Download This Paper
Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com.
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
30 Pages Posted: 22 Jan 2021
More...Abstract
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 Quımicos 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.
Keywords: COVID-19; Nitazoxanide; randomized controlled clinical trial; lymphocytes cell activation markers, interleukins
Suggested Citation: Suggested Citation