Nebulised Dornase Alfa for Treatment of COVID-19 (Coronavirus Disease 2019)

A Single-site, Randomised, Controlled, Parallel Design, Open-label Investigation of an Approved Nebulised Recombinant Human DNase Enzyme (Dornase Alfa) to Reduce Hyperinflammation in Hospitalised Participants With COVID-19

An open-label, randomised, Best-Available-Care (BAC) and historic-controlled trial of nebulised dornase alfa [2.5 mg BID (bis in die)] 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 University College London Hospitals NHS Foundation Trust (UCLH) patients with COVID-19 and biobanked samples will be used to demonstrate an effect of dornase alfa. C-reactive protein (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 (tumour necrosis factor alpha) 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 (United Kingdom) and prevent ICU (intensive care unit) 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 2a 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.

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 (chronic obstructive pulmonary disease) and/or ILD (interstitial lung disease).

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.