Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19

著者: Gilmar Reis, Eduardo Augusto dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Vitoria Helena de Souza Campos, Thiago Santiago Ferreira, Castilho Vitor Quirino dos Santos, Ana Maria Ribeiro Nogueira, Ana Paula Figueiredo Guimaraes Almeida, Leonardo Cançado Monteiro Savassi, Adhemar Dias de Figueiredo Neto, Carina Bitarães, Aline Cruz Milagres, Eduardo Diniz Callegari, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, Rosemary Oliveira, Ofir Harari, Lindsay A. Wilson, Jamie I. Forrest, Hinda Ruton, Sheila Sprague, Paula McKay, Christina M. Guo, Gordon Guyatt, Craig R. Rayner, David R. Boulware, Nicole Ezer, Todd C. Lee, Emily G. McDonald, Mona Bafadhel, Christopher Butler, Josue Rodrigues Silva, Mark Dybul, Edward J. Mills, TOGETHER Investigators, Gilmar Reis, Eduardo Augusto dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Castilho Vitor Quirino dos Santos, Ana Maria Ribeiro Nogueira, Ana Paula Figueiredo Guimaraes Almeida, Adhemar Dias de Figueiredo Neto, Leonardo Cançado Monteiro Savassi, Luciene Barra Ribeiro, Maria Izabel Campos Simplicio, Thiago Santiago Ferreira, Vitoria Helena de Souza Campos, Lehana Thabane, Jamie I. Forrest, Edward J. Mills, D. William Cameron, James Orbinski, Sonal Singh, Kristian Thorlund, Jonas Häggström, Heloísa A. Costa, Nayara S. Drumont, Stephanny Kelvyn Bessa, João V.B. Vieira, Vania R Campos, Rosemary Oliveira, Lineria HM Suterio, Josue Rodrigues Silva, Adelino de Melo Freire Júnior, Ana Carolina Fialho Dias Rocha, Ana Paula de Faria Gonçalves, Andressa França, Carlos Eduardo Dias Igídio, Igor César de Oliveira Sousa, Iracema Luisa Quintino de Carvalho, Larissa Maria Manini Benavides, Patrícia de Oliveira Pereira, Phelipy Marques de Sousa, Sabrina de Almeida Lima, Silvia Helena Sousa Pietra Pedroso, Snaydia Viegas Resende, Wellington da Silva Rocha, Thamiris Caldeira Alves, Aline Lúcia de Jesus Martins, Amanda Gouvêa Mesquita, Amanda Larissa Alves Mendes, Anna Beatriz Oliveira Mendes, Anna Clara de Jesus Oliveira, Carolina Couto de Azevedo Cysne, Clara Bensemann Gontijo Pereira, Cecília Campos Siqueira, Ednilson Barbosa Dias, Emanuelle Cristina Soares Gonçalves, Fernanda Leal Guimarães, Flavio E Giorgeto, Gabriel Torga Saade Rodrigues, Gislânia Neres de Sousa, Júlia Campos de Rezende, Júlia Diniz Assis Moreira, Isabela Canabrava Soares, João Victor Barbosa Silveira, Joselaine Gomes de Souza, Juliana Marques Santos Ferreira, Kênia Sthéfhane Guimarães Gonçalves, Laura Campos Oliveira, Layane Maria de Almeida, Letícia Campos Siqueira, Letícia de Fátimas Costa, Lorena Gabrielle Miranda Maciel, Lorena Giovanna Silva Peixoto, Lorena Mesquita Alves, Luana Rosa Rodrigues, Luisa Andrade de Almeida, Marcela Luíza Amaral Resende Lara, Luíza Lanna França Reis, M. Horacio, Maria Eduarda Martins Soares, Maria Luiza Magalhães Parreiras, Mariana Campos Siqueira, Mariana Cristina Flores Mariano, Marina Guimarães Bragatto, Matheus Andrade Almeida e Silva, Mayra Estefane Silva dos Santos, Mirele Augusta Batista Ribeiro, Nayara Santos Drumond, Pedro Hosken Fernandes Guimarães, Pollyana Maria Silva Diniz, Roberta Dumont Paiva Lopes, Rosemary Oliveira, Stephanny Kelvyn Bessa, Sheila Soares Anselmo, Tainara Silva Vieira, Tatiana Aparecida Gomes da Silva, Thais Campos Siqueira, Vânia Regina Carmo, Vitor Augusto Lima do Vale, Vitor Vilaça Oliveira, Wedsley Sander Lopes dos Santos, Aline Daniele de Almeida Abreu, Bernardo Saraiva Resende de Camargos, Camila Araújo Heringer, Daniel Jacinto Mendonça Filho, Eriane Damasia Faria de Almeida Abreu, Felipe augusto Pereira Barnabé, Felipe Alves Vieira, Gabriella Fagundes Carvalho, Higor Gomes Mussi, Hilton Cardoso Arruda Macedo, Igor Bernardes Caciquinho, João Pedro Ribeiro Santos, João Ricardo Garcia Costa, José Lauro Guimarães Cardoso, Júlia Berlim de Abreu, Lorena Rodrigues de Carvalho, Lorena Amaral de Oliveira, Luana Rocha Oliveira Matos, Marcela Ferreira Brito, Mariana Cavaliere Batista e Silva, Matheus Lucca Ângelo Costa Rodrigues, Mateus de Oliveira Ferreira, Murilo Passinati Perez, Natalia Batista Zanetti, Rafaela Ribeiro de Almeida, Sarah Jeniffer da Silva Jamar, Sofia Caporalli Barbosa, Sofia Vianna von Bentzeen Rios, Stella Silva Rosa, Thomaz Takashi Ferreira Morimoto, Verônica de Araújo Libânio costa, Vitor Augusto Alves da Silva, Amanda Cypestre Alves Batista, Ana Flávia Gomes Viana, Ângela Rodrigues Vieira Santos, Anna Luiza Ribeiro Flores, Arthur Guimarães Rodrigues Dutra, Bruna Luiza Maia, Clarisse Lourdes Nadú de Almeida, Daniel Domingues Barbosa, Daniela Medeiros, D Silva, Diuly Ane Faria Rezende, Felipe Menezes Andrade, Fernanda Rúbia Batista, Gabriela Ferreira Reis, Giovane Carvalho Constantino Ferreira de Paula, Geovani de Araújo Júnior, Henrique Amaral Fonseca Pires, Jéssica Aguilar da Silva, Isabela Lovatti Rovetta, Júlia Silva Rangel, Julia Lima Soares de Paula, Juliana de Oliveira Costa, Lucas Júnio da Silva, Luis Gustavo Fernandes Dias, Lívia Francino Oliveira, Lucas Rodrigues Pereira Barros, Lucas de Souza Gontijo Pessoa, Lucas Klier Silva, Maria Luísa Lara Lanza Stabile, Mariana da Rocha Assis Pinto, Nicholas Vanzin Cunha, Paloma Álister Vilela da Silva, Rafael Silva Rodrigues Soares, Thais Gomes de Oliveira, Victor Oliveira de Araújo, Wesley Costa Arcanjo, A Vanetti, Ana Carolina Araújo Lage Santos, Ariade Gomes Freitas, Felipe Viana Santos, Fernanda Freitas Pinheiro, Fernanda Perez Rocha, Filipe Viana Santos, Giulia de Jesus Marcolino, Humberto Drumond Filho, Isabela Gontijo Mendonça, Isadora Gomides Faria, José Victor Mendes Milhomem, Larissa Milagres Mol, Letícia de Fátima Costa, Marcelo Bernardes Rocha Júnior, Maria Constancio Miranda, Nathália Euclides Gonçalves, Suzana Cristina Ricco, Thiago Araújo do Nascimento, Amanda Luiza do Espírito Santo Pinheiro, Ana Carolina Matos Ferreira, Ana Carolina Matos Ferreira, Ana Luiza Silva Taveira, Bruno Victor de Souza Lima, Débora Siqueira Diana, Emanuela Pontes Pereira Silveira, Francisca Lina Campos Gonçalves, Gabriel C. Costa, Geraldo César Barroso de Souza, Guilherme Aurelio D'Oliveira Alves, Isadora Luiza Teixeira Neto, Jordanna Porto Inácio, J. Silverio, Lara Silveira Marques, Larissa Martins do Nascimento, Larissa Oliveira Moreira, Lorena Luiza Soares de Oliveira, Lucas Eduardo Lessa Mussi, Lucas Medeiros Ruas, Luiza Nogueira Assis Barbosa, Luiz Otávio de Sousa, Marcelo Rodrigues da Costa Fernandes, Maria Eduarda Guimarães de Souza, Maria Thereza Figueiredo Bélem Calazans, Mariana Rodrigues Marinho de Bastos, Pedro Henrique Arcanjo Alvarenga, Quimberli Vassinave Cujuí, Rafaela Valadares Diniz, Rafael Cota Andrade Ferreira de Souza, Rita de Cássia Silva, Vinícius Alves Corrêa, Vinícius Carvalho de Oliveira, Vitória Aparecida Cunha, Viviane Costa Santos, Ana Paula Figueiredo Guimaraes Almeida, Ana Paula Guimarães Alves de Carvalho, Antônio Henrique Batista Jorge, Artur Pimenta Ribeiro, Elisângela Santos Sena, Cleide Rocha Veloso, Gonçalvino Eleutério Murta, Inara Maria Gomes Cardoso, João Warley Alves, Jorge Fernando Rocha Veloso, Joyce Souto Barbosa Pimenta de Figueiredo, Karolina Campos Sampaio Lopes, Larissa Vieira Souza, Loren Montanha Costa, Ludimila Pereira de Souza, Maria de Fátima César Lima, Maria Izabel Silveira Gonçalves, Marizete Gislaine Mendes, Mayra Darlliane Loiola Silva, Raissa Rocha e Fonseca, Samuel de Oliveira, Thiago Rodrigues Ferro, Aline Cruz Milagres, Ana Carolina Aguiar Estevam, Ana Martins de Oliveira, André Henrique de Sousa Oliveira, Carina Bitarães, Carla Stefany Oliveira França, Hayka K. Rodrigues Freire, Laís Aparecida dos Reis Gama, Laylla Michelle Pereira, Luciléia Alcântara Gomes e Silva, Patrícia Santana Assis, Regiane Aparecida de Andrade, Thaís de Paula Ferreira da Silva, Thiago de Alcântara César, Adriana Marcos Mendes Rabelo, Aline do Carmo Rosa, Ana Paula Vilas Boas Wherberth, André Gustavo Pinto de Souza, André Luiz Souza Gomes, Arthur Henrique Nunes Leite Oliveira, Damiana Rogai Siqueira, Emanuel Peixoto Pinto, Felipe Coelho Soares de Oliveira, Felipe Fraga Damaceno, Guilherme Rhis, Iandra Silva Almeida, Igor Barros de Araújo Borges, Igor Brandão Rocha, Jéssica Genoveva Boline Passarelli Capaz Pinto da Silva, Jorge Carlos do Amaral Júnior, José Pio Marques, Laura Lima Vargas, Lorena Cristina Ferreira Batista, Luiz Eduardo Coelho Fava, Luiza de Azevedo Freitas Giles, Marina Lacerda Marques, Maura Alina Morais Veríssimo, Neila Rodrigues Vargas de Paula, Pâmela de Sousa Dias Demuner, Ramail Santos Pouzas, Roberta Coelho de Marco, Renata Guimarães Siqueira Fernandes, Rita Lopes Mourão, Sabrina Stefany da Silva Souza, Sara Silva Ferraz, Ana Beatriz Amorim, Carolina Francisca Martins, Eduardo Diniz Callegari, Geovanna Carla Cordeiro, Huisnei Ferreira Lourenço, João Victor Fagundes dos Santos, João Veloso, Júlia Alves Santos, Júlia senra Nogueira, Jussara Carolina Assis Ribeiro Nascimento, Lavínia de Fátima Baldim Martins, Lucca Batista Rocha de Menezes, Maria Clara Damaso da Silva, Mariana das Graças de Aquino Santos, Rafael Augusto de Carvalho Leão, Solange Santos Moreira Sales, Vitor Franco Moreira, Amanda Diniz Friedmann, Bárbara Carvalho Chaves, Janaína Leyner de Andrade Oliveira, Júlia Silva Diniz, Luiz Felipe de Oliveira Braga, Luiza Gabriele Dutra Duarte, Marcela Julia Rufino Duque, M. Emiliano, Rafaela Carolina Silveira, Virgínia Mara Santos Moreira, Aline Dias Bedetti, Amanda Faria Simoni Campos, Andressa Cartaxo de Almeida, Anna Carolina Motta Costa, Clara Tornelli de Almeida Cunha, Cristiana Silva Mascarenhas, Daniel Ananias da silva, Diana Antoniazzi de Sá Ribeiro, D. Brandão, Érico Henrique Araújo de Morais, Felipe César Soares, Flávia Marcella Sena Gonçalves Borba, Karinna Guimarães Gomes, Marco Wellington Junio Estevam, Matheus Ramos Lopes, Marina Eduarda Santos, Maryane de Oliveira Silva, Nágella Samara Eleutério da Silva, Rafael Rocha Carneir, Rayane Elen Fernandes Silva, Ruan Carling Schott Wondollinger, Yuri Barbosa de Menezes, Bárbara Ellen Souza Rezende, Catarina Giovanna Simões Costa, Gabriel Antônio Simões Costa, Gabriel Marcos theodoro Cardoso, Graziela Cesar de Sousa, Graziele Aparecida Silva, Isabela Cristina de Oliveira Campos, Lara Silva Souza, Laura Nacife Rabello, Roberta Ellen Santos Oliveira, Bárbara Nogueira Roberti, Bruno Reis Garcia, Bruno Rocha Gelape, Carina Daniela Lira Moreira Figueiredo, João Vitor Rocha Cachoeira, Júlia Romano Ferreira Santos, Sarah de Resende Silva, Thalita Oliva Rios, Túlio Fonseca e Silva Quadros, Bethany Barber, Camelia Capraru, Camille Lemieux, Daniel Li, David Smookler, Joshua Booth, Magdalena Kuczynski, Maria Kristina Marquez, Seham Noureldin, S Jeganathan, Tharmegan Tharmaratnam, Wesam Aleyadeh, Jeff Powis, Maureen Taylor, Adrienne K. Chan, Elsa Salvant, Christopher J Graham, Marc Dagher, William Parreira Duarte, Duílio de Castro, Flávio Pimenta Silveira, Alber Alípio Ribeiro, Vittorio Medioli, Augusto Viana da Rocha, Hilton Soares de Oliveira, Tânia Maria de Resende Amaral, Christiano Augusto Xavier Pereira, Nádia Cristina Dias Duarte Tomé, João Marcelo Diegues Pereira, Diogo Jonata Ribeiro, Humberto Guimarães Souto, Dulce Pimenta Gonçalves, A. Barcelos, André Luiz Coelho Merlo, Edna Gomes Leite, Caroline Martins Sangali, Angelo Oswaldo de Araujo Santos, Glauciane Resende do Nascimento - Annals of Internal Medicine 2023 被引用: 36

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.