or standard of care (SoC). Throughout the study period, clinical data, safety evaluations, virology and pharmacokinetics were collected at predefined timepoints. FVP was quantified using validated LC-MS methods with FVP concentrations expressed as ng/mL. The primary outcome was safety, with toxicity considered to be unacceptable if the probability of 30% or greater dose-limiting toxicity related to FVP over controls was 25% or greater, as calculated by the Bayesian model. Secondary outcomes included clinical progression scores, pharmacokinetic parameters and virological endpoints.

Results: Of 30 participants screened, 24 were enrolled between 10 September 2022 and 1 November 2023 [10/24 female; median age was 74 years (range 52–93)]. FVP was well tolerated at all doses, despite a high background rate of adverse events reflecting the frailty and comorbidity of participants. As in previous studies of FVP, transient hyperuricaemia was observed in patients in the treatment cohorts. This was asymptomatic in all cases and resolved on completion of treatment. There were no serious adverse events or severe (≥grade 3) adverse events that were deemed possibly or probably related to FVP by an independent, blinded assessor. The probability of greater than 30% excess toxicity over controls at 2400 mg, as estimated by the Bayesian model, was 2.7%. PK exposures increased proportionally to dose, although there was notable variability between participants within each cohort. Significant FVP accumulation in plasma occurred; for cohorts 1–4 respectively (600/1200/1800/2400 mg BD), median day 1 clast (6–12 h post-infusion) was 500 (below LLQ)/4242/5109/23 573 ng/mL, and median day 3 clast was 1335/38 730/47 000/125 468 ng/mL.

Conclusions: In this phase Ib multiple ascending dose study of a novel IV formulation of FVP, we administered higher sustained doses than previously used, up to 2400 mg twice daily. Despite the frail and comorbid nature of the population admitted to hospital with COVID-19, IV FVP was safe and well tolerated at this dose. Plasma PK studies demonstrated accumulation at days 3 and 5, in contrast to previous studies that employed loading doses. Significant PK variability was noted between individuals. Although well tolerated, based on PK data, we report and recent FVP EC90 data, and we do not recommend FVP for later stage clinical trial evaluation as a treatment for COVID-19. FVP remains a potentially important candidate as a treatment for emerging viral threats including pandemic influenza.