Clinical trial NCT04409925: DISmantling COvid iNduced Neutrophil ExtraCellular Traps (DISCONNECT-1)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: COVID-19 Infection
Keywords: Neutrophil Extracellular Traps
NETs
Neutrophils
rhDNase1
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: Hamilton Health Sciences Corporation
name: Hoffmann-La Roche
name: Exactis Innovation
First posted: 2020-06-01
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety of inhaled rhDNase1 in non-ventilated COVID-19 patients by reporting of adverse events
timeFrame: 9 months
Secondary outcomes:
measure: Time to first study participant enrolment
timeFrame: Up to 2 weeks
measure: Enrolment rate
timeFrame: Up to 9 months
measure: Eligible patient consent rate
timeFrame: Up to 9 months
measure: Completeness of drug delivery
timeFrame: Up to 9 months
measure: Completeness of study-specific tests or procedures
timeFrame: Up to 9 months
measure: Completeness of data collection
timeFrame: Up to 9 months
measure: Hypoxia rate
timeFrame: Up to 9 months
measure: Supplemental oxygen requirement type
timeFrame: Up to 9 months
measure: Progression to mechanical ventilation rate
timeFrame: Up to 9 months
measure: Duration of mechanical ventilation
timeFrame: Up to 9 months
measure: Radiological progression
timeFrame: Up to 9 months
measure: Renal dysfunction rate
timeFrame: Up to 9 months
measure: Renal dysfunction extent
timeFrame: Up to 9 months
measure: Secondary bacterial infections rate
timeFrame: Up to 9 months
measure: Duration of ICU admission
timeFrame: Up to 9 months
measure: Time to hospital discharge or in-hospital mortality
timeFrame: Up to 9 months
Other outcomes:
measure: Exploratory: NET quantification in blood, correlated to COVID-19 disease severity and complications.
timeFrame: Up to 9 months
measure: Exploratory: Blood clotting and fibrinolysis assays, correlated to COVID-19 disease severity and complications.
timeFrame: Up to 9 months
measure: Exploratory: Cytokine profile alterations in blood, correlated to COVID-19 disease severity and complications
timeFrame: Up to 9 months
measure: Exploratory: Neutrophil RNA sequencing in blood, correlated to COVID-19 disease severity and complications
timeFrame: Up to 9 months
measure: Length of PCR positivity
timeFrame: Up to 9 months
Locations:
city: Hamilton
country: Canada
facility: Hamilton General Hospital, Hamilton Health Sciences
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Jonathan Spicer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: