Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial
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Abstract
Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (M pro ), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication.
Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples.
Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log 10 viral load was 5.25 copies/mL vs . 4.79 copies/mL at baseline in the atovaquone vs . placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho −0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho −0.54, p = 0.005).
Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients.
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SciScore for 10.1101/2022.05.24.22275411: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The trial protocol was approved by UT Southwestern Institutional Review Board and was overseen by an independent data safety and monitoring board, and all patients provided written informed consent.
Consent: The trial protocol was approved by UT Southwestern Institutional Review Board and was overseen by an independent data safety and monitoring board, and all patients provided written informed consent.
Field Sample Permit: RNA Isolation: Saliva was collected using the DNA/RNA Shield Saliva Collection Kit (Zymo Research) following the manufacturer’s protocol.Sex as a biological variable Patients were excluded if they met any of the following criteria: enrolled in another COVID-19 … SciScore for 10.1101/2022.05.24.22275411: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The trial protocol was approved by UT Southwestern Institutional Review Board and was overseen by an independent data safety and monitoring board, and all patients provided written informed consent.
Consent: The trial protocol was approved by UT Southwestern Institutional Review Board and was overseen by an independent data safety and monitoring board, and all patients provided written informed consent.
Field Sample Permit: RNA Isolation: Saliva was collected using the DNA/RNA Shield Saliva Collection Kit (Zymo Research) following the manufacturer’s protocol.Sex as a biological variable Patients were excluded if they met any of the following criteria: enrolled in another COVID-19 antiviral therapy, breastfeeding women, known hypersensitivity to atovaquone, treatment with rifampin, patients with AIDS who required treatment for Pneumocystis jirovecii or Toxoplasma gondii, not expected to survive for 72 hours, >14 days from symptom onset. Randomization Design: This is a randomized, double-blind, placebo-controlled trial of atovaquone therapy in adult participants hospitalized with COVID-19. Blinding All investigators remained blinded to study assignment until completion of follow-up and database lock. Power Analysis not detected. 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 NCT04456153 Completed Atovaquone for Treatment of 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.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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