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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04409925
Recruitment Status : Not yet recruiting
First Posted : June 1, 2020
Last Update Posted : June 17, 2020
Sponsor:
Collaborators:
Jewish General Hospital
Hamilton Health Sciences Corporation
McGill University Health Centre/Research Institute of the McGill University Health Centre
Hoffmann-La Roche
Information provided by (Responsible Party):
Exactis Innovation

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

Condition or disease Intervention/treatment Phase
COVID-19 Infection Drug: rhDNase I Phase 1

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, and (3) 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, renal dysfunction, and time to discharge or mortality.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Pilot Study Investigating the Safety and Tolerability of Inhaled rhDNase1 and Its Impact on Neutrophil Extracellular Traps (NETs) in Non-Ventilated COVID-19 Infected Patients
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


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 Name: Pulmozyme




Primary Outcome Measures :
  1. 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, drug-related adverse events. [ Time Frame: 9 months ]

Secondary Outcome Measures :
  1. Time to first study participant enrolment [ Time Frame: Up to 2 weeks ]
    Time to first study participant enrolment is defined as the time elapsed between the study opening date and the first patient enrolment date.

  2. Enrolment rate [ Time Frame: Up to 9 months ]
    Enrolment rate is defined as the number of patients enrolled per week following the start of the study.

  3. Eligible patient consent rate [ Time Frame: Up to 9 months ]
    Eligible patient consent rate is defined as the number of patients meeting eligibility through inclusion and exclusion criteria that are consented and enrolled into the study.

  4. Completeness of drug delivery [ Time Frame: Up to 9 months ]
    The percentage of doses missed compared to completed, including reasons for missed doses, per patient.

  5. Completeness of study-specific tests or procedures [ Time Frame: Up to 9 months ]
    The percentage of tests or procedures missed compared to completed, per patient.

  6. Completeness of data collection [ Time Frame: Up to 9 months ]
    The percentage of missing data compared to completed data, per patient.

  7. Hypoxia rate [ Time Frame: Up to 9 months ]
    Extent of hypoxia rate is defined as the number of patients requiring supplemental oxygen, categorized by type of oxygen requirement.

  8. Supplemental oxygen requirement type [ Time Frame: Up to 9 months ]
    The type of oxygen in FiO2 requirements needed by each patient in the study, if applicable.

  9. Progression to mechanical ventilation rate [ Time Frame: Up to 9 months ]
    Number of patients progressing to requiring intubation and mechanical ventilation.

  10. Duration of mechanical ventilation [ Time Frame: Up to 9 months ]
    Duration in days, for patients requiring intubation and mechanical ventilation, if applicable.

  11. Radiological progression [ Time Frame: Up to 9 months ]
    Number of patients who show progression on imaging suggestive of ARDS such as bilateral lung involvement, as reviewed by study's thoracic radiologist.

  12. Renal dysfunction rate [ Time Frame: Up to 9 months ]
    Number of patients with renal dysfunction, classified by stage (1, 2 or 3).

  13. Renal dysfunction extent [ Time Frame: Up to 9 months ]
    Extent of change in creatinine from baseline.

  14. Time to hospital discharge or in-hospital mortality [ Time Frame: Up to 9 months ]
    Time to hospital discharge of in-hospital mortality is defined as the time elapsed between enrolment into the study (at admission), and endpoint (discharge or in-hospital mortality).

  15. Overall safety of health care workers and study personnel [ Time Frame: Up to 9 months ]
    Number of health care workers in direct contact with study participants and developing a COVID-19 infection.

  16. Daily safety of health care workers and study [ Time Frame: Up to 9 months ]
    Number of times per day a health care worker enters each study participant's room.


Other Outcome Measures:
  1. Exploratory: NET quantification in blood and sputum, correlated to COVID-19 disease severity and complications (hypoxia, radiological progression, renal dysfunction, and time to hospital discharge or in-hospital mortality) [ Time Frame: 9 months ]
  2. Exploratory: Blood clotting and fibrinolysis assays, correlated to COVID-19 disease severity and complications [ Time Frame: 9 months ]
  3. Exploratory: Cytokine profile alterations in blood and sputum, correlated to COVID-19 disease severity and complications [ Time Frame: 9 months ]
  4. Exploratory: Neutrophil RNA sequencing in blood and sputum, correlated to COVID-19 disease severity and complications [ Time Frame: 9 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  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. Male or female participants who are at least 18 years of age on the day of signing the informed consent
  3. COVID-19 (SARS-CoV2) positive test by nasopharyngeal swab
  4. Mild to severe respiratory illness (defined as requiring admission* and/or supplemental oxygen), not 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

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): NCT04409925


Contacts
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Contact: Aya Siblini, MSc 514-934-1934 ext 44327 aya.siblini@muhc.mcgill.ca
Contact: Caroline Huynh, MD 514-934-1934 ext 44327 caroline.huynh@mail.mcgill.ca

Sponsors and Collaborators
Exactis Innovation
Jewish General Hospital
Hamilton Health Sciences Corporation
McGill University Health Centre/Research Institute of the McGill University Health Centre
Hoffmann-La Roche
Investigators
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Principal Investigator: Jonathan Spicer, MD, PhD McGill University Health Centre/Research Institute of the McGill University Health Centre
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Responsible Party: Exactis Innovation
ClinicalTrials.gov Identifier: NCT04409925    
Other Study ID Numbers: DISCONNECT-1
First Posted: June 1, 2020    Key Record Dates
Last Update Posted: June 17, 2020
Last Verified: June 2020

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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
Keywords provided by Exactis Innovation:
Neutrophil Extracellular Traps
NETs
neutrophils
rhDNase1