An Open Label, Adaptive, Phase 1 Trial of High‐Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS‐CoV‐2

Abstract

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID‐19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically‐based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high‐dose nitazoxanide. Participants received 1500 mg nitazoxanide orally twice‐daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (C min ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self‐limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median C min was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID‐19.

Randomized clinical trial of nitazoxanide or sofosbuvir/daclatasvir for the prevention of SARS-CoV-2 infection

“…Recently, acceptable safety was confirmed in the AGILE Phase I/IIa platform trial at a higher (1500 mg twice daily) dose in healthy volunteers, with Phase 1b evaluations assessing its role in treatment of COVID-19 currently ongoing in South Africa. 36 Neither nitazoxanide nor sofosbuvir/daclatasvir demonstrated any clinical benefit in the prevention of SARS-CoV-2 infection in the COVER trial.…”

Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial

“… 39 The FPV + NTZ arm had the highest frequency of adverse events in this study, though in healthy volunteers NTZ doses of up to 1500 mg are well tolerated. 40 However, the safety of high-dose FPV + NTZ would require careful evaluation, particularly in patients with renal or hepatic impairment. 39 …”

A randomized, open-label trial of combined nitazoxanide and atazanavir/ritonavir for mild to moderate COVID-19

“…Reports from other completed clinical studies are pending while several others are still recruiting, including a phase Ib/IIa study investigating within the AGILE clinical trial platform (NCT04746183) ( 38 ) the efficacy of the 1,500 mg b.i.d. dosage which was shown to be safe with acceptable tolerability ( 39 ) in mild to moderate COVID-19. As it is unlikely that doses higher than 1,500 mg b.i.d.…”