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Dornase Alfa for ARDS in Patients With SARS-CoV-2 (DORNASESARS2)

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ClinicalTrials.gov Identifier: NCT04402970
Recruitment Status : Recruiting
First Posted : May 27, 2020
Last Update Posted : June 26, 2020
Sponsor:
Information provided by (Responsible Party):
Zach Holliday, University of Missouri-Columbia

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 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. JCI 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 MPO-DNA complexes and analysis of bronchoalveolar lavage samples for quantification of NETs and cell count and differential.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Single Group 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 cmH2O, targeted driving pressure < 15, neuromuscular blockade if indicated, and prone positioning based upon PaO2/FiO2 ratio < 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 : June 19, 2020
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine


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 Name: Pulmozyme

No Intervention: Standard of care
Standard of care provided for ARDS.



Primary Outcome Measures :
  1. Improvement in PaO2/FiO2 [ Time Frame: 14 days ]
    Daily evaluation of PaO2/FiO2 ratio on the day prior to starting therapy and then repeat daily for 14 days after starting therapy.


Secondary Outcome Measures :
  1. Change in static lung compliance [ Time Frame: 14 days ]
    Daily evaluation of static lung compliance, measured by change in driving pressure over volume delivered, on the day prior to starting therapy and then repeated daily for 14 days after the first dose of therapy.

  2. Duration of mechanical ventilation [ Time Frame: From date of randomization until extubation or date of death from any cause, whichever came first, assessed up to 12 months ]
    Number of days on mechanical ventilation

  3. Length of ICU stay [ Time Frame: From date of randomization until discharge/transfer out of the ICU or date of death from any cause, whichever came first, assessed up to 12 months ]
    Number of days in the medical intensive care unti

  4. Length of hospitalization [ Time Frame: From date of randomization until discharge from acute care hospital or date of death from any cause, whichever came first, assessed up to 12 months ]
    Number of days as an inpatient at the University of Missouri

  5. 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 ]
    Determination of secondary bacterial infections based upon positive culture results and clinical diagnosis by treating physician.

  6. Mortality [ Time Frame: Evaluation at 30 and 90 days ]
    All cause mortality



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age > 18 years
  • Hospitalized and mechanically ventilated for illness related to SARS-CoV-2
  • Confirmed positive SARS-CoV-2 infection by 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04402970


Contacts
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Contact: Zachary M Holliday, MD 5738829072 hollidayz@health.missouri.edu
Contact: Mohammed Alnijoumi, MD 5738822013 alnijoumim@health.missouri.edu

Locations
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United States, Missouri
University of Missouri Hospital and Clinics Recruiting
Columbia, Missouri, United States, 65212
Contact: Zach Holliday, MD    573-882-9072    hollidayz@health.missouri.edu   
Contact: Mohammed Alnijoumi, MD    5738822013    alnijoumim@health.missouri.edu   
Sponsors and Collaborators
University of Missouri-Columbia
Investigators
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Principal Investigator: Zachary M Holliday, MD University of Missouri-Columbia
Study Director: Adam Schrum, PhD University of Missouri-Columbia
Publications:
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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    Key Record Dates
Last Update Posted: June 26, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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