DORNASESARS2: Dornase Alfa for ARDS in Patients With Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)

• Sponsor: University of Missouri-Columbia (Other)
• Overall Status: Completed
• CT.gov ID: NCT04402970
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 6.4
• Patients Per Site Per Month: 4.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
SARS-CoV 2; ARDS	Drug: Dornase Alfa Inhalation Solution	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• 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.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 (Participant)
• Primary Purpose: Treatment
• Official Title: Inhaled Dornase Alfa for Treatment of ARDS in Patients With SARS-CoV-2
• Actual Study Start Date: Jun 19, 2020
• Actual Primary Completion Date: Dec 31, 2020
• Actual Study Completion Date: Dec 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Dornase Alfa Inhalation Solution; Nebulized dornase alfa; Other Names: Pulmozyme
No Intervention: Standard of care Standard of care provided for ARDS.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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

4. 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

5. 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.

6. Mortality [28 and 90 day evaluation]

   All cause mortality

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Missouri Hospital and Clinics	Columbia	Missouri	United States	65212

Sponsors and Collaborators

• University of Missouri-Columbia

Investigators

• Principal Investigator: Zachary M Holliday, MD, University of Missouri-Columbia
• Study Director: Adam Schrum, PhD, University of Missouri-Columbia

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 8, 2021
• Informed Consent Form - Apr 30, 2020

More Information

Publications

• 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). pii: e20200652. doi: 10.1084/jem.20200652.
• 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.
• 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.
• 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.
• 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). pii: 138999. doi: 10.1172/jci.insight.138999.

• Responsible Party: Zach Holliday, Assistant Professor of Clinical Medicine, University of Missouri-Columbia
• ClinicalTrials.gov Identifier: NCT04402970
• Other Study ID Numbers: 2022206
• First Posted: May 27, 2020
• Last Update Posted: Apr 14, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Study Results

Participant Flow

Recruitment Details	Non-randomized 10 patients in inhaled dornase alfa arm and 20 patients in case-control (standard of care) arm

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for Acute Respiratory Distress Syndrome (ARDS)
Period Title: Overall Study
STARTED	10	20
COMPLETED	10	20
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care	Total
Arm/Group Description	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	Standard of care provided for ARDS.	Total of all reporting groups
Overall Participants	10	20	30
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	62	58	60
Sex: Female, Male (Count of Participants)
Female	4 40%	7 35%	11 36.7%
Male	6 60%	13 65%	19 63.3%
Race/Ethnicity, Customized (Count of Participants)
White, non-Hispanic	8 80%	16 80%	24 80%
Black or African American	0 0%	1 5%	1 3.3%
Hispanic or Latino	2 20%	3 15%	5 16.7%
Region of Enrollment (participants) [Number]
United States	10 100%	20 100%	30 100%
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	7 70%	11 55%	18 60%
Hypertension (Count of Participants)
Count of Participants [Participants]	9 90%	14 70%	23 76.7%
Coronary artery disease (Count of Participants)
Count of Participants [Participants]	5 50%	7 35%	12 40%
Chronic lung disease (COPD, asthma, ILD) (Count of Participants)
Count of Participants [Participants]	3 30%	7 35%	10 33.3%
Obesity (Count of Participants)
Count of Participants [Participants]	8 80%	17 85%	25 83.3%
Remdesivir (Count of Participants)
Count of Participants [Participants]	9 90%	20 100%	29 96.7%
Corticosteroids (Count of Participants)
Count of Participants [Participants]	9 90%	20 100%	29 96.7%
Antibiotics (Count of Participants)
Count of Participants [Participants]	10 100%	19 95%	29 96.7%
Convalescent Plasma (Count of Participants)
Count of Participants [Participants]	9 90%	11 55%	20 66.7%
Anticoagulation (Count of Participants)
Count of Participants [Participants]	4 40%	10 50%	14 46.7%
Paralytics (Count of Participants)
Count of Participants [Participants]	8 80%	19 95%	27 90%
Prone positioning (Count of Participants)
Count of Participants [Participants]	8 80%	16 80%	24 80%

Outcome Measures

1. Primary Outcome

Title	Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2)
Description	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

Outcome Measure Data

Analysis Population Description

Number of patients still on mechanical ventilation and who underwent arterial blood gas monitoring to determine PaO2/FiO2 ratio

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for ARDS.
Measure Participants	10	20
Day 1	10.7	21.4
Day 2	61.1	11.8
Day 3	23.5	12.5
Day 4	24.1	3.5
Day 5	37.6	5
Day 14	55	-11.2

2. Secondary Outcome

Title	Change in Static Lung Compliance
Description	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

Outcome Measure Data

Analysis Population Description

Patients on mechanical ventilation with acute respiratory distress syndrome secondary to COVID-19

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for ARDS.
Measure Participants	10	20
Day 1	3.1	-0.1
Day 2	4	-0.4
Day 3	6.3	-5.7
Day 4	4	-5.6
Day 5	7.4	-4.8
Day 14	0.8	-10.2

3. Secondary Outcome

Title	Duration of Mechanical Ventilation
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for ARDS.
Measure Participants	10	20
Mean (Full Range) [Days]	15.2	18.2

4. Secondary Outcome

Title	Length of ICU Stay
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for ARDS.
Measure Participants	10	20
Mean (Full Range) [Days]	16.5	22.1

5. Secondary Outcome

Title	Length of Hospitalization
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for ARDS.
Measure Participants	10	20
Mean (Full Range) [Days]	22.5	28.7

6. Secondary Outcome

Title	Secondary Bacterial Infections
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for ARDS.
Measure Participants	10	20
Number (95% Confidence Interval) [Percentage of participants]	30 300%	25 125%

7. Secondary Outcome

Title	Mortality
Description	All cause mortality
Time Frame	28 and 90 day evaluation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inhaled/Nebulized Dornase Alfa	Standard of Care
Arm/Group Description	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	Standard of care provided for ARDS.
Measure Participants	10	20
28 days	40 400%	45 225%
90 days	40 400%	55 275%

Adverse Events

Time Frame	Adverse event data was collected until end of hospitalization, death or up to 120 days whichever came first.
Adverse Event Reporting Description	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.
Arm/Group Title	Inhaled/Nebulized Dornase Alfa		Standard of Care
Arm/Group Description	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		Standard of care provided for ARDS.
All Cause Mortality
	Inhaled/Nebulized Dornase Alfa		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/10 (40%)		11/20 (55%)
Serious Adverse Events
	Inhaled/Nebulized Dornase Alfa		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/10 (40%)		10/20 (50%)
Infections and infestations
Bacteremia	1/10 (10%)	1	3/20 (15%)	3
Ventilator associated pneumonia	3/10 (30%)	3	5/20 (25%)	5
Respiratory, thoracic and mediastinal disorders
Venovenous extracorporeal membrane oxygenation	0/10 (0%)	0	2/20 (10%)	2
Other (Not Including Serious) Adverse Events
	Inhaled/Nebulized Dornase Alfa		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic reaction to drug	0/10 (0%)	0	0/20 (0%)	0

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.