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. 2023 Apr:20:100466.
doi: 10.1016/j.lana.2023.100466. Epub 2023 Mar 8.

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial

Israel S Maia  1   2   3   4 , Aline Marcadenti  1 , Viviane C Veiga  3   5 , Tamiris A Miranda  1 , Samara P C Gomes  1 , Mariana B S Carollo  1 , Karina L Negrelli  1 , Jackeline O Gomes  1 , Lucas Tramujas  1 , Erlon O Abreu-Silva  1 , Glauco A Westphal  6 , Ruthy P Fernandes  6 , Jacques G A Horta  7 , Deborah C Oliveira  7 , Uri A P Flato  8 , Ricardo C R Paoliello  8 , Camilo Fernandes  2 , Cássio L Zandonai  2 , Juliana C Coelho  5 , Waldemar C Barros  9 , Juliana C Lemos  9 , Renata S Bolan  10 , Marcela M Dutra  10 , Otavio C E Gebara  11 , Ana T A Lopes  11 , Meton S Alencar Filho  12 , Jussara A Arraes  12 , Victor A Hamamoto  13   14 , Mauro E Hernandes  15 , Nicole A Golin  16 , Tiago M Santos  1   17 , Renato H N Santos  1 , Lucas P Damiani  1   18 , Fernando G Zampieri  3   18 , João Gesto  19   20 , Flávia R Machado  3   21 , Régis G Rosa  3   22 , Luciano C P Azevedo  3   23   24 , Alvaro Avezum  14 , Renato D Lopes  25   26 , Thiago M L Souza  19   27 , Otávio Berwanger  18 , Alexandre B Cavalcanti  1   3   4 ; BRICNet
Affiliations

Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial

Israel S Maia et al. Lancet Reg Health Am. 2023 Apr.

Abstract

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 SpO2 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).

Keywords: Acute respiratory failure; Antiviral; Atazanavir; COVID-19; Daclatasvir; Hypoxemia; Randomised controlled trial; SARS-CoV2; Sofosbuvir; Viral load.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Trial profile.
Fig. 2
Fig. 2
SARS-CoV2 viral loads in nasopharyngeal swabs in the modified intention to treat population at each time point and as change from baseline according to treatment group. ATV = Atazanavir, DCV = Daclatasvir, SOF + DCV = Sofosbuvir + Daclatasvir. Results of the median decrease in viral loads in each of the groups at baseline, days 3, 6, 10 (plus or minus 2). The depicted boxplots showed that there is no significant variation in viral load among groups on the same day of collection. The median decrease in viral loads between baseline and day 10 was similar in the treatment groups and placebo group.
See this image and copyright information in PMC

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