A randomized, open-label trial of combined nitazoxanide and atazanavir/ritonavir for mild to moderate COVID-19
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Abstract
The nitazoxanide plus atazanavir/ritonavir for COVID-19 (NACOVID) trial investigated the efficacy and safety of repurposed nitazoxanide combined with atazanavir/ritonavir for COVID-19.
Methods
This is a pilot, randomized, open-label multicenter trial conducted in Nigeria. Mild to moderate COVID-19 patients were randomly assigned to receive standard of care (SoC) or SoC plus a 14-day course of nitazoxanide (1,000 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 symptom resolution. Safety and pharmacokinetics were also evaluated ( ClinicalTrials.gov ID: NCT04459286).
Results
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 2–28 in the 35% of patients with detectable virus at baseline (20/57) (aHR = 0.948, 95% CI: 0.341–2.636, p = 0.919). There was no significant difference in time to complete symptom 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 1,546 ng/ml (95% CI: 797–2,557), above its putative EC 90 in 54% of patients. Tizoxanide was undetectable in saliva.
Conclusion
Nitazoxanide co-administered with atazanavir/ritonavir was safe but not better than standard of care in treating COVID-19. These findings should be interpreted in the context of incomplete enrollment (64%) and the limited number of patients with detectable SARS-CoV-2 in saliva at baseline in this trial.
Clinical trial registration
[ https://clinicaltrials.gov/ct2/show/NCT04459286 ], identifier [NCT04459286].
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SciScore for 10.1101/2022.02.03.22270152: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The National Health Research Ethics Committee, Nigeria (approval number: NHREC/01/01/2007-26/08/2020) and the Central University Research Ethics Committee, University of Liverpool (reference number: 8074) approved the protocol.
Consent: All patients provided written informed consent as per the ethics committee’s approved process.Sex as a biological variable Site clinical investigators documented demographic and anthropometric information, recent and current medical history including confirmation of COVID-19 diagnosis and disease severity, pregnancy test for reproductive age women, concomitant medications, physical examination, vital signs, and safety blood for haematology and … SciScore for 10.1101/2022.02.03.22270152: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The National Health Research Ethics Committee, Nigeria (approval number: NHREC/01/01/2007-26/08/2020) and the Central University Research Ethics Committee, University of Liverpool (reference number: 8074) approved the protocol.
Consent: All patients provided written informed consent as per the ethics committee’s approved process.Sex as a biological variable Site clinical investigators documented demographic and anthropometric information, recent and current medical history including confirmation of COVID-19 diagnosis and disease severity, pregnancy test for reproductive age women, concomitant medications, physical examination, vital signs, and safety blood for haematology and biochemistry. Randomization Study design: The nitazoxanide plus atazanavir/ritonavir for COVID-19 (NACOVID) trial is a pilot open-label randomised phase 2, multicentre, two-arm controlled trial conducted in Nigeria. Blinding not detected. Power Analysis Statistical analysis: A sample size of 98 was estimated to provide more than 80% power to show or exclude 60% improvement in time to SARS-CoV-2 RT-PCR negativity in the intervention group compared with the control group at a two-sided type 1 error rate of 5%. Cell Line Authentication Authentication: Tizoxanide quantification was by validated LC-MS/MS methods on TSQ Vantage (Thermo Electron Corporation, Hemel Hempstead, Hertfordshire, UK) with 50 ng/ml lowest limit of quantification. Table 2: Resources
No key resources detected.
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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04459286 Completed The Nitazoxanide Plus Atazanavir for COVID-19 Study NCT04463264 Recruiting Efficacy and Safety Study of Nitazoxanide (NTX) in the Treat… NCT04486313 Completed Trial to Evaluate Efficacy and Safety of Nitazoxanide in the… NCT04392427 Not yet recruiting New Antiviral Drugs for Treatment of COVID-19 NCT04552483 Completed Effects of Early Use of Nitazoxanide in Patients With COVID-… NCT04746183 Recruiting AGILE (Early Phase Platform Trial for COVID-19) 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.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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