Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients
Abstract Background Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of...
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2020-03-01
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Online Access: | http://link.springer.com/article/10.1186/s13063-020-4141-6 |
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doaj-67f29c332bfc45fc9ec88c1610e37e63 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Julien Pottecher Eric Noll Marie Borel Gérard Audibert Sébastien Gette Christian Meyer Elisabeth Gaertner Vincent Legros Raphaël Carapito Béatrice Uring-Lambert Erik Sauleau Walter G. Land Seiamak Bahram Alain Meyer Bernard Geny Pierre Diemunsch |
spellingShingle |
Julien Pottecher Eric Noll Marie Borel Gérard Audibert Sébastien Gette Christian Meyer Elisabeth Gaertner Vincent Legros Raphaël Carapito Béatrice Uring-Lambert Erik Sauleau Walter G. Land Seiamak Bahram Alain Meyer Bernard Geny Pierre Diemunsch Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients Trials Acute respiratory distress syndrome Adult Hypoxaemia Multiple trauma Deoxyribonuclease I Neutrophil extracellular traps |
author_facet |
Julien Pottecher Eric Noll Marie Borel Gérard Audibert Sébastien Gette Christian Meyer Elisabeth Gaertner Vincent Legros Raphaël Carapito Béatrice Uring-Lambert Erik Sauleau Walter G. Land Seiamak Bahram Alain Meyer Bernard Geny Pierre Diemunsch |
author_sort |
Julien Pottecher |
title |
Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients |
title_short |
Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients |
title_full |
Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients |
title_fullStr |
Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients |
title_full_unstemmed |
Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients |
title_sort |
protocol for traumadornase: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients |
publisher |
BMC |
series |
Trials |
issn |
1745-6215 |
publishDate |
2020-03-01 |
description |
Abstract Background Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. Methods TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals. Discussion If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. Trial registration ClinicalTrials.gov, NCT03368092 . Registered on 11 December 2017. |
topic |
Acute respiratory distress syndrome Adult Hypoxaemia Multiple trauma Deoxyribonuclease I Neutrophil extracellular traps |
url |
http://link.springer.com/article/10.1186/s13063-020-4141-6 |
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doaj-67f29c332bfc45fc9ec88c1610e37e632020-11-25T02:35:17ZengBMCTrials1745-62152020-03-0121111310.1186/s13063-020-4141-6Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patientsJulien Pottecher0Eric Noll1Marie Borel2Gérard Audibert3Sébastien Gette4Christian Meyer5Elisabeth Gaertner6Vincent Legros7Raphaël Carapito8Béatrice Uring-Lambert9Erik Sauleau10Walter G. Land11Seiamak Bahram12Alain Meyer13Bernard Geny14Pierre Diemunsch15Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Service d’Anesthésie-Réanimation ChirurgicaleHôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Service d’Anesthésie-Réanimation ChirurgicaleSorbonne Universités, UPMC Université Paris 06, INSERM UMR_S 1158 Neurophysiologie Respiratoire Expérimentale et Clinique, AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Département d’Anesthésie RéanimationCHRU Nancy, Hôpital Central, Service d’Anesthésie-RéanimationCHR Metz-Thionville—Site de Mercy, Service de Réanimation PolyvalenteGroupe Hospitalier de la Région de Mulhouse et Sud Alsace (GHRMSA), Pôle d’Anesthésie-RéanimationHôpital Louis Pasteur, Service d’Anesthésie-Réanimation Pôle 2CHU de Reims, Hôpital Maison Blanche, Réanimation Chirurgicale et TraumatologiqueFédération Hospitalo-Universitaire OMICARE, Centre de Recherche d’Immunologie et d’HématologieFédération Hospitalo-Universitaire OMICARE, Centre de Recherche d’Immunologie et d’HématologieHôpitaux Universitaires de Strasbourg, Hôpital Civil, Pôle Santé Publique, Groupe Méthode en Recherche Clinique (GMRC)Fédération Hospitalo-Universitaire OMICARE, Centre de Recherche d’Immunologie et d’HématologieFédération Hospitalo-Universitaire OMICARE, Centre de Recherche d’Immunologie et d’HématologieUniversité de Strasbourg, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS)Université de Strasbourg, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS)Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Service d’Anesthésie-Réanimation ChirurgicaleAbstract Background Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. Methods TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals. Discussion If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. Trial registration ClinicalTrials.gov, NCT03368092 . Registered on 11 December 2017.http://link.springer.com/article/10.1186/s13063-020-4141-6Acute respiratory distress syndromeAdultHypoxaemiaMultiple traumaDeoxyribonuclease INeutrophil extracellular traps |