Nebulised Dornase Alfa for Treatment of COVID-19
Condition: COVID19; Hypoxia
MeSH terms: COVID-19; Hypoxia
Study type: Interventional
Phase: Phase 2

Summary: 
      An open-label, randomised, Best-Available-Care (BAC) and historic-controlled trial of
      nebulised dornase alfa [2.5 mg BID] for 7 days in participants with COVID-19 who are admitted
      to hospital and are at risk of ventilatory failure (the COVASE study). Controls will include
      a randomised arm to receive BAC, historic data from UCLH patients with COVID-19 and biobanked
      samples will be used to demonstrate an effect of dornase alfa. CRP will be measured to assess
      the effect of dornase alfa on inflammation. Clinical endpoints and biomarkers (e.g. d-dimer)
      will be used to assess the clinical response. Exploratory endpoints will explore the effects
      of dornase alfa on features of neutrophil extracellular traps (NETs).
    

Detailed description: 
      Dornase alfa is a recombinant human DNase enzyme indicated in conjunction with standard
      therapies for the management of cystic fibrosis (CF) to improve pulmonary function. Dornase
      alfa degrades extracellular DNA, and so promotes the clearance of NETs and lead to a
      significant improvement in lung function for treated CF patients by facilitating mucus
      clearance in the lung. Dornase alfa is approved worldwide as a nebulised formulation, with an
      excellent safety profile and is well tolerated. The most common side effect is a hoarse
      voice. Moreover, dornase alfa could be administered in addition to effective antiviral
      therapy and should not interfere with antiviral drugs that could be used for COVID-19.

      By facilitating the clearance of NETs, dornase alfa not only facilitates sputum clearance in
      CF patients, but has additional anti-inflammatory activity. Dornase alfa has been shown to
      reduce NETs in the bronchoalveolar lavage (BAL) and sputum of participants with CF (Konstan
      et al 2012). In the Bronchoalveolar Lavage for the Evaluation of Anti-inflammatory Treatment
      (BEAT) study, the percentage of neutrophils in bronchoalveolar lavage fluid significantly
      increased in untreated CF patients (P<0.02) while remaining constant in the dornase
      alfa-treated group. Levels of elastase and IL-8 also significantly increased from baseline in
      the untreated group (P<0.007 and P<0.02 for elastase and IL-8, respectively), but remained
      stable in patients receiving dornase alfa (Konstan and Ratjen, J. Cyst. Fibros. 2012).

      There is scientific evidence to support the potential benefits of dornase alfa in COVID-19
      infection. Viral sepsis driven by a hyperinflammation is thought to be a major cause of
      mortality in COVID-19 infection. Interleukin-1β (IL-1β), IL-6 and TNFα are key cytokines in
      microbial sepsis. Positive outcomes with Roche's Actemra (tocilizumab), an antibody that
      blocks the pro-inflammatory cytokine interleukin-6 (IL-6), in COVID-19 treatment has led to
      several anti-inflammatory trials.

      Our hypothesis is that nebulised dornase alfa will break down the DNA backbone of NETs in the
      COVID-19 lung which will promote the degradation of pro-inflammatory extracellular histones
      and prevent the amplification of the inflammatory response and the resultant lung damage.

      Positive data will enable rapid testing into a large clinical trial in the UK and prevent ICU
      capacity issues faced today. Dornase alfa is a cost-effective drug and is currently available
      for prescription.

      We propose to test this hypothesis with this COVASE Phase IIa trial. We propose that all
      people with COVID-19 who are admitted to hospital for supplementary oxygen, who showed
      evidence of systemic inflammation but did not immediately require intubation and ventilation,
      would be eligible for nebulised dornase alfa, a safe and cost-effective treatment, twice
      daily for 7 days.
    

Intervention name(s): Dornase Alfa Inhalation Solution [Pulmozyme]
Intervention type(s): Drug
Intervention description(s): Nebulised Dornase alfa 2.5mg bd for 7 days
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: An open-label, randomised, Best-Available-Care (BAC) and historic-controlled trial of nebulised dornase alfa [2.5 mg BID] for 7 days in participants with COVID-19 who are admitted to hospital and are at risk of ventilatory failure
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: COVID; COVID19; Pneumonia; Coronavirus; Hypoxia; C-Reactive Protein