Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients.

In a prospective observational study (pre-AndroCoV Trial), the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated unexpected improvements in COVID-19 outcomes when compared to untreated patients. The apparent yet likely positive results raised ethical concerns on the employment of further full placebo controlled studies in early-stage COVID-19. The present analysis aimed to elucidate, through a comparative analysis with two control groups, whether full placebo-control randomized clinical trials (RCTs) on early-stage COVID-19 are still ethically acceptable. The Active group (AG) consisted of patients enrolled in the Pre-AndroCoV-Trial (n = 585). Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients of the same population (n = 137), and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes based on a thorough and structured review of indexed articles and official statements. Patients were matched for sex, age, comorbidities and disease severity at baseline. Compared to CG1 and CG2, AG showed reduction of 31.5-36.5% in viral shedding (p < 0.0001), 70-85% in disease duration (p < 0.0001), and 100% in respiratory complications, hospitalization, mechanical ventilation, deaths and post-COVID manifestations (p < 0.0001 for all). For every 1000 confirmed cases for COVID-19, at least 70 hospitalizations, 50 mechanical ventilations and five deaths were prevented. Benefits from the combination of early COVID-19 detection and early pharmacological approaches were consistent and overwhelming when compared to untreated groups, which, together with the well-established safety profile of the drug combinations tested in the Pre-AndroCoV Trial, precluded our study from continuing employing full placebo in early COVID-19.