Dornase Alfa for ARDS in Patients With Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)

Study Overview
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Brief Summary
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This study is designed to evaluate a potential mechanism by which a hyperactive immune response may contribute to death from SARS-CoV-2; by an excessive neutrophil-mediated deposition of cell-free DNA in neutrophil extracellular traps (NET). Excessive amounts of NETs can increase rigidity of mucus, clog airways, and be agents for the development of acute respiratory distress (Narasaraju et al., Am J Pathol. 2011). Many aspects of this pathway have been observed in severe SARS-CoV-2 (Zhang et al., Respiratory research. 2020). Dornase alfa (DNAse I; Pulmozyme (Genentech) is a nebulized drug that works by degrading cell-free DNA and thus promoting airway clearance and recovery. The investigators hypothesize that by thinning mucus and degrading these NETs further lung damage may be prevented and a reduction in time to recovery may occur. The two aims of the study are to see if inhaled/nebulized dornase alfa will improve clinical outcome measures in SARS-CoV-2 related acute respiratory distress syndrome (ARDS) and to see if dornase alfa reduces the amount of bronchoalveolar lavage and blood markers of NET activity. The study will recruit patients who are on mechanical ventilation for respiratory failure related to SARS-CoV-2 positive infection and have ARDS based upon Berlin criteria. The investigators aim to recruit 10-20 patients for this study.

Detailed Description
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Severe cases of SARS-CoV-2 infection have shown an inflammatory neutrophil and mucus-mediated airway exclusion pathway similar to previously described acute respiratory distress syndrome (ARDS) in other viral syndromes (Narasaraju et al., Am J Pathol. 2011). Lung neutrophilia in ARDS is related to significant neutrophil extracellular trap (NET) production and formation. Thus, NET production is likely contributing to the severe lung pathology in SARS-CoV-2 (Yu Zuo et al. Journal of Clinical Investigation Insight. 2020). Recent connections have been made between NET formation in SARS-CoV-2 patients and excessive thrombosis and the development of cytokine storm further warranting evaluation as a potential site for consideration of treatment (Barnes, Betsy et al. J exp Med. 2020). Dornase alfa (Pulmozyme) is a recombinant human deoxyribonuclease I, that acts as a mucolytic by cleaving extracellular chromosomal DNA from NETs and other cell-free DNA. Unknown are the effects of dornase alfa therapy on SARS-CoV-2 related ARDS and if therapy with dornase alfa truly reduces the amount of NETs in the severely damaged lungs. This study is a non-randomized, single-center, open-label clinical trial to evaluate the potential benefit and cellular mechanism of nebulized dornase alfa administration in mechanically ventilated patients with SARS-CoV-2 related ARDS. Evaluation of dornase alfa effects at a cellular level will be measured by analysis of blood samples before and after the 3 days of therapy for cell-free DNA, quantification of citrullinated histone H3, quantification of Myeloperoxidase-DNA complexes and analysis of bronchoalveolar lavage samples for quantification of NETs and cell count and differential.

Official Title
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Inhaled Dornase Alfa for Treatment of ARDS in Patients With SARS-CoV-2

Conditions
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SARS-CoV 2, ARDS

Intervention / Treatment
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* Drug: Dornase Alfa Inhalation Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Hospitalized and mechanically ventilated for illness related to SARS-CoV-2 Confirmed positive SARS-CoV-2 infection by Polymerase chain reaction (PCR) individual or surrogate ability to sign informed consent negative, urine-based pregnancy test in females Exclusion Criteria: contraindication or intolerance to dornase alfa mechanical ventilation expected to be less than 48 hours life expectancy less than 24 hours based upon judgement of treating physician pregnant inability to obtain informed consent

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Nebulized dornase alfa will be administered through the ventilator circuit at a dose of 2.5 mg, 12 hours apart, for 3 consecutive days. Patients will also receive lung protective ventilation (VC 6-8 ml/kg predicted body weight), plateau pressure < 30 centimeters of water pressure (cmH2O), targeted driving pressure < 15, neuromuscular blockade if indicated, and prone positioning based upon arterial blood content to fraction of inspired oxygen ratio (PaO2/FiO2) < 150 or upon treating physician decision; along with all other ICU care based upon best practice standards and evidence based medicine.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled/nebulized dornase alfa<br>Patient to receive inhaled/nebulized dornase alfa (Pulmozyme) 2.5 mg twice daily in the ventilator circuit for 3 days, along with standard of care for ARDS. | Drug: Dornase Alfa Inhalation Solution<br>* Nebulized dornase alfa<br>* Other names: Pulmozyme;|
| No Intervention: Standard of care<br>Standard of care provided for ARDS. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Daily evaluation of PaO2/FiO2 ratio at baseline prior to starting therapy and on days 1,2,3,4,5 and 14 if applicable | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Static Lung Compliance | Daily evaluation of static lung compliance, measured by change in driving pressure over volume delivered, at baseline prior to starting therapy and on days 1,2,3,4,5 and 14 if applicable | 14 days | 
| Duration of Mechanical Ventilation | Number of days on mechanical ventilation | From start of mechanical ventilation until extubation or date of death from any cause, whichever came first, assessed up to 6 months | 
| Length of ICU Stay | Number of days in the medical intensive care unit | From date of first admission to intensive care unit until discharge/transfer out of the ICU or date of death from any cause, whichever came first, assessed up to 6 months | 
| Length of Hospitalization | Number of days as an inpatient at the University of Missouri | From date of hospital admission until discharge from acute care hospital or date of death from any cause, whichever came first, assessed up to 6 months | 
| Secondary Bacterial Infections | Determination of secondary bacterial infections based upon positive culture results and clinical diagnosis by treating physician. | From date of randomization until first positive culture or clinical diagnosis of infection if occurs, assessed up to 3 months | 
| Mortality | All cause mortality | 28 and 90 day evaluation |