Nitazoxanide superiority to placebo to treat moderate COVID-19 – A Pilot prove of concept randomized double-blind clinical trial.
Vinicius Fontanesi Blum, Sérgio Cimerman, James R Hunter, Paulo Tierno, Acioly Lacerda, Alexandre Soeiro, Florentino Cardoso, Nancy Cristina Bellei, Juliana Maricato, Nathalia Mantovani, Marcella Vassao, Danilo Dias, Juliana Galinskas, Luis Mário Ramos Janini, Joanna Reis Santos-Oliveira, Alda Maria Da-Cruz, Ricardo Sobhie Diaz
eClinicalMedicine, doi:10.1016/j.eclinm.2021.100981
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.
Declaration of Competing Interest 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 Ind ustria 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.
Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.eclinm.2021.100981.
References
Akbari, Tabrizi, Lankarani, The role of cytokine profile and lymphocyte subsets in the severity of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis, Life Sci
Arshad, Pertinez, Box, Prioritization of Anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human Pharmacokinetics, Clin Pharmacol Ther
Baggiolini, Walz, Kunkel, Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils, J Clin Invest
Bobrowski, Chen, Eastman, Synergistic and antagonistic drug combinations against SARS-CoV-2, Molecular Therapy
Borba, Val, Sampaio, Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection: a randomized clinical trial, JAMA Netw Open
Cevik, Kuppalli, Kindrachuk, Peiris, Virology, transmission, and pathogenesis of SARS-CoV-2, BMJ
Chen, Zheng, Liu, Plasma CRP level is positively associated with the severity of COVID-19, Ann Clin Microbiol Antimicrob
Feldmann, Maini, Woody, Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed, Lancet
García, Immune Response, Inflammation, and the Clinical Spectrum of COVID-19, Front Immunol
Guan, Ni, Hu, Clinical Characteristics of Coronavirus Disease 2019 in China, N Engl J Med
Gubernatorova, Gorshkova, Polinova, Drutskaya, IL-6: relevance for immunopathology of SARS-CoV-2, Cytokine Growth Fact Rev
Haffizulla, Hartman, Hoppers, Effect of Nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial, Lancet Infect Dis
Han, Ma, Li, Liu, Zhao et al., Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors, Emerg Microbes Infect
Helios, Rosario, Package PWR title basic functions for power analysis
Hickson, Margineantu, Hockenbery, Simon, Geballe, Inhibition of vaccinia virus replication by Nitazoxanide, Virology
Huang, Chen, Yang, SARS-CoV-2 viral load in clinical samples from critically ill patients, Am J Respir Crit Care Med
Huang, Wang, Li, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, The Lancet
Jafarzadeh, Chauhan, Saha, Jafarzadeh, Nemati, Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: lessons from SARS and MERS, and potential therapeutic interventions, Life Sci
Labro, Jandeaux, Rusu, Macrophage activation in COVID-19 patients in intensive care unit, J Med Cases
Liu, Li, Luo, Lymphopenia predicted illness severity and recovery in patients with COVID-19: a single-center, retrospective study, PLoS ONE
Lokhande, Devarajan, A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19, Eur J Pharmacol
Moore, June, Cytokine release syndrome in severe COVID-19, Science
Naveca, Nascimento, Souza, COVID-19 epidemic in the Brazilian state of Amazonas was driven by long-term persistence of endemic SARS-CoV-2 lineages and the recent emergence of the new Variant of Concern P, Review,
doi:10.21203/rs.3.rs-275494/v1Okabayashi, Kariwa, Yokota, Cytokine regulation in SARS coronavirus infection compared to other respiratory virus infections, J Med Virol
Park, Macrophages: a Trojan horse in COVID-19?, Nat Rev Immunol
Pepperrell, Pilkington, Owen, Wang, Hill, Review of safety and minimum pricing of nitazoxanide for potential treatment of COVID-19, Journal of Virus Eradication
Pizzorno, Padey, Terrier, Rosa-Calatrava, Drug repurposing approaches for the treatment of influenza viral infection: reviving old drugs to fight against a long-lived enemy, Front Immunol
Qin, Zhou, Hu, Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China, Clinical Infectious Diseases
Rajoli, Pertinez, Arshad, Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis, Br J Clin Pharmacol
Rello, Storti, Belliato, Serrano, Clinical phenotypes of SARS-CoV-2: implications for clinicians and researchers, Eur Respir J
Ribero, Jouvenet, Dreux, Nisole, Interplay between SARS-CoV-2 and the type I interferon response, PLoS Pathog
Robson, Khan, Le, Coronavirus RNA proofreading: molecular basis and therapeutic targeting, Molecular Cell
Rocco, Silva, Cruz, Early use of nitazoxanide in mild Covid-19 disease: randomised, placebo-controlled trial, Eur Respir J
Romagnoli, Peris, Gaudio, Geppetti, SARS-CoV-2 and COVID-19: from the bench to the bedside, Physiological Reviews
Rossignol, Frazia, Chiappa, Ciucci, Santoro, Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level, J Biol Chem
Rossignol, Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus, J Infect Public Health
Rossignol, Nitazoxanide: a first-in-class broad-spectrum antiviral agent, Antiviral Res
Ruan, Yang, Wang, Jiang, Song, Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China, Intens Care Med
Stockis, Bruyn, Gengler, Rosillon, Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5g and 1g b.i.d, CP
Tang, Liu, Zhang, Xu, Wen, Cytokine Storm in COVID-19: the current evidence and treatment strategies, Front Immunol
Valle, Kim-Schulze, Huang, An inflammatory cytokine signature predicts COVID-19 severity and survival, Nat Med
Vergara, Samer, Thalidomide is associated with increased T cell activation and inflammation in Antiretroviral-naive HIV-infected individuals in a randomised clinical trial of efficacy and safety, E Bio Med
Xu, Shi, Wang, Pathological findings of COVID-19 associated with acute respiratory distress syndrome, Lancet Respir Med
Ye, Wang, Mao, The pathogenesis and treatment of the 'Cytokine Storm" in COVID-19, Journal of Infect
Zhang, Dong, Cao, Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China, Allergy
Zhang, Guo, Lei, Frontline Science: COVID-19 infection induces readily detectable morphologic and inflammation-related phenotypic changes in peripheral blood monocytes, J Leukoc Biol
Zheng, Yu, Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study, BMJ
Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, The Lancet
