Nitazoxanide superiority to placebo to treat moderate COVID-19 - A Pilot prove of concept randomized double-blind clinical trial.

Abstract

The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates' drugs. Nitazoxanide (NTZ) has a broad antiviral effect. This was a randomized, double-blind pilot clinical trial comparing NTZ 600 mg BID versus Placebo for seven days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency from May 20^th, 2020, to September 21^st, 2020 (ClinicalTrials.gov NCT04348409). Clinical and virologic endpoints and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used. Two patients died in the NTZ arm compared to 6 in the placebo arm (<i>p</i> = 0.564). NTZ was superior to placebo when considering SSD (<i>p</i> < 0001), the mean time for hospital discharge (6.6 vs. 14 days, <i>p</i> = 0.021), and negative PCR at day 21 (<i>p</i> = 0.035), whereas the placebo group presented more adverse events (<i>p</i> = 0.04). Among adverse events likely related to the study drug, 14 were detected in the NTZ group and 22 in placebo (<i>p</i> = 0.24). Among the 30 adverse events unlikely related, 21 occurred in the placebo group (<i>p</i> = 0.04). A decrease from baseline was higher in the NTZ group for d-Dimer (<i>p</i> = 0.001), US-RCP (<i>p</i> < 0.002), TNF (<i>p</i> < 0.038), IL-6 (<i>p</i> < 0.001), IL-8 (<i>p</i> = 0.014), HLA DR. on CD4⁺ <i>T</i> lymphocytes (<i>p</i> < 0.05), CD38 in CD4⁺ and CD8⁺ <i>T</i> (both <i>p</i> < 0.05), and CD38 and HLA-DR. on CD4+ (<i>p</i> < 0.01). Compared to placebo in clinical and virologic outcomes and improvement of inflammatory outcomes, the superiority of NTZ warrants further investigation of this drug for moderate COVID-19 in larger clinical trials. A higher incidence of adverse events in the placebo arm might be attributed to COVID-19 related symptoms.