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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
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. METHO...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Ltd.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451499/ https://www.ncbi.nlm.nih.gov/pubmed/36087611 http://dx.doi.org/10.1016/S2213-2600(22)00297-1 |
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author | Vlaar, Alexander P J Witzenrath, Martin van Paassen, Pieter Heunks, Leo M A Mourvillier, Bruno de Bruin, Sanne Lim, Endry H T Brouwer, Matthijs C Tuinman, Pieter R Saraiva, José F K Marx, Gernot Lobo, Suzana M Boldo, Rodrigo Simon-Campos, Jesus A Cornet, Alexander D Grebenyuk, Anastasia Engelbrecht, Johannes M Mukansi, Murimisi Jorens, Philippe G Zerbib, Robert Rückinger, Simon Pilz, Korinna Guo, Renfeng van de Beek, Diederik Riedemann, Niels C |
author_facet | Vlaar, Alexander P J Witzenrath, Martin van Paassen, Pieter Heunks, Leo M A Mourvillier, Bruno de Bruin, Sanne Lim, Endry H T Brouwer, Matthijs C Tuinman, Pieter R Saraiva, José F K Marx, Gernot Lobo, Suzana M Boldo, Rodrigo Simon-Campos, Jesus A Cornet, Alexander D Grebenyuk, Anastasia Engelbrecht, Johannes M Mukansi, Murimisi Jorens, Philippe G Zerbib, Robert Rückinger, Simon Pilz, Korinna Guo, Renfeng van de Beek, Diederik Riedemann, Niels C |
author_sort | Vlaar, Alexander P J |
collection | PubMed |
description | 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 a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government. |
format | Online Article Text |
id | pubmed-9451499 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94514992022-09-07 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 Vlaar, Alexander P J Witzenrath, Martin van Paassen, Pieter Heunks, Leo M A Mourvillier, Bruno de Bruin, Sanne Lim, Endry H T Brouwer, Matthijs C Tuinman, Pieter R Saraiva, José F K Marx, Gernot Lobo, Suzana M Boldo, Rodrigo Simon-Campos, Jesus A Cornet, Alexander D Grebenyuk, Anastasia Engelbrecht, Johannes M Mukansi, Murimisi Jorens, Philippe G Zerbib, Robert Rückinger, Simon Pilz, Korinna Guo, Renfeng van de Beek, Diederik Riedemann, Niels C Lancet Respir Med Articles 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 a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government. Elsevier Ltd. 2022-12 2022-09-07 /pmc/articles/PMC9451499/ /pubmed/36087611 http://dx.doi.org/10.1016/S2213-2600(22)00297-1 Text en © 2022 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Articles Vlaar, Alexander P J Witzenrath, Martin van Paassen, Pieter Heunks, Leo M A Mourvillier, Bruno de Bruin, Sanne Lim, Endry H T Brouwer, Matthijs C Tuinman, Pieter R Saraiva, José F K Marx, Gernot Lobo, Suzana M Boldo, Rodrigo Simon-Campos, Jesus A Cornet, Alexander D Grebenyuk, Anastasia Engelbrecht, Johannes M Mukansi, Murimisi Jorens, Philippe G Zerbib, Robert Rückinger, Simon Pilz, Korinna Guo, Renfeng van de Beek, Diederik Riedemann, Niels C 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451499/ https://www.ncbi.nlm.nih.gov/pubmed/36087611 http://dx.doi.org/10.1016/S2213-2600(22)00297-1 |
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