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

Background: The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates' drugs. Nitazoxanide (NTZ) has a broad antiviral effect.
Methods: 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.
Findings: Two patients died in the NTZ arm compared to 6 in the placebo arm ( p  = 0.564). NTZ was superior to placebo when considering SSD ( p  < 0001), the mean time for hospital discharge (6.6 vs. 14 days, p  = 0.021), and negative PCR at day 21 ( p  = 0.035), whereas the placebo group presented more adverse events ( p  = 0.04). Among adverse events likely related to the study drug, 14 were detected in the NTZ group and 22 in placebo ( p  = 0.24). Among the 30 adverse events unlikely related, 21 occurred in the placebo group ( p  = 0.04). A decrease from baseline was higher in the NTZ group for d-Dimer ( p  = 0.001), US-RCP ( p  < 0.002), TNF ( p  < 0.038), IL-6 ( p  < 0.001), IL-8 ( p  = 0.014), HLA DR. on CD4 ⁺ T lymphocytes ( p  < 0.05), CD38 in CD4 ⁺ and CD8 ⁺ T (both p  < 0.05), and CD38 and HLA-DR. on CD4+ ( p  < 0.01).
Interpretation: 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.
Competing Interests: VB exerts activities of clinical research at FQM Farmoquímica, sponsor of the study. AL reports grants from FQM, during the conduct of the study; personal fees from Daiicho Sankyo Brasil, Pfizer, Mantecorp Indústria Química e Farmacêutica, Libs Farmacêutica, Sanofi-Aventis; grants, personal fees and non-financial support from Janssen Pharmaceutical; personal fees and non-financial support from Cristalia Produtos Químicos e Farmacêuticos; grants and personal fees from Eli Lilly; grants from H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Forum Pharmaceuticals, Biophytis, Ganentech, Cellavita, Celltrion (outside the submitted work). JG, DD, JH, and NM report personal fees from FMQ during the conduct of the study. SC reports grants from FQM during the conduct of the study; grants from MERCK SHARP & DOME, NOVARTIS, ROCHE, ABBVIE, GILEAD, and PFIZER (outside the submitted work). Other authors do not have any conflict of interest to declare.
(© 2021 The Authors.)