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

NCT04402970 | Completed Phase 3 Results FDA Drug

• 1 other identifier: 2022206
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

SARS-CoV 2; ARDS

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (6)

• Change in Static Lung Compliance

  14 days

• 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

• 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

• 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

• Secondary Bacterial Infections

  From date of randomization until first positive culture or clinical diagnosis of infection if occurs, assessed up to 3 months

Study Arms (2)

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.

Drug: Dornase Alfa Inhalation Solution

Standard of care

NO INTERVENTION

Standard of care provided for ARDS.

Interventions

Dornase Alfa Inhalation Solution DRUG

Nebulized dornase alfa

Also known as: Pulmozyme

Inhaled/nebulized dornase alfa

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Missouri-Columbia: lead

Study Sites (1)

University of Missouri Hospital and Clinics

Columbia, Missouri, 65212, United States

Location

Related Publications (6)

• 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.

  PMID: 32302401 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.

  PMID: 21703402 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.

  PMID: 32216803 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.

  PMID: 32355564 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.

  PMID: 32329756 BACKGROUND

• 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.

  PMID: 34745093 DERIVED

MeSH Terms

Interventions

dornase alfa

Limitations and 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.

Results Point of Contact

• Title: Dr. Zach Holliday
• Organization: University of Missouri

hollidayz@health.missouri.edu

5738829072

Study Officials

• Zachary M Holliday, MD

  University of Missouri-Columbia

  PRINCIPAL INVESTIGATOR

• Adam Schrum, PhD

  University of Missouri-Columbia

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Clinical Medicine

Model Details: 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.

Study Record Dates

• First Submitted: May 20, 2020
• First Posted: May 27, 2020
• Study Start: June 19, 2020
• Primary Completion: December 31, 2020
• Study Completion: December 31, 2020
• Last Updated: April 14, 2021
• Results First Posted: April 14, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)