Review 1: "Anti-inflammatory Therapy with Nebulised Dornase Alfa in Patients with Severe COVID-19 Pneumonia"

Tracey Daniels

doi:doi:10.1162/2e3983f5.a9bd954f

Anti-inflammatory therapy with nebulised dornase alfa in patients with severe COVID-19 pneumonia A Randomised Clinical Trial

by Joanna C. Porter, Jamie Inshaw, Vincente Joel Solis, Emma Denneny, Rebecca Evans, Mia I. Temkin, Nathalia De Vasconcelos, Iker Valle Aramburu, Dennis Hoving, Donna Basire, Tracey Crissell, Jesusa Guinto, Alison Webb, Hanif Esmail, Victoria Johnston, Anna Last, Thomas Rampling, Bryan Williams, Aiden Flynn, Pauline T Lukey, Veronique Birault, and Venizelos Papayannopoulos

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dx.doi.org

Description

ABSTRACTBackgroundSARS-CoV2 infection causes severe, life-threatening pneumonia. Hyper-inflammation, coagulopathy and lymphopenia are associated with pathology and poor outcomes in these patients. Cell-free (cf) DNA is prominent in COVID-19 patients, amplifies inflammation and promotes coagulopathy and immune dysfunction. We hypothesized that cf-DNA clearance by nebulised dornase alfa may reduce inflammation and improve disease outcomes. Here, we evaluated the efficacy of nebulized dornase alfa in patients hospitalised with severe COVID-19 pneumonia.MethodsIn this randomised controlled single-centre phase 2 proof-of-concept trial, we recruited adult patients admitted to hospital that exhibited stable oxygen saturation (≥94%) on supplementary oxygen and a C-reactive protein (CRP) level ≥30mg/L post dexamethasone treatment. Participants were randomized at a 3:1 ratio to receive twice-daily nebulised dornase alfa in addition to best available care (BAC) or BAC alone for seven days or until hospital discharge. A 2:1 ratio of historical controls to treated individuals (HC, 2:1) were included as the primary endpoint comparators. The primary outcome was a reduction in systemic inflammation measured by blood CRP levels over 7 days post-randomisation, or to discharge if sooner. Secondary and exploratory outcomes included time to discharge, time on oxygen, D-dimer levels, lymphocyte counts and levels of circulating cf-DNA.ResultsWe screened 75 patients and enrolled 39 participants out of which 30 in dornase alfa arm, and 9 in BAC group. We also matched the recruited patients in the treated group (N=30) to historical controls in the BAC group (N=60). For the the primary outcome, 30 patients in the dornase alfa were compared to 69 patients in the BAC group. Dornase alfa treatment reduced CRP by 33% compared to the BAC group at 7-days (P=0.01). The dornase alfa group least squares mean CRP was 23.23 mg/L (95% CI 17.71 to 30.46) and the BAC group 34.82 mg/L (95% CI 28.55 to 42.47). A significant difference was also observed when only randomised participants were compared. Furthermore, compared to the BAC group, the chance of live discharge was increased by 63% in the dornase alfa group (HR 1.63, 95% CI 1.01 to 2.61, P=0.03), lymphocyte counts were improved (least-square mean: 1.08 vs 0.87, P=0.02) and markers of coagulopathy such as D-dimer were diminished (least-square mean: 570.78 vs 1656.96μg/mL, P=0.004). Moreover, the dornase alfa group exhibited lower circulating cf-DNA levels that correlated with CRP changes over the course of treatment. No differences were recorded in the rates and length of stay in the ICU or the time on oxygen between the groups. Dornase alfa was well-tolerated with no serious adverse events reported.ConclusionsIn this proof-of-concept study in patients with severe COVID-19 pneumonia, treatment with nebulised dornase alfa resulted in a significant reduction in inflammation, markers of immune pathology and time to discharge. The effectiveness of dornase alfa in patients with acute respiratory infection and inflammation should be investigated further in larger trials.

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

This is a strong phase 2 proof of concept study which I recommend to be published. The manuscript is detailed in dealing with study design, ethics and statistical analysis. It is well written and will be appealing to the target audience. There is a clear overview of the theories which drive the choice of Dornase Alfa as a therapy to study. There is also detailed theoretical background given to help the understanding of the choice of outcome measures.

The small number of existing studies assessing the use of Dornase Alfa in COVID-19 are referenced and this study clearly adds to the knowledge base in both study design and endpoints. The results are documented in a clear and detailed way. The reasoning and data for the different comparisons are given, including those demonstrating significant findings as well as those where no significant difference was seen. The outcomes detailed in the study design and the results given show completeness with the outcomes reported. Where the study wasn’t powered for a particular observation, such as mortality, this is stated. This all adds to the general feeling of transparency that this manuscript gives.

The potential place of Dornase Alfa in COVID-10 pneumonia is articulated both as an add-on therapy to existing treatments, as a virally agnostic therapy, and with the potential to administer at home. The place of this study as a phase 2 study with larger studies needed is clearly acknowledged.

At the authors discretion, some suggestions to enhance the paper are:

Cystic fibrosis is only referred to three times. For ease of reading, I’d suggest not abbreviating given that cell free also abbreviates to CF.
There is some switching between using Dornase Alfa and Pulmozyme in the introduction and safety sections which may cause some confusion in readers who are less familiar with Dornase Alfa.
Some paragraphs, particularly in the trial oversight section, are long and less readable.
I would suggest adding detail about the delivery of Dornase Alfa. As a nebulised medication the delivered dose is dependent both on the priming dose, which is described here as 2.5mg twice daily, and the delivery. A controllable aspect of delivery is the device which could be described here in terms of the compressor or flow rate and the nebuliser. Consistent and appropriate delivery will have been important to the outcomes of this study and will be important for future studies.
Airway clearance/physiotherapy has been suggested as important in optimising outcomes of Dornase Alfa and in the treatment of pneumonia. It may be helpful to describe the available airway clearance for the different groups described in this study. There is a possibility that the treatment group may have experienced less viscous sputum due to DNase treatment and this could have triggered increased airway clearance intervention under usual care. An imbalance in the airway clearance available to each group could be a potential confounder to be acknowledged, detailed and discussed.
I note that dysphonia has been recorded in the adverse events table and that this was identified as not related to Dornase Alfa. This is surprising as dysphonia is a recognised undesirable effect of Dornase Alfa. Chest pain is also seen and documented as a potential Dornase Alfa adverse event so again it is surprising to see it listed as not related. It may be helpful to detail why these particular events were defined as not related.