Early COVID-19 Therapy with Azithromycin Plus Nitazoxanide, Ivermectin or Hydroxychloroquine in Outpatient Settings Significantly Reduced Symptoms Compared to Known Outcomes in Untreated Patients.
Authors: Cadegiani Flavio A. , Goren Andy , Wambier Carlos G. , McCoy John 
Published: November 2020

Abstract
Background: While there was a lack of pharmacological interventions proven to be effective in early, outpatient settings for COVID-19, in a prospective, open-label observational study (pre-AndroCoV Trial) the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated similar effects, and apparent improvement of outcomes compared to untreated patients. The unexpected apparent positive results led to ethical questions on the employment of further full placebo-control studies in early stage COVID-19. The objective of the present study was to elucidate whether the conduction of a full placebo-control RCT was still ethically viable, through a comparative analysis with two control-groups.Materials and methods: Active group (AG) consisted of mild-to-moderate early stage COVID-19 patients enrolled in the Pre AndroCoV-Trial, treated with nitazoxanide ivermectin, or hydroxychloroquine in selected cases, in association with azithromycin. Vitamin D, vitamin C, zinc, glucocorticoids and anticoagulants, when clinically recommended. Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients from the same population as those from the Pre-AndroCoV Trial, and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes, based on a thorough and structured review of articles indexed in PubMed and MEDLINE and statements by official government agencies and specific medical societies. For both CGs, patients were matched for proportion between sex, age, obesity and other comorbidities. Results: Compared to CG1 and CG2, AG showed a reduction of 31.5 to 36.5% in viral shedding (p < 0.0001), 70 to 85% and 70 to 73% in duration of COVID-19 clinical symptoms when including and not including anosmia and ageusia, respectively ((p < 0.0001 for both), and 100% in respiratory complications through the parameters of the Brescia COVID-19 Respiratory Scale (p < 0.0001). For every 1,000 confirmed cases for COVID-19, a minimum of 140 patients were prevented from hospitalization (p < 0.0001), 50 from mechanical ventilation, and five deaths, when comparing to age-, sex- and comorbidity-matched non-treated patients with similar initial disease severity at the moment of diagnosis.Conclusion: Apparent benefits of the combination between early detection and early pharmacological approaches for COVID-19 demonstrated to be consistent when when compared to different control groups of untreated patients. The potential benefits could allow a large number of patients prevented from hospitalizations, deaths and persistent symptoms after COVID-19 remission. The potential impact on COVID-19 disease course and numbers of negative outcomes and the well-established safety profile of the drugs proposed by the Pre-AndroCoV Trial led to ethical questions regarding the conduction of further placebo control randomized clinical trials (RCTs) for early COVID-19. Early pharmacological approaches including azithromycin in combination with any of the options between nitazoxanide, ivermectin or optionally hydroxychloroquine should be considered for those diagnosed with COVID-19 presenting less than seven days of symptoms. Of the three drugs, we opted for nitazoxanide, due to more extensive demonstration of in vitro and in vivoantiviral activity, proven efficacy against other viruses in humans, and steadier safety profile.