Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
Prof Alexander P J Vlaar, Martin Witzenrath, MD Pieter Van Paassen, Leo M A Heunks, Bruno Mourvillier, Endry Sanne De Bruin, Endry H T Lim, Matthijs C Brouwer, Pieter R Tuinman, José F K Saraiva, Gernot Marx, Suzana M Lobo, Rodrigo Boldo, Jesus A Simon-Campos, Alexander D Cornet, Anastasia Grebenyuk, MD Johannes M Engelbrecht, Murimisi Mukansi, Philippe G Jorens, MSc Robert Zerbib, Simon Rückinger, MD Korinna Pilz, Renfeng Guo, Prof Diederik Van De Beek, Niels C Riedemann, Prof Alexander P J Vlaar, Martin Witzenrath, MD Pieter Van Paassen, Leo M A Heunks, Bruno Mourvillier, Endry Sanne De Bruin, Endry H T Lim, Matthijs C Brouwer, Pieter R Tuinman, José Francisco K Saraiva, Gernot Marx, Suzana M Lobo, Rodrigo Boldo, Jesus A Simon-Campos, Alexander D Cornet, Anastasia Grebenyuk, MD Johannes M Engelbrecht, Murimisi Mukansi, Philippe G Jorens, MSc Robert Zerbib, Simon Rückinger, MD Korinna Pilz, Renfeng Guo, Prof Diederik Van De Beek, Niels C Riedemann, Pierre Bulpa, Fabio S Taccone, Greet Hermans, Marc Diltoer, Michael Piagnerelli, Nikolaas De Neve, Antonio T Freire, Felipe D Pizzol, Anna Karolina Marinho, Victor H Sato, Clovis Arns Da Cunha, Mathilde Neuville, Jean Dellamonica, Djillali Annane, Antoine Roquilly, Jean Luc Diehl, Francis Schneider, Jean Paul Mira, Jean Baptiste Lascarrou, Luc Desmedt, Claire Dupuis, Carole Schwebel, Guillaume Thiéry, Matthias Gründling, Marc Berger, Tobias Welte, Michael Bauer, Ulrich Jaschinski, Klaus Matschke, Roberto Mercado-Longoria, Belinda Gomez Quintana, Jorge Alberto Zamudio-Lerma, Juan Moreno Hoyos Abril, Angel Aleman Marquez, Peter Pickkers, Luuk Otterspoor, Luis Hercilla Vásquez, Carlos Rafael Seas Ramos, Alejandro Peña Villalobos, Gonzalo Gianella Malca, Victoria Chávez, Victor Filimonov, Vladimir Kulabukhov, Pinak Acharya, Sjoerd A M E G Timmermans, Matthias H Busch, Floor L F Van Baarle, Rutger Koning, Liora Ter Horst, Nora Chekrouni, Thijs M Van Soest, Marleen A Slim, Lonneke A Van Vught, Rombout B E Van Amstel, Sabine E Olie, Ingeborg E Van Zeggeren, Marcel C G Van De Poll, Claus Thielert, Dorothee Neukirchen
The Lancet Respiratory Medicine, doi:10.1016/s2213-2600(22)00297-1
Background Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. Methods This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO 2 /FiO 2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420.
Findings From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0•73, 95% CI 0•50-1•06; p=0•094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0•67, 95% CI 0•48-0•96; p=0•027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. Interpretation In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to..
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