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Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients., Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO 2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087., Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups., Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less., Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13)., Competing Interests: ISM reports devices supply from Fisher & Paykel outside the submitted work; ISM and ABC reports funding paid to HCor by Ministerio da Ciência, Tecnologia e Inovação (MCTIC)/Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ), Cia Latino Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz; LPD reports personal statistical Consulting fees from Servier Laboratories, Aché Laboratory and Astra Zeneca; FGZ reports grants for investigator initiated trials paid to his institution from Bactiguard, Ionis Pharmaceuticals and statistical Consulting from Bactiguard; RGR reported research grants from Pfizer and Brazilian Ministry of Health-PROADI-SUS; LCPA reported participation on advisory board of COVID-19 drugs for MSD; OB reported grants or contracts from: AstraZeneca, Amgen, Bayer, Pfizer, BMS Servier, Novartis Boehringer-Ingelheim, RDL reports grants or contracts from Bristol-Myers Squibb, Glaxo Smith Kline, Medtronic, Pfizer, Sanofi with payments to his institution, payment or honoraria for lectures, presentations, speakers, manuscript writing from Pfizer, Participation on a Data Safety Monitoring Board or Advisory Board of Glaxo Smith Kline and Consulting fees from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, Glaxo Smith Kline, Medtronic, Merck, Pfizer, Portola and Sanofi; AA reports grants form Population Health Research Institute, EMS and Bayer as funding to his institution, payment for lectures for EMS and Bayer. All other authors declare no competing interests., (© 2023 The Authors.)