1. Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial
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Juan Pulido, Michael Boger, John Hollingsworth, Homero Paniagua, Lucas GuimarÃes, Lisa Davidson, Victor Matheus Rolim de Souzafrom, Ana Elizabeth G. Maldonado, Colleen F. Kelley, Ricardo Diaz, Caitlin Moran, Jennifer Fulton, Ana Carolina M. Beheregaray, Valeria Telles, Khang Vo, Cameron Durrant, Omar Ahmed, Alpesh Amin, Daniel Barbaro, EstevÃo Figueiredo, David Weinrib, Noah Wald-Dickler, Daniel Wagner de Castro Lima Santos, Rebeca C. Lacerda Garcia, Brian Metzger, Paulo Ferreira, Andrew Miller, Marina Andrade Lima, Wilfred Onyia, William S Aronstein, Chrisoula Politis, Maqsood Alam, Celso Silva, Ana Maria T. Ortiz, Julia Minghini, Gualter CanÇado, Charles D. Burger, Mindy Sampson, Martin Cearras, Anne Frosch, Maysa B. Alves, Roy Poblete, Felipe Dal Pizzol, Carmen Polito, TÁcito do Nascimento JÁcome, Adilson Joaquim Westheimer Cavalcante, John Burk, Camila Anton, Eveline Pipolo Milan, Cristiane Ritter, Vincent C. Marconi, Dale Chappell, Loni Dorigo, Ricardo Albaneze, Renata Bezerra Onofre, Carlos del Rio, Miki Watanabe, Joshua Berg, Claudia R. Libertin, Janine Soares de Castro, Seife Yohannes, Juvencio José Duailibe Furtado, Linda Sher, May M. Lee, Robert Orenstein, Obinna Okoye, Linh Ngo, Jeffrey Lennox, Richard Zuckerman, Stephanie Strollo, Lakshmi Sambathkumar, Jason Sniffen, Paula Pietrobom, Kiran Gajurel, Lewis McCurdy, Matheus José Barbosa Moreira, Subarna Biswas, Valeria Cantos, Ana Caroline Iglessias, Jason Baker, Leopoldo T. Trevelin, John Gharbin, Victor Barreto Garcia, Marcelo B. Vinhas, Kleber Luz, Henrikki Antila, Fernando Carvalho Neuenschwander, Zelalem Temesgen, Cheryl McDonald, Sara Zulfigar, Michael Leonard, Fabiano Ramos, Gabrielle Chappell, William Gill, Martti Anton Antila, Anandi Sheth, Meghan Lewis, Sheetal Kandiah, Michael Bowdish, Lanny Hsieh, Paulina Rebolledo, Francini Correa, Chaitanya Mandapakala, Stuart McDonald, Natalia Bacellar, Zainab Shahid, Victoria M Catterson, Matthew Robinson, Rebeca Brugnolli, Richard Lee, Marina de A. R. Da Silva, Amay Parikh, Anup Patel, Gustavo Araujo, Andrew D. Badley, Caroline Uber Ghisi, Roberto Patron, Douglass Hutcheon, Marianna M. Lago, Christopher Polk, Nestor Quezada, Lionel Lewis, Marina Salgado Miranda, and Lydia Lam
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Placebo-controlled study ,Antibodies, Monoclonal, Humanized ,Placebo ,Double-Blind Method ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,education ,Mechanical ventilation ,education.field_of_study ,SARS-CoV-2 ,business.industry ,Hazard ratio ,COVID-19 ,Granulocyte-Macrophage Colony-Stimulating Factor ,Articles ,Middle Aged ,COVID-19 Drug Treatment ,Treatment Outcome ,Respiratory failure ,business - Abstract
Summary Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. Funding Humanigen.
- Published
- 2022
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