Abstract: ORIGINAL ARTICLE 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 F. A. Cadegiani1,2, A. Goren2, C. G. Wambier3 and J. McCoy2 1) Corpometria Institute, Brasília, DF, Brazil, 2) Applied Biology, Inc., Irvine, CA and 3) Department of Dermatology, The Alpert Medical School of Brown University, RI, USA Abstract 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 PreAndroCoV Trial, precluded our study from continuing employing full placebo in early COVID-19. © 2021 The Author(s). Published by Elsevier Ltd. Keywords: Antiandrogen, clinical equipoise, COVID-19, dutasteride, hydroxychloroquine, ivermectin, nitazoxanide, proxalutamide, SARSCoV-2, spironolactone Article published online: 7 July 2021 Corresponding author: F.A. Cadegiani, Corpometria Institute, SGAS 915 Sala 260/262/264, Brasilia, DF, 70-390150, Brazil E-mails: flavio.cadegiani@unifesp.br, f.cadegiani@gmail.com Background Coronavirus Disease 2019 (COVID-19) is a highly heterogeneous and multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) [1] that is particularly harmful to those aged above 60 y/o, with uncontrolled diabetes, hypertension, obesity, androgenetic alopecia (AGA), abuse of anabolic steroids in males and hyperandrogenism in females [2–7]. Effective treatments to improve COVID-19 clinical outcomes, mortality and to prevent post-COVID manifestations are highly desired, while definitive solutions such as effective and safe vaccines are not universally available. Pharmacological interventions during the viral replication stage are likely the best timing to antagonize SARS-CoV-2 infectivity and prevent complications [1,3]. Hydroxychloroquine..