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Nebulised Heparin to Reduce COVID-19 Induced Acute Lung Injury (CHARTER-Irl)

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ClinicalTrials.gov Identifier: NCT04511923
Recruitment Status : Recruiting
First Posted : August 13, 2020
Last Update Posted : February 10, 2021
Sponsor:
Information provided by (Responsible Party):
John Laffey, University College Hospital Galway

Brief Summary:
The investigators present a randomised open label phase Ib/IIa trial of nebulised unfractionated heparin to evaluate the effect of nebulised unfractionated heparin on the procoagulant response in ICU patients with SARS-CoV-2 requiring advanced respiratory support. As this is one of the first studies of nebulised heparin in COVID 19 lung disease the investigators will assess safety as a co-primary outcome.

Condition or disease Intervention/treatment Phase
Covid19 ARDS, Human Lung Injury, Acute Ventilation Perfusion Mismatch Drug: Nebulised heparin Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Can Nebulised HepArin Reduce acuTE Lung Injury in Patients With SARS-CoV-2 Requiring Respiratory Support in Ireland
Actual Study Start Date : December 23, 2020
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : January 2022


Arm Intervention/treatment
No Intervention: Standard Care
Standard care
Experimental: Heparin
Standard care plus nebulised unfractionated heparin 25000 units every 6 hours for 10 days
Drug: Nebulised heparin
Nebulised unfractionated heparin 25000 units administered 6 hourly for 10 days




Primary Outcome Measures :
  1. D-dimer profile [ Time Frame: Up to day 10. ]
    Effect of nebulised heparin on d-dimer profile, assessed via d-dimer AUC and via a mixed effects model, with data collected on days 1, 3, 5 and 10.

  2. Frequenccy of Severe Adverse Outcomes [ Time Frame: Up to day 60 ]
    Safety of nebulised heparin delivered by aerogen solo nebuliser in patients with COVID-19 induced severe respiratory failure, as measured by the incidence of severe adverse events.


Secondary Outcome Measures :
  1. Oxygenation Index [ Time Frame: Up to day 10 ]
    Determine the impact of nebulised heparin on oxygenation index

  2. Indices of Inflammation [ Time Frame: Up to day 10 ]
    Effect of nebulised heparin on indices of inflammation (Interleukin (IL)-1β, IL-6, IL-8, IL-10 and soluble TNF receptor 1 (sTNFR1), C-reactive protein, procalcitonin, Ferritin,) will be assessed (AUC on days 1, 3, 5 and 10)

  3. Ratios of Indices of Inflammation [ Time Frame: Up to day 10 ]
    Effect of nebulised heparin on the ratios of IL-1β/IL-10 and IL-6/IL-10 will also be assessed.

  4. Indices of Coagulation [ Time Frame: Up to day 10 ]
    Effect of nebulised heparin on other indices of coagulation (Fibrinogen; lactate dehydrogenase) will be assessed (AUC on days 1, 3, 5 and 10).

  5. Quasi-Static Lung Compliance [ Time Frame: Up to day 10 ]
    Determine the effect of nebulised heparin on Quasi-Static Lung Compliance (i.e. tidal volume/(Plateau pressure-PEEP) measured on days 1,3,5,10.

  6. Time to separation from advanced respiratory support [ Time Frame: Up to day 28 ]
    Time to separation from advanced respiratory support, where non survivors are treated as though not separated from advanced respiratory support.

  7. Number treated with neuromuscular blockers [ Time Frame: Up to day 10 ]
    Number treated with neuromuscular blockers instituted after enrolment

  8. Number treated with Prone positioning [ Time Frame: Up to day 10 ]
    Number treated with prone positioning instituted after enrolment

  9. Number treated with extra-corporeal membrane oxygenation [ Time Frame: Up to day 10 ]
    Number treated with extra-corporeal membrane oxygenation instituted after enrolment

  10. Number requiring Tracheostomy [ Time Frame: Up to day 28 ]
    Number tracheotomised

  11. Time to separation from invasive ventilation among survivors [ Time Frame: Up to day 28 ]
    Time to separation from invasive ventilation among survivors

  12. Discharge to ward [ Time Frame: Up to day 28 ]
    Time to separation from the ICU to day 28, where non-survivors to day 28 are treated as though not separated from invasive care

  13. Discharge to ward in survivors [ Time Frame: Up to day 28 ]
    Time to discharge from the ICU to day 28, among survivors

  14. Patient Survival [ Time Frame: Up to day 60 ]
    Survival to day 28; Survival to day 60; and Survival to hospital discharge, censored at day 60

  15. Number of patients residing at home or in a community setting at day 60 [ Time Frame: Up to day 60 ]
    Number residing at home or in a community setting at day 60

  16. Number of surviving patients residing at home or in a community [ Time Frame: Up to day 60 ]
    Number residing at home or in a community setting at day 60, among survivors

  17. Ventilatory ratio [ Time Frame: Up to day 10 ]
    Effect of nebulised heparin on ventilatory ratio measured every 6 hours

  18. Number treated with awake prone positioning [ Time Frame: Up to day 10 ]
    Number of patients treated with awake prone positioning



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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:

To be eligible, a patient must satisfy all these inclusion criteria:

  1. Confirmed or suspected COVID-19. Note, if 'suspected', results must be pending or testing intended
  2. Ability to obtain informed consent/assent to participate in study
  3. Age 18 years or older
  4. Requiring high flow nasal oxygen or positive pressure ventilator support or invasive mechanical ventilation for a time period of no greater than 48 hours
  5. D-dimers > 200 ng/ml
  6. PaO2 to FIO2 ratio less than or equal to 300
  7. Acute opacities on chest imaging affecting at least one lung quadrant. Note 'Acute opacities' do not include effusions, lobar/lung collapse or nodules
  8. Currently in a higher level of care area designated for inpatient care of patients where therapies including non-positive pressure ventilatory support can be provided.

Exclusion criteria

To be eligible, a patient must have none of these exclusion criteria:

  1. Enrolled in another clinical trial that is unapproved for co-enrolment
  2. Heparin allergy or heparin-induced thrombocytopaenia
  3. APTT > 100 seconds
  4. Platelet count < 50 x 109 per L
  5. Pulmonary bleeding, which is frank bleeding in the trachea, bronchi or lungs with repeated haemoptysis or requiring repeated suctioning
  6. Uncontrolled bleeding
  7. Pregnant or suspected pregnancy (Urine or serum HCG will be recorded)
  8. Receiving or about to commence ECMO or HFOV
  9. Myopathy, spinal cord injury, or nerve injury or disease with a likely prolonged incapacity to breathe independently e.g. Guillain-Barre syndrome
  10. Usually receives home oxygen
  11. Dependent on others for personal care due to physical or cognitive decline (pre-morbid status)
  12. Death is imminent or inevitable within 24 hours
  13. The clinical team would not be able to set up the study nebuliser and ventilator circuit as required including with active humidification
  14. Clinician objection.
  15. The use or anticipated use of nebulised tobramycin during this clinical episode
  16. Any other specific contraindication to anticoagulation including prophylactic anticoagulation not otherwise listed here
  17. Relapse in clinical condition in patient that had fully weaned from advanced respiratory support
  18. Any systemic anticoagulation other than prophylactic anticoagulation

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): NCT04511923


Contacts
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Contact: John Laffey +353 91 544074 John.laffey@nuigalway.ie
Contact: David Cosgrave +35391544074 davidw.cosgrave@hse.ie

Locations
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Ireland
University Hospital Galway Recruiting
Galway, Ireland
Contact: David Cosgrave, MDBChBAOFCAI       davidw.cosgrave@hse.ie   
Sponsors and Collaborators
University College Hospital Galway
Investigators
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Principal Investigator: John Laffey Professor of Anaesthesia and Intensive Care Medicine, National University of Ireland, Galway, Ireland
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Responsible Party: John Laffey, Professor, Anaesthesia and Intensive Care Medicine, School of Medicine, NUI Galway; Consultant, Anaesthesia and ICM, Galway University Hospitals; Vice-Dean Research, College of Medicine, Nursing, University College Hospital Galway
ClinicalTrials.gov Identifier: NCT04511923    
Other Study ID Numbers: NUIG-2020-003
First Posted: August 13, 2020    Key Record Dates
Last Update Posted: February 10, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Investigator will consider requests to share anonymised data for the purposes of meta-analysis following discussion with the sponsor.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Investigator will consider release of the above data once the study report has been completed.
Access Criteria: To be confirmed, prior to enrollment of the first patient.

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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
Additional relevant MeSH terms:
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COVID-19
Lung Injury
Acute Lung Injury
Respiratory Distress Syndrome
Wounds and Injuries
Respiratory Tract Infections
Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Thoracic Injuries
Respiration Disorders
Heparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action