Abstract: International Journal of Antimicrobial Agents 58 (2021) 106428 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents journal homepage: www.elsevier.com/locate/ijantimicag Hydroxychloroquine plus azithromycin early treatment of mild COVID-19 in an outpatient setting: a randomized, double-blinded, placebo-controlled clinical trial evaluating viral clearance ✩ Cristhieni Rodrigues a,∗, Rodrigo S. Freitas-Santos b,∗∗, José Eduardo Levi c, Andreza A. Senerchia d, Ana Tarina A. Lopes b, Sergio R. Santos e, Rinaldo F. Siciliano f, Lígia C. Pierrotti g,h a Hospital Infection Control Committee, Hospital Santa Paula, Ímpar Serviços Hospitalares S.A., São Paulo, São Paulo, Brazil Institute for Education and Research, Hospital Santa Paula, Ímpar Serviços Hospitalares S.A., São Paulo, São Paulo, Brazil c Research and Development Department, Diagnósticos da América S.A. (Dasa), Brazil d Clinical Research Department, Diagnósticos da América S.A. (Dasa), Brazil e Strategy Board, Diagnósticos da América S.A. (Dasa), Brazil f Heart Institute (InCor), Medical School, Universidade de São Paulo, São Paulo, São Paulo, Brazil g Infectious Diseases Division, Hospital das Clínicas, Universidade de São Paulo, São Paulo, São Paulo, Brazil h Infectious Diseases Department, Diagnósticos da América S.A. (Dasa), Brazil b a r t i c l e i n f o Article history: Received 3 November 2020 Accepted 13 August 2021 Editor: Dr Jim Gray Keywords: COVID-19 SARS-CoV-2 RCT Hydroxychloroquine Azithromycin a b s t r a c t Background: Hydroxychloroquine has shown potential to block viral replication of SARS-CoV-2 in some in vitro studies. This randomised, double-blinded, placebo controlled clinical trial evaluated the efficacy of hydroxychloroquine plus azithromycin (HCQ/AZT) in reducing viral loads in patients with early and mild SARS-CoV-2 infection. Methods: A single-centre randomised placebo-controlled clinical trial was conducted with outpatients with early and mild SARS-CoV-2 infection. Inclusion criteria were: patients aged 18–65 years with symptoms suggestive of COVID-19 for < 5 days, no significant comorbidities, and positive nasopharyngeal/oropharyngeal swab screening tests (POCT-PCR). Randomised patients received either hydroxychloroquine for 7 days plus azithromycin for 5 days or placebo. The primary endpoint was viral clearance within a 9-day period. Secondary endpoints included viral load reduction, clinical evolution, hospitalization rates, chest computed tomography evolution, and adverse effects. Results: From 107 potential trial participants, 84 were enrolled following predetermined criteria. Statistical analyses were performed on an intention-to-treat (N = 84) and per-protocol (PP) basis (N = 70). On the PP analysis, the treatment (N = 36) and placebo (N = 34) groups displayed similar demographic characteristics. At 95% CI, no statistically significant between-group differences were found in viral clearance rates within 9 days following enrolment (P = 0.26). Conclusions: This randomised, double-blinded, placebo-controlled clinical trial evaluating outpatients with early and mild COVID-19 showed that viral clearance rates within a 9-day period from enrolment did not change with HCQ/AZT treatment compared with placebo, although no major cardiovascular events were observed in participants without comorbidities. Secondary outcomes were also not significantly improved with HCQ/AZT treatment compared with placebo. These findings do..