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Nebulised Dornase Alfa for Treatment of COVID-19 (COVASE)

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ClinicalTrials.gov Identifier: NCT04359654
Recruitment Status : Recruiting
First Posted : April 24, 2020
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
University College, London

Study Description
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Brief 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).

Condition or disease Intervention/treatment Phase
COVID19 Hypoxia Drug: Dornase Alfa Inhalation Solution [Pulmozyme] Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
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
Official Title: 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
Actual Study Start Date : June 16, 2020
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : November 1, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Dornase alfa treatment
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]
Nebulised Dornase alfa 2.5mg bd for 7 days
No Intervention: Best available care
Best available standard of care


Outcome Measures
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Primary Outcome Measures :
  1. Measuring the change in inflammation [ Time Frame: 7 days ]
    Analysing stabilisation of C-reactive protein


Secondary Outcome Measures :
  1. Number of patients that are alive at 28 days [ Time Frame: 28 days ]
    How many patients that are still alive

  2. Amount of days that patient requires oxygen [ Time Frame: 7 days ]
    How many days on oxygen

  3. Average oxygenation index [ Time Frame: 7 days ]
    Calculating index with Fi02, mean airways pressure and Pa02 via https://www.mdcalc.com/oxygenation-index#use-cases

  4. Days patient admitted to hospital [ Time Frame: 7 days ]
    How many days as an inpatient

  5. Percentage of patients that need mechanical ventilation [ Time Frame: 7 days ]
    How many patients require mechanical ventilation


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04359654


Contacts
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Contact: Misha Ladva 0044 20 3108 6223 misha.ladva@ucl.ac.uk
Contact: Novin Fard 0044 20 3447 7428 uclh.randd@nhs.net

Locations
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United Kingdom
University College London Hospital Recruiting
London, United Kingdom, NW1 2BU
Contact: Joanna Porter, MD PhD    0044 20 3447 9102    joanna.porter@ucl.ac.uk   
Contact: Donna Basire       d.basire@ucl.ac.uk   
Sponsors and Collaborators
University College, London
Investigators
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Principal Investigator: Joanna Porter, MD PhD University College, London
More Information
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT04359654    
Other Study ID Numbers: 132333
First Posted: April 24, 2020    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Anonymised results will be published in a scientific journal (TBC) and posted on the Breathing Matters website www.breathingatters@ucl.ac.uk

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
COVID
COVID19
Pneumonia
 Coronavirus
Hypoxia
C-Reactive Protein
Additional relevant MeSH terms:
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Hypoxia
Signs and Symptoms, Respiratory