Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.

Humans Male Female Deoxyribonuclease I / administration & dosage Middle Aged Anti-Inflammatory Agents / administration & dosage COVID-19 Drug Treatment Aged COVID-19 Recombinant Proteins / administration & dosage Extracellular Traps / drug effects SARS-CoV-2 C-Reactive Protein / analysis Dexamethasone / administration & dosage Adult Nebulizers and Vaporizers Treatment Outcome Administration, Inhalation

COVID-19 DNA DNase NETs dornase alfa histone immunology inflammation medicine viruses

Journal

eLife

ISSN: 2050-084X

Titre abrégé: Elife

Pays: England

ID NLM: 101579614

Informations de publication

Date de publication:
16 Jul 2024

Historique:

medline: 16 7 2024

pubmed: 16 7 2024

entrez: 15 7 2024

Statut: epublish

Résumé

Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004). Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). NCT04359654.

Sections du résumé

Background UNASSIGNED

Methods UNASSIGNED

Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.

Results UNASSIGNED

We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).

Conclusions UNASSIGNED

Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.

Funding UNASSIGNED

LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).

Clinical trial number UNASSIGNED

NCT04359654.

Identifiants

DOI: 10.7554/eLife.87030 PMID: 39009040

pubmed: 39009040

doi: 10.7554/eLife.87030

pii: 87030

doi:

pii:

Substances chimiques

Deoxyribonuclease I EC 3.1.21.1

dornase alfa EC 3.1.21.1

Anti-Inflammatory Agents 0

Recombinant Proteins 0

C-Reactive Protein 9007-41-4

Dexamethasone 7S5I7G3JQL

Banques de données

ClinicalTrials.gov

['NCT04359654']

Types de publication

Journal Article Randomized Controlled Trial

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : LifeArc

ID : UCL-UCLH132333

Organisme : Francis Crick Institute

ID : FC0010129

Organisme : University College London

ID : Breathing Matters

Organisme : European Molecular Biology Organization

ID : ALTF 113-2019

Informations de copyright

Déclaration de conflit d'intérêts

JP, VS, ED, RE, MT, ND, IA, DH, DB, TC, JG, AW, HE, VJ, AL, TR, LL, EH, FK, BW, VB, VP No competing interests declared, JI, AF Employee of Exploristics, PL Employee of Target to Treatment Consulting Ltd