Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial.

Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (Mpro), 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 log10 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.

Lessons from an international trial evaluating vaccination strategies for recovered inpatients with COVID-19 (VATICO).

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus.

Atovaquone for Treatment of COVID-19 (Ataq COVID-19) Trial

Background Our group performed an in-silico screen to identify FDA approved drugs that inhibit SARS-C0V-2 main protease (Mpro), 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 Enrolled patients were randomized in a 2:1 fashion to atovaquone 1500 mg twice daily versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Patients agreed to allow collection of saliva at baseline and twice a day while hospitalized or up to 10 days. Saliva was collected and RNA extracted for viral load (VL) measurement by Real-time PCR. Our primary outcome was to examine the between group differences in log transformed VL(copies/mL) using generalized linear mixed-effect models of repeated measures from all samples. Additional analysis of Atovquone plasma concentrations were examined and correlated with viral load and body mass index (BMI). Results Of the 61 patients enrolled;41 were received atovaquone and 19 placebo. Overall the population was predominately male Hispanic with a mean age of 51 years. The two groups were balanced (Table 1) with regard to age, gender, race, co-morbidities, days from onset of symptoms, baseline oxygen requirements, and receipt of COVID-19 specific standard of care treatment. A higher proportion with diabetes was noted in the Atovaquone arm. The log10 VL was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Although there was a decrease in VL over time, there was no differences between the atovaquone plus standard of care arm versus the standard of care arm (Figure 1). Additional analysis of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, inverse association between atovaquone levels and BMI (rho -0.44, p=0.03), and Day 5 concentrations and VL (rho -0.54, p=0.005). Figure 1. Mean viral load of COVID-19 over time of atovaquone (blue) vs. placebo (red). Table 1. Baseline characteristics Conclusion Although atovaquone showed promising in vitro antiviral properties for COVID-19, in this pilot study we did not detect a change in VL in patients who received atovaquone compared to placebo, possibly due to failure of patients achieve adequate drug levels. Disclosures Mamta K. Jain, MD, MPH, Gilead Sciences Inc. (Individual(s) Involved: Self): Research Grant or Support, Scientific Research Study Investigator;GlaxoSmithKline (Individual(s) Involved: Self): Scientific Research Study Investigator;Merck (Individual(s) Involved: Self): Scientific Research Study Investigator;Vasgene (Individual(s) Involved: Self): Scientific Research Study Investigator