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

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://ichgcp.net/clinical-trials-registry/NCT04459286], identifier [NCT04459286].

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

Conflict of interest statement

AnO and SR are Directors of Tandem Nano Ltd. AnO received research funding from ViiV, Merck, Janssen, and consultancy from Gilead, ViiV, and Merck not related to the current manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Fowotade, Bamidele, Egbetola, Fagbamigbe, Adeagbo, Adefuye, Olagunoye, Ojo, Adebiyi, Olagunju, Ladipo, Akinloye, Onayade, Bolaji, Rannard, Happi, Owen and Olagunju.

Figures

FIGURE 1

NACOVID trial profile.

FIGURE 2

Kaplan-Meier curves of time to clinical improvement (defined as a drop of 2 levels on the 1–10 ordinal scale) by study arm. There was no difference between the two arms (7 days in the standard of care arm alone vs. 8 days in the standard of care plus intervention arm). The Cox proportional hazards model adjusted hazard ratio was 0.898 (95% Cl: 0.492–1.638, p = 0.725) after adjusting for potential co-founders, including randomization stratification variables, age and sex.

FIGURE 3

Changes in SARS-CoV-2 viral load in saliva of patients from enrollment to study day 28. In the 20 patients with detectable saliva viral load at enrollment, baseline viral load was 5.05 log10 copies/ml in the SoC alone arm (n = 12), and 5.17 log10 copies/ml in the SoC plus intervention arm (n = 8). In this small cohort, there was no difference in the rate of viral load decline between the two arms (Cox proportional hazards model aHR = 0.948, 95% Cl: 0.341–2.636, p = 0.919).

FIGURE 4

Kaplan-Meier curves of median time to complete symptom resolution by study arm. Overall, there was no significant difference between the two arms, even after adjusting for potential co- founders (Cox proportional hazards model aHR = 0.535, 95% Cl: 0.251–1.140, p = 0.105).

FIGURE 5

Tizoxanide Concentration-time profiles in healthy volunteers and plasma concentration in COVID-19 patients. (A) Co-administration of nitazoxanide (NTZ) with atazanavir/ritonavir (ATZ/r) increased plasma tizoxanide AUC0-12 by 68.3% (37.6μg.h/ml vs. 63.3 μg.h/ml) and its Cmax by 14.4% (7,630 ng/ml vs. 8,730 ng/ml). (B) Using samples collected at 11–12 h after the last nitazoxanide dose (1,000 mg b.i.d.), the median concentration was 1,546 ng/ml, above the EC90 of SARS-COV-2 in 54% of patient samples.