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).
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.
Drug: Dornase Alfa Inhalation Solution [Pulmozyme]
Nebulised Dornase alfa 2.5mg bd for 7 days
Inclusion Criteria:
1. Male and female participants, aged ≥ 18 years.
2. Participants who are hospitalised for suspected Coronavirus (SARS-CoV)-2 infection
confirmed by polymerase chain reaction (PCR) test or radiological confirmation.
3. Participants with stable oxygen saturation (>=94%) on supplementary oxygen
4. CRP >= 30 mg/L.
5. Participants will have given their written informed consent to participate in the
study and are able to comply with instructions and nebuliser.
Exclusion Criteria:
1. Females who are pregnant, planning pregnancy or breastfeeding.
2. Concurrent and/or recent involvement in other research or use of another experimental
investigational medicinal product that is likely to interfere with the study
medication within the last 3 months before study enrolment.
3. Serious condition meeting one of the following:
I. respiratory distress with respiratory rate >=40 breaths/min II. oxygen saturation
<=93% on high-flow oxygen
4. Require mechanical invasive or non-invasive ventilation at screening
5. Concurrent severe respiratory disease such as asthma, COPD and/or ILD.
6. Any major disorder that in the opinion of the Investigator would interfere with the
evaluation of the results or constitute a health risk for the study participant.
7. Terminal disease and life expectancy <12 months without COVID-19.
8. Known allergies to the dornase alfa and excipients.
9. Participants who are unable to inhale or exhale orally throughout the entire
nebulisation period.
University College London Hospital
London, United Kingdom
Joanna Porter, MD PhD, Principal Investigator
University College, London