Early use of nitazoxanide in mild Covid-19 disease: randomized, placebo-controlled trial
Abstract
The antiparasitic drug nitazoxanide is widely available and exerts broad-spectrum antiviral activity in vitro . However, there is no evidence of its impact on SARS-CoV-2 infection.
In a multicenter, randomized, double-blind, placebo-controlled trial, adult patients who presented up to 3 days after onset of Covid-19 symptoms (dry cough, fever, and/or fatigue) were enrolled. After confirmation of SARS-CoV2 infection by RT-PCR on nasopharyngeal swab, patients were randomized 1:1 to receive either nitazoxanide (500 mg) or placebo, TID, for 5 days. The primary outcome was complete resolution of symptoms. Secondary outcomes were viral load, general laboratory tests, serum biomarkers of inflammation, and hospitalization rate. Adverse events were also assessed.
From June 8 to August 20, 2020, 1,575 patients were screened. Of these, 392 (198 placebo, 194 nitazoxanide) were analyzed. Median time from symptom onset to first dose of study drug was 5 (4-5) days. At the 5-day study visit, symptom resolution did not differ between the nitazoxanide and placebo arms. However, at the 1-week follow-up, 78% in the nitazoxanide arm and 57% in the placebo arm reported complete resolution of symptoms ( p =0.048). Swabs collected were negative for SARS-CoV-2 in 29.9% of patients in the nitazoxanide arm versus 18.2% in the placebo arm (p=0.009). Viral load was also reduced after nitazoxanide compared to placebo (p=0.006). No serious adverse events were observed.
In patients with mild Covid-19, symptom resolution did not differ between the nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly.
Take home message
This was the first study to evaluate the effect of early nitazoxanide therapy in mild Covid-19. Nitazoxanide did not accelerate symptom resolution after 5 days of therapy; however, reduced viral load significantly with no serious adverse events.
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Review 1: "Early use of nitazoxanide in mild Covid-19 disease: randomized, placebo-controlled trial"
This paper presents potentially informative findings of the applicability of nitazoxanide in reducing viral load in patients with mild COVID-19. However, the reviewer raised concerns regarding the methods of analysis used in the study which may have had misleading implications
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Review of "Early use of nitazoxanide in mild Covid-19 disease: randomized, placebo-controlled trial"
Reviewer: Andrew Hill (University of Liverpool) | 📒📒📒 ◻️◻️
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SciScore for 10.1101/2020.10.21.20217208: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The trial was designed by the executive committee and approved by the Brazilian National Commission for Research Ethics and individual ethics committees of the participating sites (CAAE: 32258920.0.1001.5257).
Consent: Informed consent was obtained from each patient or, if the patient was unable to provide consent, from a healthcare proxy.Randomization Randomization and masking: Patients were randomly assigned (1:1) using a computer-generated random number list to receive either placebo or nitazoxanide (500 mg oral solution, 20 mg/mL [25 mL], three times daily for 5 days), dispensed by the pharmacy of each study site. Blinding not detected. Power Analysis Statis… SciScore for 10.1101/2020.10.21.20217208: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The trial was designed by the executive committee and approved by the Brazilian National Commission for Research Ethics and individual ethics committees of the participating sites (CAAE: 32258920.0.1001.5257).
Consent: Informed consent was obtained from each patient or, if the patient was unable to provide consent, from a healthcare proxy.Randomization Randomization and masking: Patients were randomly assigned (1:1) using a computer-generated random number list to receive either placebo or nitazoxanide (500 mg oral solution, 20 mg/mL [25 mL], three times daily for 5 days), dispensed by the pharmacy of each study site. Blinding not detected. Power Analysis Statistical Analyses: We estimated a sample size of 392 patients (196 per arm, allocation ratio 1:1) would provide 85% power to detect an 11% increase in symptom-free days after nitazoxanide initiation compared to placebo at a two-sided significance level of α=0.05. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analyses were performed in the SPSS Version 27 environment SPSSsuggested: (SPSS, RRID:SCR_002865)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This study has several limitations. A long-term analysis of the effects of therapy (e.g., beyond 28 days) was not performed. Only three symptoms (dry cough, fever, and fatigue) were considered for analysis of primary outcome, even though Covid-19 is now known to have protean manifestations and patients reported other symptoms. Initially, patients were followed during the 5-day course of therapy; only those who continued to have one of the symptoms of interest after completion of therapy were contacted again 1 week later. At this second time point, nitazoxanide therapy was found to have reduced symptom duration significantly as compared to placebo. All patients were instructed to take their study medication 3 times daily as prescribed, return to the study site if symptoms worsened or adverse effects developed, and complete their symptom journals with data on any adverse events, the intensity of each Covid-19 symptom, and when symptoms abated and resolved. However, we cannot ascertain the extent to which patients followed these instructions. Nevertheless, given the placebo-controlled design, nonadherence may have occurred in both groups. In summary, in patients with mild Covid-19 enrolled within 3 days of symptom onset, nitazoxanide as compared with placebo was not an effective therapy in terms of accelerating symptom resolution after 5 days of therapy. However, at the 1-week follow-up, 78% in the nitazoxanide arm and 57% in the placebo arm reported complete resolution of sympt...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04552483 Completed Effects of Early Use of Nitazoxanide in Patients With COVID-… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
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SciScore for 10.1101/2020.10.21.20217208: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The trial was designed by the executive committee and approved by the Brazilian National Commission for Research Ethics and individual ethics committees of the participating sites (CAAE: 32258920.0.1001.5257). Randomization After confirmation of SARS-CoV2 infection by RT-PCR on nasopharyngeal swab, patients were randomized 1:1 to receive either nitazoxanide (500 mg) or placebo, TID, for 5 days. Blinding not detected. Power Analysis Statistical Analyses We estimated a sample size of 392 patients (196 per arm, allocation ratio 1:1) would provide 85% power to detect an 11% increase in symptom-free days after nitazoxanide initiation compared to placebo at a two-sided … SciScore for 10.1101/2020.10.21.20217208: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The trial was designed by the executive committee and approved by the Brazilian National Commission for Research Ethics and individual ethics committees of the participating sites (CAAE: 32258920.0.1001.5257). Randomization After confirmation of SARS-CoV2 infection by RT-PCR on nasopharyngeal swab, patients were randomized 1:1 to receive either nitazoxanide (500 mg) or placebo, TID, for 5 days. Blinding not detected. Power Analysis Statistical Analyses We estimated a sample size of 392 patients (196 per arm, allocation ratio 1:1) would provide 85% power to detect an 11% increase in symptom-free days after nitazoxanide initiation compared to placebo at a two-sided significance level of α=0.05. Sex as a biological variable Just over half (53%) were women and 69% were white. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analyses were performed in the SPSS Version 27 environment SPSSsuggested: (SPSS, RRID:SCR_002865)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
This study has several limitations. A long-term analysis of the effects of therapy (e.g., beyond 28 days) was not performed. Only three symptoms (dry cough, fever, and fatigue) were considered for analysis of primary outcome, even though Covid-19 is now known to have protean manifestations and patients reported other symptoms. Initially, patients were followed during the 5-day course of therapy; only those who continued to have one of the symptoms of interest after completion of therapy were contacted again 1 week later. At this second time point, nitazoxanide therapy was found to have reduced symptom duration significantly as compared to placebo. All patients were instructed to take their study medication 3 times daily as prescribed, return to the study site if symptoms worsened or adverse effects developed, and complete their symptom journals with data on any adverse events, the intensity of each Covid-19 symptom, and when symptoms abated and resolved. However, we cannot ascertain the extent to which patients followed these instructions. Nevertheless, given the placebo-controlled design, nonadherence may have occurred in both groups. In summary, in patients with mild Covid-19 enrolled within 3 days of symptom onset, nitazoxanide as compared with placebo was not an effective therapy in terms of accelerating symptom resolution after 5 days of therapy. However, at the 1-week follow-up, 78% in the nitazoxanide arm and 57% in the placebo arm reported complete resolution of sympt...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04552483 Completed Effects of Early Use of Nitazoxanide in Patients With COVID-... Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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