DISmantling COvid iNduced Neutrophil ExtraCellular Traps (DISCONNECT-1) (DISCONNECT-1)

Phase I Pilot Study Investigating the Safety and Feasibility of Inhaled rhDNase1 and Its Impact on Neutrophil Extracellular Traps (NETs) in Non-Ventilated COVID-19 Infected Patients

This is a pilot study to investigate the safety and feasibility of rhDNase1 and its impact on neutrophil extracellular traps (NETs) in COVID-19 infected patients.

Study Overview

• Status: Completed
• Conditions: COVID-19 Infection
• Intervention / Treatment: Drug: rhDNase I

Detailed Description

It has been reported that elevated numbers of neutrophils (PMNs) in the blood predicts poor outcomes and severity in patients with COVID-19 infections. Acute inflammation results in formation of neutrophil extracellular traps (NETs) by PMNs and NK cells. Pre-clinical studies showed that NETs are critically involved in the pathophysiology of ARDS and increased capacity of PMNs to form NETs was shown to correlated with increased severity and mortality in patients with ARDS after community-acquired pneumonia. In early reports, patients with severe COVID-19 infections were also found to have radiological and clinical findings of Acute Respiratory Distress Syndrome (ARDS). NETs can be degraded by DNase1 for which there is a human recombinant equivalent rhDNase1.

This study proposes:

1. to evaluate the safety and feasibility of inhaled rhDNase1 in severely ill COVID-19 patients requiring admission;
2. to evaluate the impact of rhDNase1 in limiting progression of disease and COVID-19 related complications in these patients;
3. and to investigate NETs as possible therapeutic targets in severe COVID-19 patients by quantifying levels of circulating NETs in the blood and sputum and correlating these with oxygen requirements, need for mechanical ventilation, duration of mechanical ventilation, radiological progression of ARDS, secondary bacterial infections (pneumonia, bacteremia and other), renal dysfunction, duration of ICU admission, and time to discharge or mortality.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Aya Siblini, MSc; Phone Number: 44327 514-934-1934; Email: aya.siblini@muhc.mcgill.ca
• Study Contact Backup: Name: Caroline Huynh, MD; Phone Number: 44327 514-934-1934; Email: caroline.huynh@mail.mcgill.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital, Hamilton Health Sciences
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

1. Verbal informed consent by patient (or legal representative), done in the presence of an impartial witness. The consent is signed by the Principal Investigator (or Co-Investigator) and the impartial witness.
2. Participants who are at least 18 years of age on the day of consenting to the informed consent
3. COVID-19 (SARS-CoV2) positive test by nasopharyngeal swab
4. Admitted to the ICU in negative pressure rooms

5. Mild to severe respiratory illness (defined as requiring admission* and/or supplemental oxygen), not intubated or on mechanical ventilation at screening and enrolment.

   • Admission respiratory criteria (1 of the following):

     1. Dyspnea at rest or during minimal activity (sitting, talking, coughing, swallowing);
     2. Respiratory rate > 22/minute;
     3. PaO2 < 65mmHg or oxygen saturation < 90% or PaO2/FiO2 ratio of less than 300
     4. Infiltrate on CXR (or worsening CXR, if baseline CXR at admission was already abnormal)

   • Mild disease with hospitalization:

     • No oxygen therapy;
     • Oxygen by mask or nasal prongs.

   • Severe disease with hospitalization (requiring greater than 40% oxygen):

     • Oxygen by non-invasive ventilation or high flow oxygen/Optiflow.

Exclusion criteria:

1. Patients requiring mechanical ventilation at screening
2. Previous or current treatment with rhDNase1
3. Ongoing experimental treatment with other inhaled therapies through COVID-19-related clinical trials
4. Known hypersensitivity to NET inhibitor or recombinant protein products
5. Known hypersensitivity to Chinese Hamster Ovary cell products or any component of the product
6. Known history of immunodeficiency, HBV, HCV, HIV (Note: No HBV, HCV or HIV testing is required unless mandated by local health authority)
7. Known history of immunosuppressive disorders, such as primary/secondary immunodeficiencies, lymphoproliferative diseases
8. Active pregnancy at any stage or lactation
9. Patients deemed incapable and/or incompetent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rhDNase1 (Pulmozyme, Roche/Genentech); Single Arm: rhDNase1 (Pulmozyme, Roche/Genentech) 2.5 mg inhaled nebulisations BID, for a maximum of 14 consecutive days.	Drug: rhDNase I; Inhaled nebulisations; Other Names: Pulmozyme

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of inhaled rhDNase1 in non-ventilated COVID-19 patients by reporting of adverse events	Rate of all adverse events, rate of serious adverse events, rate of grade 3/4/5 adverse events, rate of drug-related adverse events.	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first study participant enrolment	Time elapsed between the study opening date and the first patient enrolment date.	Up to 2 weeks
Enrolment rate	Number of patients enrolled per week following the start of the study.	Up to 9 months
Eligible patient consent rate	Number of patients meeting eligibility through inclusion and exclusion criteria that are consented and enrolled into the study, as compared to the total number of patients meeting criteria (enrolled and non-enrolled).	Up to 9 months
Completeness of drug delivery	Percentage of doses missed compared to completed, including reasons for missed doses, per patient.	Up to 9 months
Completeness of study-specific tests or procedures	Percentage of tests or procedures missed compared to completed, per patient.	Up to 9 months
Completeness of data collection	Percentage of missed data compared to completed data, per patient.	Up to 9 months
Hypoxia rate	Extent of hypoxia rate is defined as the number of patients requiring supplemental oxygen, categorized by type of oxygen requirement.	Up to 9 months
Supplemental oxygen requirement type	Type of oxygen in FiO2 requirements needed by each patient in the study, if applicable.	Up to 9 months
Progression to mechanical ventilation rate	Number of patients progressing to requiring intubation and mechanical ventilation.	Up to 9 months
Duration of mechanical ventilation	Duration in days, for patients requiring intubation and mechanical ventilation, if applicable.	Up to 9 months
Radiological progression	Number of patients who show progression on imaging suggestive of ARDS such as bilateral lung involvement, as reviewed by study's thoracic radiologist.	Up to 9 months
Renal dysfunction rate	Number of patients with renal dysfunction, classified by stage (1, 2 or 3).	Up to 9 months
Renal dysfunction extent	Extent of change in creatinine from baseline.	Up to 9 months
Secondary bacterial infections rate	Number of patients contracting secondary bacterial infections (pneumonia, bacteremia and other).	Up to 9 months
Duration of ICU admission	In days, length of stay in the ICU.	Up to 9 months
Time to hospital discharge or in-hospital mortality	Time elapsed between enrolment into the study (at admission), and endpoint (discharge from ICU or in-hospital mortality).	Up to 9 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: NET quantification in blood, correlated to COVID-19 disease severity and complications.		Up to 9 months
Exploratory: Blood clotting and fibrinolysis assays, correlated to COVID-19 disease severity and complications.		Up to 9 months
Exploratory: Cytokine profile alterations in blood, correlated to COVID-19 disease severity and complications		Up to 9 months
Exploratory: Neutrophil RNA sequencing in blood, correlated to COVID-19 disease severity and complications		Up to 9 months
Length of PCR positivity	Defined as number of days between first positive PCR test and last positive PCR test, usually done by nasopharyngeal swabs. Tests will be performed as mandated by standard of care only.	Up to 9 months

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborators: Hoffmann-La Roche; Hamilton Health Sciences Corporation; Exactis Innovation
• Investigators: Principal Investigator: Jonathan Spicer, MD, PhD, McGill University Health Centre/Research Institute of the McGill University Health Centre

Study record dates

Study Major Dates

• Study Start (Actual): December 25, 2020
• Primary Completion (Actual): April 1, 2021
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: May 13, 2020
• First Submitted That Met QC Criteria: May 28, 2020
• First Posted (Actual): June 1, 2020

Study Record Updates

• Last Update Posted (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 16, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Neutrophils; NETs; Neutrophil Extracellular Traps; rhDNase1
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: DISCONNECT-1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No