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

Joint Public Review:

In this study, Porter et al report on outcomes from a small, open-label, pilot randomized clinical trial comparing dornase-alfa to the best available care in patients hospitalized with COVID-19 pneumonia. As the number of randomized participants is small, investigators describe also a contemporary cohort of controls and the study concludes about a decrease of inflammation (reflected by CRP levels) after 7 days of treatment but no other statistically significant clinical benefit.

Suggestions to the authors:
• The RCT does not follow CONSORT statement and reporting guidelines
• The authors have chosen a primary outcome that cannot be at least considered as clinically relevant or interesting. After 3 years of the pandemic with so much research, why investigate if a drug reduces CRP levels as we already have marketed drugs that provide beneficial clinical outcomes such as dexamethasone, anakinra, tocilizumab and baricitinib.
• Please provide in Methods the timeframe for the investigation of the primary endpoint
• Why day 35 was chosen for the read-out of the endpoint?
• The authors performed an RCT but in parallel chose to compare also controls. They should explain their rationale as this is not usual. I am not very enthusiastic to see mixed results like Figures 2c and 2d.
• Analysis is performed in mITT; this is a major limitation. The authors should provide at least ITT results. And they should describe in the main manuscript why they chose mITT analysis.
• It is also not usual to exclude patients from analysis because investigators just do not have serial measurements. This is lost to follow up and investigators should have pre-decided what to do with lost-to-follow-up.
• In Table 1 I would like to see all randomized patients (n=39), which is missing. There are also baseline characteristics that are missing, like which other treatments as BAT received by those patients except for dexamethasone.
• In the first paragraph of clinical outcomes, the authors refer to a cohort that is not previously introduced in the manuscript. This is confusing. And I do not understand why this analysis is performed in the context of this RCT although I understand its pilot nature.
• Propensity-score selected contemporary controls may introduce bias in favor of the primary study analysis, since controls are already adjusted for age, sex and comorbidities.
• The authors do not clearly present numerically survivors and non-survivors at day 34, even though this is one of the main secondary outcomes.
• It is unclear why another cohort (Berlin) was used to associate CRP with mortality. CRP association with mortality should (also) be performed within the current study.