A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19

Rossignol, Jean‐François; Bardin, Matthew; Fulgencio, Jessica; Mogelnicki, Dena; Bréchot, Christian

doi:10.1016/j.eclinm.2022.101310

Cited by 36 publications

(55 citation statements)

References 23 publications

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“…Whereas the antiviral activity of nitazoxanide against SARS-CoV-2 replication has been reported in vitro and in clinical settings [ 37 – 42 ], the effect of tizoxanide on SARS-CoV-2 infection is not well established. Therefore, the antiviral activity of tizoxanide was examined in a model of SARS-CoV-2 (SARS-CoV-2/England/2/2020) infection in Vero E6 cells.…”

Section: Resultsmentioning

confidence: 99%

“…As for SARS-CoV-2, at an early stage of the pandemic, Wang et al reported that nitazoxanide inhibits SARS-CoV-2 replication in Vero E6 cells at low-µM concentrations (EC 50 = 2.12 μM) [ 37 ]; these observations were recently confirmed in different types of cells, including human lung-derived Calu-3 cells [ 38 , 39 ]. More importantly several studies have recently shown an antiviral activity and clinical benefits of nitazoxanide in COVID-19 patients [ 39 – 42 ]. In particular, a recent multicenter, randomized, double-blind, placebo-controlled trial has shown that a 5-day oral treatment with nitazoxanide (600 mg twice daily) prevents the progression to severe respiratory symptoms and hospitalization when administered to patients in the early stages of SARS-CoV-2 infection [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…More importantly several studies have recently shown an antiviral activity and clinical benefits of nitazoxanide in COVID-19 patients [ 39 – 42 ]. In particular, a recent multicenter, randomized, double-blind, placebo-controlled trial has shown that a 5-day oral treatment with nitazoxanide (600 mg twice daily) prevents the progression to severe respiratory symptoms and hospitalization when administered to patients in the early stages of SARS-CoV-2 infection [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that NTZ and its active circulating-metabolite tizoxanide (TIZ) are effective against different RNA viruses including influenza and parainfluenza viruses, hepatitis C and rotavirus infection in vitro [ 28 – 31 ], as well as in clinical studies [ 32 – 34 ]. Interestingly nitazoxanide was also found to be effective against different animal and human coronaviruses, including MERS-CoV [ 26 , 35 , 36 ] and, more recently, SARS-CoV-2 in vitro [ 37 – 39 ] and in COVID-19 patients [ 39 – 42 ].…”

Section: Introductionmentioning

confidence: 99%

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Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence

Riccio

Santopolo

Rossi

et al. 2022

Cell. Mol. Life Sci.

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SARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here, we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell–cell fusion assays, we show that nitazoxanide-induced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell–cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence

Riccio

Santopolo

Rossi

et al. 2022

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…In mild COVID-19, nitazoxanide significantly reduced the viral load with no serious adverse events ( 7 ). More recently, a randomized, double-blind placebo-controlled clinical trial provides evidence that treatment of outpatients with mild or moderate COVID-19 with nitazoxanide may reduce the progression to severe illness, thus suggesting larger trials with adequate statistical power to confirm this hypothesis ( 11 ). Nitazoxanide and its metabolite (tizoxanide) decreased inflammation in vitro and in vivo ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Nitazoxanide in Patients Hospitalized With COVID-19 Pneumonia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial

et al. 2022

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BackgroundNitazoxanide exerts antiviral activity in vitro and in vivo and anti-inflammatory effects, but its impact on patients hospitalized with COVID-19 pneumonia is uncertain.MethodsA multicentre, randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals in Brazil. Hospitalized adult patients requiring supplemental oxygen, with COVID-19 symptoms and a chest computed tomography scan suggestive of viral pneumonia or positive RT-PCR test for COVID-19 were enrolled. Patients were randomized 1:1 to receive nitazoxanide (500 mg) or placebo, 3 times daily, for 5 days, and were followed for 14 days. The primary outcome was intensive care unit admission due to the need for invasive mechanical ventilation. Secondary outcomes included clinical improvement, hospital discharge, oxygen requirements, death, and adverse events within 14 days.ResultsOf the 498 patients, 405 (202 in the nitazoxanide group and 203 in the placebo group) were included in the analyses. Admission to the intensive care unit did not differ between the groups (hazard ratio [95% confidence interval], 0.68 [0.38–1.20], p = 0.179); death rates also did not differ. Nitazoxanide improved the clinical outcome (2.75 [2.21–3.43], p < 0.0001), time to hospital discharge (1.37 [1.11–1.71], p = 0.005), and reduced oxygen requirements (0.77 [0.64–0.94], p = 0.011). C-reactive protein, D-dimer, and ferritin levels were lower in the nitazoxanide group than the placebo group on day 7. No serious adverse events were observed.ConclusionsNitazoxanide, compared with placebo, did not prevent admission to the intensive care unit for patients hospitalized with COVID-19 pneumonia.Clinical Trial RegistrationBrazilian Registry of Clinical Trials (REBEC) RBR88bs9x; ClinicalTrials.gov, NCT04561219.

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Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles

et al. 2023

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ImportanceRandomized clinical trials (RCTs) on COVID-19 are increasingly being posted as preprints before publication in a scientific, peer-reviewed journal.ObjectiveTo assess time to journal publication for COVID-19 RCT preprints and to compare differences between pairs of preprints and corresponding journal articles.Evidence ReviewThis systematic review used a meta-epidemiologic approach to conduct a literature search using the World Health Organization COVID-19 database and Embase to identify preprints published between January 1 and December 31, 2021. This review included RCTs with human participants and research questions regarding the treatment or prevention of COVID-19. For each preprint, a literature search was done to locate the corresponding journal article. Two independent reviewers read the full text, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. Time to publication was analyzed using a Cox proportional hazards regression model. Differences between preprint and journal article pairs in terms of outcomes, analyses, results, or conclusions were described. Statistical analysis was performed on October 17, 2022.FindingsThis study included 152 preprints. As of October 1, 2022, 119 of 152 preprints (78.3%) had been published in journals. The median time to publication was 186 days (range, 17-407 days). In a multivariable model, larger sample size and low risk of bias were associated with journal publication. With a sample size of less than 200 as the reference, sample sizes of 201 to 1000 and greater than 1000 had hazard ratios (HRs) of 1.23 (95% CI, 0.80-1.91) and 2.19 (95% CI, 1.36-3.53) for publication, respectively. With high risk of bias as the reference, medium-risk articles with some concerns for bias had an HR of 1.77 (95% CI, 1.02-3.09); those with a low risk of bias had an HR of 3.01 (95% CI, 1.71-5.30). Of the 119 published preprints, there were differences in terms of outcomes, analyses, results, or conclusions in 65 studies (54.6%). The main conclusion in the preprint contradicted the conclusion in the journal article for 2 studies (1.7%).Conclusions and RelevanceThese findings suggest that there is a substantial time lag from preprint posting to journal publication. Preprints with smaller sample sizes and high risk of bias were less likely to be published. Finally, although differences in terms of outcomes, analyses, results, or conclusions were observed for preprint and journal article pairs in most studies, the main conclusion remained consistent for the majority of studies.

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A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19

Cited by 36 publications

References 23 publications

Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence

Impairment of SARS-CoV-2 spike glycoprotein maturation and fusion activity by nitazoxanide: an effect independent of spike variants emergence

Nitazoxanide in Patients Hospitalized With COVID-19 Pneumonia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles

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