Early Treatment With Nitazoxanide Prevents Worsening of Mild and Moderate COVID-19 and Subsequent Hospitalization

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

doi:10.2139/ssrn.3937568

Cited by 3 publications

(4 citation statements)

References 24 publications

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“…We chose the Syrian hamster model of SARS-CoV-2 infection, where animals develop severe pneumonia and clinical outcomes (i.e., peak weight loss around 5 days and complete resolution by 14 days post infection), which are predictable (Chan et al, 2020; Imai et al, 2020; Sia et al, 2020). We used a new extended-release formulation of NTZ (NT-300) currently under phase III evaluation (Rossignol et al, 2021), which reaches peak levels 6-8 hrs after ingestion (Haffizulla et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…Intriguingly, an initial trial of NTZ treatment in patients (n=50) with moderate COVID-19 disease showed that 5 days of treatment was associated with decreased inflammatory biomarkers, faster SARS-CoV-2 PCR negativity, and decreased time to hospital discharge (Blum et al, 2021). Furthermore, a randomized controlled trial (RCT) (n=379) of 5 days of placebo or NTZ treatment for mild or moderate COVID-19 using the extended-release formulation of NTZ (NT-300) was associated with an 85% reduction in progression to severe illness (Rossignol et al, 2021). In both trials NTZ was well tolerated and there were no major adverse events.…”

Section: Discussionmentioning

confidence: 99%

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The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

Miorin

Mire

Hume

et al. 2022

Preprint

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A well-tolerated and cost-effective oral drug that blocks SARS-CoV-2 growth and dissemination would be a major advance in the global effort to reduce COVID-19 morbidity and mortality. Here, we show that the oral FDA-approved drug nitazoxanide (NTZ) significantly inhibits SARS-CoV-2 viral replication and infection in different primate and human cell models including stem cell-derived human alveolar epithelial type 2 cells. Furthermore, NTZ synergizes with remdesivir, and it broadly inhibits growth of SARS-CoV-2 variants B.1.351 (beta), P.1 (gamma), and B.1617.2 (delta) and viral syncytia formation driven by their spike proteins. Strikingly, oral NTZ treatment of Syrian hamsters significantly inhibits SARS-CoV-2-driven weight loss, inflammation, and viral dissemination and syncytia formation in the lungs. These studies show that NTZ is a novel host-directed therapeutic that broadly inhibits SARS-CoV-2 dissemination and pathogenesis in human and hamster physiological models, which supports further testing and optimization of NTZ-based therapy for SARS-CoV-2 infection alone and in combination with antiviral drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

Miorin

Mire

Hume

et al. 2022

Preprint

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“…After abstract screening and full-text reading, 152 RCTs were included in the analysis. All 152 RCTs were posted on the medRxiv server …”

Section: Resultsmentioning

confidence: 99%

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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“…There was no overall difference in time to sustained clinical recovery and a non-significant trend towards a quicker time to symptom resolution and return to usual health was observed. 26 The Elalfy et al study (NCT04392427, n = 113) reported a cumulative day-15 SARS-CoV-2 clearance rate of 88.7% in patients with mild COVID-19 who were treated with a combination of nitazoxanide (500 mg q.i.d. ), ribavirin, and ivermectin plus zinc supplement compared with 13.7% in those who received supportive symptomatic therapy (no data on statistical significance).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of nitazoxanide combined with ritonavir-boosted atazanavir for the treatment of mild to moderate COVID-19

Fowotade¹,

Bamidele²,

Egbetola

et al. 2022

Preprint

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Background: Finding effective therapeutics for COVID-19 continues to be an urgent need, especially considering use context limitations and cost of currently approved agents. The NACOVID trial investigated the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, used in combination for COVID-19. Methods: In this pilot, randomized, open label trial conducted in Nigeria, patients diagnosed with mild to moderate COVID-19 were randomly assigned to receive standard of care (SoC) or SoC plus 14-day course of nitazoxanide (1000 mg b.i.d.) and atazanavir/ritonavir (300/100 mg od) and followed through day 28. Study endpoints included time to clinical improvement, SARS-CoV-2 viral load change, and time to complete symptoms resolution. Safety and pharmacokinetics of nitazoxanide active metabolite, tizoxanide, were also evaluated. This trial was registered with ClinicalTrials.gov (NCT04459286). Findings: There was no difference in time to clinical improvement between the SoC (n = 26) and SoC plus intervention arms (n = 31; Cox proportional hazards regression analysis adjusted hazard ratio, aHR = 0.898, 95% CI: 0.492-1.638, p = 0.725). No difference was observed in the pattern of saliva SARS-CoV-2 viral load changes from days 2 to 28 in the 35% of patients with detectable virus at baseline (20/57) between the two arms (aHR = 0.948, 95% CI: 0.341-2.636, p = 0.919). There was no significant difference in time from enrolment to complete symptoms resolution (aHR = 0.535, 95% CI: 0.251 -1.140, p = 0.105). Atazanavir/ritonavir increased tizoxanide plasma exposure by 68% and median trough plasma concentration was 1546 ng/ml (95% CI: 797-2557), above its putative EC90 in 54% of patients. Tizoxanide was not detectable in saliva. Interpretation: These findings should be interpreted in the context of incomplete enrolment (64%) and the limited number of patients with detectable SARS-CoV-2 in saliva at baseline in this trial.

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Early Treatment With Nitazoxanide Prevents Worsening of Mild and Moderate COVID-19 and Subsequent Hospitalization

Cited by 3 publications

References 24 publications

The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

The oral drug nitazoxanide restricts SARS-CoV-2 infection and attenuates disease pathogenesis in Syrian hamsters

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

Efficacy and safety of nitazoxanide combined with ritonavir-boosted atazanavir for the treatment of mild to moderate COVID-19

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