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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Inhaled/nebulized dornase alfa | Experimental | 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. |
|
| Standard of care | No Intervention | Standard of care provided for ARDS. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dornase Alfa Inhalation Solution | Drug | Nebulized dornase alfa |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Zachary M Holliday, MD | University of Missouri-Columbia | Principal Investigator |
| Adam Schrum, PhD | University of Missouri-Columbia | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Missouri Hospital and Clinics | Columbia | Missouri | 65212 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32302401 | Background | Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Crawford JM, Dassler-Plenker J, Guerci P, Huynh C, Knight JS, Loda M, Looney MR, McAllister F, Rayes R, Renaud S, Rousseau S, Salvatore S, Schwartz RE, Spicer JD, Yost CC, Weber A, Zuo Y, Egeblad M. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med. 2020 Jun 1;217(6):e20200652. doi: 10.1084/jem.20200652. | |
| 21703402 |
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Non-randomized 10 patients in inhaled dornase alfa arm and 20 patients in case-control (standard of care) arm
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | Standard of Care | Standard of care provided for Acute Respiratory Distress Syndrome (ARDS) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Standard of Care |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Number of patients still on mechanical ventilation and who underwent arterial blood gas monitoring to determine PaO2/FiO2 ratio | Posted | Mean | 95% Confidence Interval | mmHg | 14 days |
|
Adverse event data was collected until end of hospitalization, death or up to 120 days whichever came first.
Secondary pulmonary infections after the start of mechanical ventilation was the main adverse event data collected. Additional adverse events collected included development of blood stream infections or escalation of oxygenation support by need of extracorporeal membrane oxygenation therapy.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bacteremia | Infections and infestations | SNOMED CT | Systematic Assessment | Development of blood stream infection after the start of mechanical ventilation |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Allergic reaction to drug | Respiratory, thoracic and mediastinal disorders | SNOMED CT | Systematic Assessment | Adverse reaction to inhaled dornase alfa including allergic reaction or acute need for escalation of oxygen therapy |
Study was performed in non-randomized trial as there were initial concerns for low recruitment and difficulty with randomization. Study was also not powered for most secondary outcome analyses as it was designed in a pilot/feasibility status to determine drug effects.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Zach Holliday | University of Missouri | 5738829072 | hollidayz@health.missouri.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 8, 2021 | Mar 17, 2021 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 30, 2020 | Apr 12, 2021 | ICF_004.pdf |
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| ID | Term |
|---|---|
| C568813 | dornase alfa |
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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.
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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 |
| Background |
| Narasaraju T, Yang E, Samy RP, Ng HH, Poh WP, Liew AA, Phoon MC, van Rooijen N, Chow VT. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am J Pathol. 2011 Jul;179(1):199-210. doi: 10.1016/j.ajpath.2011.03.013. Epub 2011 May 7. |
| 32216803 | Background | Zhang G, Zhang J, Wang B, Zhu X, Wang Q, Qiu S. Analysis of clinical characteristics and laboratory findings of 95 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a retrospective analysis. Respir Res. 2020 Mar 26;21(1):74. doi: 10.1186/s12931-020-01338-8. |
| 32355564 | Background | Earhart AP, Holliday ZM, Hofmann HV, Schrum AG. Consideration of dornase alfa for the treatment of severe COVID-19 acute respiratory distress syndrome. New Microbes New Infect. 2020 Apr 30;35:100689. doi: 10.1016/j.nmni.2020.100689. eCollection 2020 May. |
| 32329756 | Background | Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, Blair C, Weber A, Barnes BJ, Egeblad M, Woods RJ, Kanthi Y, Knight JS. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020 Jun 4;5(11):e138999. doi: 10.1172/jci.insight.138999. |
| 34745093 | Derived | Holliday ZM, Earhart AP, Alnijoumi MM, Krvavac A, Allen LH, Schrum AG. Non-Randomized Trial of Dornase Alfa for Acute Respiratory Distress Syndrome Secondary to Covid-19. Front Immunol. 2021 Oct 20;12:714833. doi: 10.3389/fimmu.2021.714833. eCollection 2021. |
Standard of care provided for ARDS. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Diabetes mellitus | Count of Participants | Participants |
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| Hypertension | Count of Participants | Participants |
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| Coronary artery disease | Count of Participants | Participants |
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| Chronic lung disease (COPD, asthma, ILD) | Count of Participants | Participants |
|
| Obesity | Count of Participants | Participants |
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| Remdesivir | Received Remdesivir as therapy for Coronavirus disease 2019 (COVID-19) | Count of Participants | Participants |
|
| Corticosteroids | Received oral or intravenous corticosteroids as therapy for COVID-19 | Count of Participants | Participants |
|
| Antibiotics | Received oral or intravenous antibiotics during hospital admission | Count of Participants | Participants |
|
| Convalescent Plasma | Received Convalescent Plasma therapy for COVID-19 | Count of Participants | Participants |
|
| Anticoagulation | Received therapeutic dosing of anticoagulation during hospital admission | Count of Participants | Participants |
|
| Paralytics | Received paralytics during hospital admission | Count of Participants | Participants |
|
| Prone positioning | Treatment included prone positioning during hospital admission | Count of Participants | Participants |
|
Standard of care provided for ARDS.
|
|
| 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 | Patients on mechanical ventilation with acute respiratory distress syndrome secondary to COVID-19 | Posted | Mean | 95% Confidence Interval | mL/cmH20 | 14 days |
|
|
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| Secondary | Duration of Mechanical Ventilation | Number of days on mechanical ventilation | Posted | Mean | Full Range | Days | From start of mechanical ventilation until extubation or date of death from any cause, whichever came first, assessed up to 6 months |
|
|
|
| Secondary | Length of ICU Stay | Number of days in the medical intensive care unit | Posted | Mean | Full Range | Days | 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 |
|
|
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| Secondary | Length of Hospitalization | Number of days as an inpatient at the University of Missouri | Posted | Mean | Full Range | Days | 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 |
|
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| Secondary | Secondary Bacterial Infections | Determination of secondary bacterial infections based upon positive culture results and clinical diagnosis by treating physician. | Posted | Number | 95% Confidence Interval | Percentage of participants | From date of randomization until first positive culture or clinical diagnosis of infection if occurs, assessed up to 3 months |
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| Secondary | Mortality | All cause mortality | Posted | Number | 95% Confidence Interval | Percentage of participants | 28 and 90 day evaluation |
|
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| 4 |
| 10 |
| 4 |
| 10 |
| 0 |
| 10 |
| EG001 | Standard of Care | Standard of care provided for ARDS. | 11 | 20 | 10 | 20 | 0 | 20 |
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| Ventilator associated pneumonia | Infections and infestations | SNOMED CT | Systematic Assessment | Development of ventilator associated pneumonia as determined by treating clinical physician |
|
| Venovenous extracorporeal membrane oxygenation | Respiratory, thoracic and mediastinal disorders | SNOMED CT | Systematic Assessment | Need for escalation of respiratory support to venovenous extracorporeal membrane oxygenation support |
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| Day 5 |
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| Day 14 |
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