Nitazoxanide In Vitro Efficacy Against SARS CoV-2 and In Vivo Superiority to Placebo to Treat Moderate COVID-19 – A Phase 2 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:  The in vitro effect of NTZ in VERO E6 cells was evaluated, followed by a randomized double-blind phase two clinical trial comparing NTZ 600 mg BID versus placebo for 7 days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency. Clinical and virologic end-points and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used. Results: The in vitro inhibition of SARS-CoV-2 infection was 90% with 0.5 µM, with no cytotoxicity. Two patients died in the NTZ arm compared to 6 in the placebo arm (p=NS). NTZ was superior to placebo when considering SSD (p<0001), mean time for hospital discharge (6.6 vs 14 days, p=0.021), and negative PCR at day 21 (p=0.035), whereas placebo group presented more adverse events (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), and CD38+ on CD4+ T lymphocytes (p=0.271), HLA-DR+ on CD4 (p=.0.199), CD38+ on CD8 (p=0.431) and CD38+/HLADR+ on CD4 (p=0.694). Conclusions: The superiority of NTZ as compared to placebo in clinical and virologic outcomes, as wells as improvement of inflammatory outcomes, 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. Trial Registration: This study was registered at ClinicalTrials.gov (NCT04348409). Funding Statement: This clinical trial was funded by FQM Farma. Declaration of Interests: AL has received grants and personal fees from Janssen Pharmaceutical; has received personal fees from Daiichi Sankyo, Cristalia Produtos Quimicos e Farmaceuticos, Libbs, Pfizer, Myralis Farma, Ache Laboratorios, Hypera Pharma, and Sanofi-Aventis; and has received grants from FQM Farma, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Biophytis, and Forum Pharmaceutical. All other authors have nothing to declare. Ethics Approval Statement: This trial was approved by the Brazilian National Institutional Review Board (CONEP; approval # CAAE- 30628420.0.0000.5412) and each local Institutional Review Boards. Informed consent has been obtained.