Nebulised Dornase Alfa for Treatment of COVID-19

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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COVID19, Hypoxia

Intervention / Treatment
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* Drug: Dornase Alfa Inhalation Solution [Pulmozyme]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants, aged ≥ 18 years. Participants who are hospitalised for suspected Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test or radiological confirmation. Participants with stable oxygen saturation (>=94%) on supplementary oxygen CRP >= 30 mg/L. Participants will have given their written informed consent to participate in the study and are able to comply with instructions and nebuliser. Exclusion Criteria: Females who are pregnant, planning pregnancy or breastfeeding. 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. Serious condition meeting one of the following: I. respiratory distress with respiratory rate >=40 breaths/min II. oxygen saturation <=93% on high-flow oxygen Require mechanical invasive or non-invasive ventilation at screening Concurrent severe respiratory disease such as asthma, COPD and/or ILD. 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. Terminal disease and life expectancy <12 months without COVID-19. Known allergies to the dornase alfa and excipients. Participants who are unable to inhale or exhale orally throughout the entire nebulisation period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dornase alfa treatment<br>Best available care and 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 | Drug: Dornase Alfa Inhalation Solution [Pulmozyme]<br>* Nebulised Dornase alfa 2.5mg bd for 7 days<br>|
| No Intervention: Best available care<br>Best available standard of care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measuring the change in inflammation | Analysing stabilisation of C-reactive protein | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients that are alive at 28 days | How many patients that are still alive | 28 days | 
| Amount of days that patient requires oxygen | How many days on oxygen | 7 days | 
| Average oxygenation index | Calculating index with Fi02, mean airways pressure and Pa02 via https://www.mdcalc.com/oxygenation-index#use-cases | 7 days | 
| Days patient admitted to hospital | How many days as an inpatient | 7 days | 
| Percentage of patients that need mechanical ventilation | How many patients require mechanical ventilation | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxia, COVID, COVID19, Pneumonia, Coronavirus, C-Reactive Protein