AUTHOR=Fowotade Adeola , Bamidele Folasade , Egbetola Boluwatife , Fagbamigbe Adeniyi F. , Adeagbo Babatunde A. , Adefuye Bolanle O. , Olagunoye Ajibola , Ojo Temitope O. , Adebiyi Akindele O. , Olagunju Omobolanle I. , Ladipo Olabode T. , Akinloye Abdulafeez , Onayade Adedeji , Bolaji Oluseye O. , Rannard Steve , Happi Christian , Owen Andrew , Olagunju Adeniyi 

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

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.956123

DOI=10.3389/fmed.2022.956123

ISSN=2296-858X

ABSTRACT=<sec><title>Background</title><p>The nitazoxanide plus atazanavir/ritonavir for COVID-19 (NACOVID) trial investigated the efficacy and safety of repurposed nitazoxanide combined with atazanavir/ritonavir for COVID-19.</p></sec><sec><title>Methods</title><p>This is a pilot, randomized, open-label multicenter trial conducted in Nigeria. Mild to moderate COVID-19 patients were randomly assigned to receive standard of care (SoC) or SoC plus a 14-day course of nitazoxanide (1,000 mg b.i.d.) and atazanavir/ritonavir (300/100 mg od) and followed through day 28. Study endpoints included time to clinical improvement, SARS-CoV-2 viral load change, and time to complete symptom resolution. Safety and pharmacokinetics were also evaluated (<ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link> ID: NCT04459286).</p></sec><sec><title>Results</title><p>There was no difference in time to clinical improvement between the SoC (<italic>n</italic> = 26) and SoC plus intervention arms (<italic>n</italic> = 31; Cox proportional hazards regression analysis adjusted hazard ratio, aHR = 0.898, 95% CI: 0.492–1.638, <italic>p</italic> = 0.725). No difference was observed in the pattern of saliva SARS-CoV-2 viral load changes from days 2–28 in the 35% of patients with detectable virus at baseline (20/57) (aHR = 0.948, 95% CI: 0.341–2.636, <italic>p</italic> = 0.919). There was no significant difference in time to complete symptom resolution (aHR = 0.535, 95% CI: 0.251–1.140, <italic>p</italic> = 0.105). Atazanavir/ritonavir increased tizoxanide plasma exposure by 68% and median trough plasma concentration was 1,546 ng/ml (95% CI: 797–2,557), above its putative EC<sub>90</sub> in 54% of patients. Tizoxanide was undetectable in saliva.</p></sec><sec><title>Conclusion</title><p>Nitazoxanide co-administered with atazanavir/ritonavir was safe but not better than standard of care in treating COVID-19. These findings should be interpreted in the context of incomplete enrollment (64%) and the limited number of patients with detectable SARS-CoV-2 in saliva at baseline in this trial.</p></sec><sec><title>Clinical trial registration</title><p>[<ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT04459286" xmlns:xlink="http://www.w3.org/1999/xlink">https://clinicaltrials.gov/ct2/show/NCT04459286</ext-link>], identifier [NCT04459286].</p></sec>