SARS-CoV 2Phase 3DORNASESARS2NCT04402970
Dornase Alfa for ARDS in Patients With Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)
A Phase 3 study testing Dornase Alfa Inhalation Solution in people with SARS-CoV 2 and ARDS, run by University of Missouri-Columbia at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- SARS-CoV 2, ARDS
- What is being tested?
- Dornase Alfa Inhalation Solution
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Jun 2020to 31 Dec 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Missouri Hospital and Clinics
Columbia, Missouri, 65212
About this study
Official title: Inhaled Dornase Alfa for Treatment of ARDS in Patients With SARS-CoV-2
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.
Read the 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.
- Conditions
- SARS-CoV 2, ARDS
- Being tested
- Dornase Alfa Inhalation Solution
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dornase Alfa Inhalation SolutionDrug
Also called Pulmozyme
Nebulized dornase alfa
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Dornase Alfa Inhalation Solution |
| Standard of care | No intervention | Standard of care provided for ARDS. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 14 days
Secondary outcomes (6)
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
Measured: 14 days
Duration of Mechanical Ventilation
Number of days on mechanical ventilation
Measured: 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
Measured: 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
Measured: 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.
Measured: From date of randomization until first positive culture or clinical diagnosis of infection if occurs, assessed up to 3 months
Mortality
All cause mortality
Measured: 28 and 90 day evaluation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2020
- Study start19 Jun 2020
- Primary completion31 Dec 2020
- Study completion31 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for SARS-CoV 2Studies of the same condition, open and under way.
- More trials run by University of Missouri-ColumbiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Missouri-Columbia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Zach Holliday, University of Missouri-Columbia
- Investigators
- Zachary M Holliday, MD, Principal investigator, University of Missouri-ColumbiaAdam Schrum, PhD, Study director, University of Missouri-Columbia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04402970
- Sponsor's protocol ID
- 2022206
- Acronym
- DORNASESARS2
- Status last verified
- Apr 2021
- First submitted
- 20 May 2020
- Last updated
- 14 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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):e20200652. doi: 10.1084/jem.20200652.
PubMed 32302401Narasaraju 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.
PubMed 21703402Zhang 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.
PubMed 32216803Earhart 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.
PubMed 32355564Zuo 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.
PubMed 32329756Holliday 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.
PubMed 34745093
Study at a glance
From the registry record, last updated by the sponsor on 14 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inhaled Dornase Alfa for Treatment of ARDS in Patients With SARS-CoV-2
- ClinicalTrials.gov ID
- NCT04402970
- Acronym / sponsor ID
- DORNASESARS2 / 2022206
- Conditions
- SARS-CoV 2, ARDS
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University of Missouri-ColumbiaUniversity, hospital or other
- Study start
- 19 Jun 2020 (actual)
- Primary completion
- 31 Dec 2020 (actual)
- Study completion
- 31 Dec 2020 (actual)
- First posted
- 27 May 2020 (actual)
- Results
- Posted 14 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Inhaled/nebulized dornase alfa | Experimental | Drug: Dornase Alfa Inhalation SolutionPatient 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dornase Alfa Inhalation SolutionAlso: PulmozymeNebulized dornase alfa | Drug | Inhaled/nebulized dornase alfa |
Primary outcome
Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2)
Time frame: 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
6 secondary outcomes
Change in Static Lung Compliance
Time frame: 14 days
Duration of 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
Length of ICU Stay
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
Length of Hospitalization
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
Secondary Bacterial Infections
Time frame: From date of randomization until first positive culture or clinical diagnosis of infection if occurs, assessed up to 3 months
Mortality
Time frame: 28 and 90 day evaluation
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 32302401Barnes 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.
- Background: PubMed 21703402Narasaraju 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.
- Background: PubMed 32216803Zhang 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.
- Background: PubMed 32355564Earhart 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.
- Background: PubMed 32329756Zuo 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.
- Derived from this study: PubMed 34745093Holliday 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Zachary M Holliday, MD principal investigator
University of Missouri-Columbia
Adam Schrum, PhD study director
University of Missouri-Columbia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Dornase Alfa Inhalation Solution in people with SARS-CoV 2 and ARDS, run by University of Missouri-Columbia at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Arterial Blood Oxygen Content to Fraction of Inspired Oxygen Ratio (PaO2/FiO2) (time frame: 14 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04402970, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Apr 2021.