COVID-19 (Coronavirus Disease 2019), Hypoxia
Conditions
Keywords
COVID, COVID19, Pneumonia, Coronavirus, Hypoxia, C-Reactive Protein
Brief summary
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).
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 (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.
Interventions
Nebulised Dornase alfa 2.5mg bd for 7 days
Sponsors
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measuring the Change in Inflammation | 7 days | Analysing stabilisation of C-reactive protein. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival at 35 Days | 35 days | Survival at 35 days (28 days post last treatment day) Participants were followed up until discharge or death or a maximum of 28 days post last treatment day. |
| Discharge Before 35 Days | Before 35 days | Number of participants discharged before 35 days |
| D-dimer (ug/L) | 7 days | Change in D-dimer (ug/L) The reported LS means are antilogs of the LS means estimated on the log scale. |
| Lymphocyte Count (×109/L) | 7 days | measure of Lymphocyte count (×109/L) |
Countries
United Kingdom
Participant flow
Recruitment details
Recruited from acute COVID-19 (Coronavirus Disease 2019) wards between between May 2020-October 2021
Participants by arm
| Arm | Count |
|---|---|
| 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
Dornase Alfa Inhalation Solution \[Pulmozyme\]: Nebulised Dornase alfa 2.5mg bd for 7 days | 30 |
| Best Available Care Best available standard of care | 9 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Dornase Alfa Treatment | Best Available Care | Total |
|---|---|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 12.5 | 53.3 years STANDARD_DEVIATION 13.7 | 56.8 years STANDARD_DEVIATION 13.7 |
| Co-morbidities | 14 Participants | 6 Participants | 20 Participants |
| C-reactive protein | 101.9 mg/L STANDARD_DEVIATION 52.2 | 91.9 mg/L STANDARD_DEVIATION 68.1 | 100.2 mg/L STANDARD_DEVIATION 63.3 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 23 Participants | 7 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 30 | 0 / 9 |
| other Total, other adverse events | 16 / 30 | 4 / 9 |
| serious Total, serious adverse events | 8 / 30 | 2 / 9 |
Outcome results
Primary
Measuring the Change in Inflammation
Analysing stabilisation of C-reactive protein.
Time frame: 7 days
Population: The reported LS (least squares) means are antilogs of the LS means estimated on the log scale.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dornase Alfa Treatment | Measuring the Change in Inflammation | 23.23 mg/L |
| Best Available Care (Randomised) | Measuring the Change in Inflammation | 34.82 mg/L |
p-value: 0.01Mixed Models Analysis
Secondary
D-dimer (ug/L)
Change in D-dimer (ug/L) The reported LS means are antilogs of the LS means estimated on the log scale.
Time frame: 7 days
Population: Those that had d-dimer measured.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dornase Alfa Treatment | D-dimer (ug/L) | 570.78 (ug/L) FEU |
| Best Available Care (Randomised) | D-dimer (ug/L) | 1656.96 (ug/L) FEU |
p-value: 0.004Mixed Models Analysis
Secondary
Discharge Before 35 Days
Number of participants discharged before 35 days
Time frame: Before 35 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dornase Alfa Treatment | Discharge Before 35 Days | 27 Participants |
| Best Available Care (Randomised) | Discharge Before 35 Days | 8 Participants |
Secondary
Lymphocyte Count (×109/L)
measure of Lymphocyte count (×109/L)
Time frame: 7 days
Population: The reported LS means are antilogs of the LS means estimated on the log scale.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dornase Alfa Treatment | Lymphocyte Count (×109/L) | 1.08 ×10^9 cells/L |
| Best Available Care (Randomised) | Lymphocyte Count (×109/L) | 0.87 ×10^9 cells/L |
Comparison: The reported LS means are antilogs of the LS means estimated on the log scale.p-value: 0.021Mixed Models Analysis
Secondary
Survival at 35 Days
Survival at 35 days (28 days post last treatment day) Participants were followed up until discharge or death or a maximum of 28 days post last treatment day.
Time frame: 35 days
Population: Patients alive at 35 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dornase Alfa Treatment | Survival at 35 Days | 29 Participants |
| Best Available Care (Randomised) | Survival at 35 Days | 9 Participants |
p-value: 0.03Mixed Models Analysis