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

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

doi:10.3389/fmed.2022.956123

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

Front Med (Lausanne). 2022 Sep 8:9:956123. doi: 10.3389/fmed.2022.956123. eCollection 2022.

Authors

Adeola Fowotade¹, Folasade Bamidele¹, Boluwatife Egbetola², Adeniyi F Fagbamigbe³, Babatunde A Adeagbo⁴, Bolanle O Adefuye², Ajibola Olagunoye⁵, Temitope O Ojo⁶, Akindele O Adebiyi⁷, Omobolanle I Olagunju⁸, Olabode T Ladipo⁹, Abdulafeez Akinloye⁴, Adedeji Onayade⁶, Oluseye O Bolaji⁴, Steve Rannard¹⁰, Christian Happi¹¹, Andrew Owen¹², Adeniyi Olagunju¹²

Affiliations

¹ Department of Medical Microbiology and Parasitology, University of Ibadan, Ibadan, Nigeria.
² Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria.
³ Department of Epidemiology and Medical Statistics, University of Ibadan, Ibadan, Nigeria.
⁴ Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria.
⁵ State Specialist Hospital, Osogbo, Nigeria.
⁶ Department of Community Health, Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria.
⁷ Department of Community Medicine, University of Ibadan, Ibadan, Nigeria.
⁸ Department of Surveillance and Epidemiology, Nigeria Centre for Disease Control, Abuja, Nigeria.
⁹ Oyo State Ministry of Health, Ibadan, Nigeria.
¹⁰ Department of Chemistry, University of Liverpool, Liverpool, United Kingdom.
¹¹ African Centre of Excellence for Genomics of Infectious Diseases, Redeemer's University, Ede, Nigeria.
¹² Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.

Abstract

Background: 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.

Methods: 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 (ClinicalTrials.gov ID: NCT04459286).

Results: There was no difference in time to clinical improvement between the SoC (n = 26) and SoC plus intervention arms (n = 31; Cox proportional hazards regression analysis adjusted hazard ratio, aHR = 0.898, 95% CI: 0.492-1.638, p = 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, p = 0.919). There was no significant difference in time to complete symptom resolution (aHR = 0.535, 95% CI: 0.251-1.140, p = 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 EC₉₀ in 54% of patients. Tizoxanide was undetectable in saliva.

Conclusion: 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.

Clinical trial registration: [https://clinicaltrials.gov/ct2/show/NCT04459286], identifier [NCT04459286].

Keywords: COVID-19; SARS-CoV-2; atazanavir/ritonavir; nitazoxanide (NTZ); pharmacokinetics.

Associated data

ClinicalTrials.gov/NCT04459286