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Completed

NCT Number: NCT04402970

Dornase Alfa for ARDS in Patients With Severe Acute Respiratory Syndrome-Coronavirus-2 (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.

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Key information

Conditions

SARS-CoV 2 ARDS

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

University of Missouri Hospital and Clinics

Columbia, Missouri, 65212, United States

About 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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Dornase Alfa Inhalation Solution

Drug

Nebulized dornase alfa

Other names: Pulmozyme

Primary outcomes

  1. 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

Secondary outcomes

  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, at baseline prior to starting therapy and on days 1,2,3,4,5 and 14 if applicable

  2. 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

    Number of days on mechanical ventilation

  3. 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

    Number of days in the medical intensive care unit

  4. 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

    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: 28 and 90 day evaluation

    All cause mortality

Sponsors and collaborators

Lead sponsor

University of Missouri-Columbia

Other

Registry information

Official study title

Inhaled Dornase Alfa for Treatment of ARDS in Patients With SARS-CoV-2

Acronym: DORNASESARS2

Important dates

Study start
2020
Primary completion
2020
Study completion
2020
First posted
May 27, 2020
Registry last updated
Apr 14, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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