ARDS, SARS-CoV 2
Conditions
Brief summary
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
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.
Interventions
DRUGDornase Alfa Inhalation Solution
Nebulized dornase alfa
Sponsors
University of Missouri-Columbia
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | 14 days | Daily evaluation of PaO2/FiO2 ratio at baseline prior to starting therapy and on days 1,2,3,4,5 and 14 if applicable |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Mechanical Ventilation | From start of mechanical ventilation until extubation or date of death from any cause, whichever came first, assessed up to 6 months | Number of days on mechanical ventilation |
| Length of ICU Stay | 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 | Number of days in the medical intensive care unit |
| Change in Static Lung Compliance | 14 days | 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 |
| Secondary Bacterial Infections | From date of randomization until first positive culture or clinical diagnosis of infection if occurs, assessed up to 3 months | Determination of secondary bacterial infections based upon positive culture results and clinical diagnosis by treating physician. |
| Mortality | 28 and 90 day evaluation | All cause mortality |
| Length of Hospitalization | 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 | Number of days as an inpatient at the University of Missouri |
Countries
United States
Participant flow
Recruitment details
Non-randomized 10 patients in inhaled dornase alfa arm and 20 patients in case-control (standard of care) arm
Participants by arm
| Arm | Count |
|---|---|
| Inhaled/Nebulized Dornase Alfa 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.
Dornase Alfa Inhalation Solution: Nebulized dornase alfa | 10 |
| Standard of Care Standard of care provided for ARDS. | 20 |
| Total | 30 |
Baseline characteristics
| Characteristic | Standard of Care | Total | Inhaled/Nebulized Dornase Alfa |
|---|---|---|---|
| Age, Continuous | 58 years | 60 years | 62 years |
| Antibiotics | 19 Participants | 29 Participants | 10 Participants |
| Anticoagulation | 10 Participants | 14 Participants | 4 Participants |
| Chronic lung disease (COPD, asthma, ILD) | 7 Participants | 10 Participants | 3 Participants |
| Convalescent Plasma | 11 Participants | 20 Participants | 9 Participants |
| Coronary artery disease | 7 Participants | 12 Participants | 5 Participants |
| Corticosteroids | 20 Participants | 29 Participants | 9 Participants |
| Diabetes mellitus | 11 Participants | 18 Participants | 7 Participants |
| Hypertension | 14 Participants | 23 Participants | 9 Participants |
| Obesity | 17 Participants | 25 Participants | 8 Participants |
| Paralytics | 19 Participants | 27 Participants | 8 Participants |
| Prone positioning | 16 Participants | 24 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized White, non-Hispanic | 16 Participants | 24 Participants | 8 Participants |
| Region of Enrollment United States | 20 participants | 30 participants | 10 participants |
| Remdesivir | 20 Participants | 29 Participants | 9 Participants |
| Sex: Female, Male Female | 7 Participants | 11 Participants | 4 Participants |
| Sex: Female, Male Male | 13 Participants | 19 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 10 | 11 / 20 |
| other Total, other adverse events | 0 / 10 | 0 / 20 |
| serious Total, serious adverse events | 4 / 10 | 10 / 20 |
Outcome results
Primary
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
Time frame: 14 days
Population: Number of patients still on mechanical ventilation and who underwent arterial blood gas monitoring to determine PaO2/FiO2 ratio
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Inhaled/Nebulized Dornase Alfa | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 1 | 10.7 mmHg |
| Inhaled/Nebulized Dornase Alfa | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 2 | 61.1 mmHg |
| Inhaled/Nebulized Dornase Alfa | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 3 | 23.5 mmHg |
| Inhaled/Nebulized Dornase Alfa | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 4 | 24.1 mmHg |
| Inhaled/Nebulized Dornase Alfa | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 5 | 37.6 mmHg |
| Inhaled/Nebulized Dornase Alfa | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 14 | 55 mmHg |
| Standard of Care | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 5 | 5 mmHg |
| Standard of Care | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 1 | 21.4 mmHg |
| Standard of Care | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 4 | 3.5 mmHg |
| Standard of Care | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 2 | 11.8 mmHg |
| Standard of Care | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 14 | -11.2 mmHg |
| Standard of Care | Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) | Day 3 | 12.5 mmHg |
Secondary
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
Time frame: 14 days
Population: Patients on mechanical ventilation with acute respiratory distress syndrome secondary to COVID-19
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Inhaled/Nebulized Dornase Alfa | Change in Static Lung Compliance | Day 14 | 0.8 mL/cmH20 |
| Inhaled/Nebulized Dornase Alfa | Change in Static Lung Compliance | Day 1 | 3.1 mL/cmH20 |
| Inhaled/Nebulized Dornase Alfa | Change in Static Lung Compliance | Day 2 | 4 mL/cmH20 |
| Inhaled/Nebulized Dornase Alfa | Change in Static Lung Compliance | Day 3 | 6.3 mL/cmH20 |
| Inhaled/Nebulized Dornase Alfa | Change in Static Lung Compliance | Day 4 | 4 mL/cmH20 |
| Inhaled/Nebulized Dornase Alfa | Change in Static Lung Compliance | Day 5 | 7.4 mL/cmH20 |
| Standard of Care | Change in Static Lung Compliance | Day 4 | -5.6 mL/cmH20 |
| Standard of Care | Change in Static Lung Compliance | Day 14 | -10.2 mL/cmH20 |
| Standard of Care | Change in Static Lung Compliance | Day 3 | -5.7 mL/cmH20 |
| Standard of Care | Change in Static Lung Compliance | Day 1 | -0.1 mL/cmH20 |
| Standard of Care | Change in Static Lung Compliance | Day 5 | -4.8 mL/cmH20 |
| Standard of Care | Change in Static Lung Compliance | Day 2 | -0.4 mL/cmH20 |
Secondary
Duration of Mechanical Ventilation
Number of days on mechanical ventilation
Time frame: From start of mechanical ventilation until extubation or date of death from any cause, whichever came first, assessed up to 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inhaled/Nebulized Dornase Alfa | Duration of Mechanical Ventilation | 15.2 Days |
| Standard of Care | Duration of Mechanical Ventilation | 18.2 Days |
Secondary
Length of Hospitalization
Number of days as an inpatient at the University of Missouri
Time frame: 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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inhaled/Nebulized Dornase Alfa | Length of Hospitalization | 22.5 Days |
| Standard of Care | Length of Hospitalization | 28.7 Days |
Secondary
Length of ICU Stay
Number of days in the medical intensive care unit
Time frame: 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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inhaled/Nebulized Dornase Alfa | Length of ICU Stay | 16.5 Days |
| Standard of Care | Length of ICU Stay | 22.1 Days |
Secondary
Mortality
All cause mortality
Time frame: 28 and 90 day evaluation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inhaled/Nebulized Dornase Alfa | Mortality | 28 days | 40 Percentage of participants |
| Inhaled/Nebulized Dornase Alfa | Mortality | 90 days | 40 Percentage of participants |
| Standard of Care | Mortality | 28 days | 45 Percentage of participants |
| Standard of Care | Mortality | 90 days | 55 Percentage of participants |
Secondary
Secondary Bacterial Infections
Determination of secondary bacterial infections based upon positive culture results and clinical diagnosis by treating physician.
Time frame: From date of randomization until first positive culture or clinical diagnosis of infection if occurs, assessed up to 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inhaled/Nebulized Dornase Alfa | Secondary Bacterial Infections | 30 Percentage of participants |
| Standard of Care | Secondary Bacterial Infections | 25 Percentage of participants |