Background: COVID-19 pandemic requires urgent responses in terms of identification of effective and safe therapies to reduce hospitalization, death, and post-COVID symptoms, while vaccines are not extensively available. Repurposing already existing medications for COVID-19 should be preferred over the development of new drugs due to their inherent advantages of well-established safety profile, familiarity, and cost. Although antiandrogens have strong plausibility to be effective against COVID-19, hydroxychloroquine, nitazoxanide and ivermectin gained unquestionable popularity due to their in vitro and in vivo direct or indirect antiviral activity, and preliminary observations of efficacy against COVID-19. The objective of the present open-label prospective observational study (the pre-AndroCoV trial) was to make a head-to-head comparative analysis between hydroxychloroquine, nitazoxanide and ivermectin, in terms of potential efficacy for COVID-19, combined with early COVID-19 detection, aiming to choose one of these three drugs to include in the AndroCoV randomized clinical trial (RCT).
Materials and methods: Participants were recruited from social media and referred from other medical centers. Patients confirmed for COVID-19 with positive rtPCR-SARS-CoV-2 with fewer than seven days of symptoms and four days of treatment were included. Patients were actively questioned for age, sex, body mass index (BMI), presence of approximately 40 existing diseases and regular use of 30 drug classes, and COVID-19 symptomatology. Hydroxychloroquine 400mg/day for five days, nitazoxanide 500mg twice daily for six days, or ivermectin 0.2mg/kg/day for three consecutive days was given in a quasi-random manner, in association with azithromycin 500mg/day for five days, and optional addition of vitamin C, vitamin D and zinc, and glucocorticoids and anticoagulants in case of signs of lung injury or higher risk for thrombosis, respectively. Patients were followed up for 60 days, including active questions on disease course and symptoms on Days 0, 1, 2, 3, 7, 14 and 30, and virtual medical visits on Days 0 and 14, and whenever symptoms got worse on in the presence of severe adverse effects.
Results: In total, 585 participants, including 270 females and 305 males, were included. Of these, 159, 357, and 110 patients received hydroxychloroquine, nitazoxanide, and ivermectin, respectively, with similar baseline characteristics and time-to-treat between them. The three groups had similar duration of positive rtPCR-SARS-CoV-2, clinical disease duration and recovery speed. Of the 585 patients, none was hospitalized, needed mechanical ventilation, or died, and 1.5% persisted with symptoms after recovery.
Conclusion: Hydroxychloroquine, nitazoxanide and ivermectin seem to be similarly effective for overall clinical outcomes in COVID-19 when used before seven days of symptoms, and overwhelmingly superior compared to untreated COVID-19 population, even for those outcomes not influenced by placebo effect, at least when combined with azithromycin, and vitamin C, D and zinc in the majority of the cases. Between these drugs, nitazoxanide demonstrated the strongest broad spectrum antiviral activity, plausibility to act as an anti-COVID agent, and safety profile, at least at the time of the choice of the drug for the AndroCoV Trial.