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

Can Nebulised HepArin Reduce acuTE Lung Injury in Patients With SARS-CoV-2 Requiring Respiratory Support in Ireland

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.

Study Overview

• Status: Completed
• Conditions: Covid19; ARDS, Human; Ventilation Perfusion Mismatch; Lung Injury, Acute
• Intervention / Treatment: Drug: Nebulised heparin

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Ireland
  • Galway, Ireland
    • University Hospital Galway

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
D-dimer profile	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.	Up to day 10.
Frequenccy of Severe Adverse Outcomes	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.	Up to day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygenation Index	Determine the impact of nebulised heparin on oxygenation index	Up to day 10
Indices of Inflammation	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)	Up to day 10
Ratios of Indices of Inflammation	Effect of nebulised heparin on the ratios of IL-1β/IL-10 and IL-6/IL-10 will also be assessed.	Up to day 10
Indices of Coagulation	Effect of nebulised heparin on other indices of coagulation (Fibrinogen; lactate dehydrogenase) will be assessed (AUC on days 1, 3, 5 and 10).	Up to day 10
Quasi-Static Lung Compliance	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.	Up to day 10
Time to separation from advanced respiratory support	Time to separation from advanced respiratory support, where non survivors are treated as though not separated from advanced respiratory support.	Up to day 28
Number treated with neuromuscular blockers	Number treated with neuromuscular blockers instituted after enrolment	Up to day 10
Number treated with Prone positioning	Number treated with prone positioning instituted after enrolment	Up to day 10
Number treated with extra-corporeal membrane oxygenation	Number treated with extra-corporeal membrane oxygenation instituted after enrolment	Up to day 10
Number requiring Tracheostomy	Number tracheotomised	Up to day 28
Time to separation from invasive ventilation among survivors	Time to separation from invasive ventilation among survivors	Up to day 28
Discharge to ward	Time to separation from the ICU to day 28, where non-survivors to day 28 are treated as though not separated from invasive care	Up to day 28
Discharge to ward in survivors	Time to discharge from the ICU to day 28, among survivors	Up to day 28
Patient Survival	Survival to day 28; Survival to day 60; and Survival to hospital discharge, censored at day 60	Up to day 60
Number of patients residing at home or in a community setting at day 60	Number residing at home or in a community setting at day 60	Up to day 60
Number of surviving patients residing at home or in a community	Number residing at home or in a community setting at day 60, among survivors	Up to day 60
Ventilatory ratio	Effect of nebulised heparin on ventilatory ratio measured every 6 hours	Up to day 10
Number treated with awake prone positioning	Number of patients treated with awake prone positioning	Up to day 10

Collaborators and Investigators

• Sponsor: University College Hospital Galway
• Investigators: Principal Investigator: John Laffey, Professor of Anaesthesia and Intensive Care Medicine, National University of Ireland, Galway, Ireland

Publications and helpful links

General Publications

• Sheehan JR, Calpin P, Kernan M, Kelly C, Casey S, Murphy D, Alvarez-Iglesias A, Giacomini C, Cody C, Curley G, McGeary S, Hanley C, McNicholas B, van Haren F, Laffey JG, Cosgrave D. The CHARTER-Ireland trial: can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial. Trials. 2022 Sep 14;23(1):774. doi: 10.1186/s13063-022-06518-z.

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2020
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): February 28, 2022

Study Registration Dates

• First Submitted: August 10, 2020
• First Submitted That Met QC Criteria: August 11, 2020
• First Posted (Actual): August 13, 2020

Study Record Updates

• Last Update Posted (Actual): July 24, 2024
• Last Update Submitted That Met QC Criteria: July 23, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Thoracic Injuries; COVID-19; Wounds and Injuries; Respiratory Distress Syndrome; Acute Lung Injury; Lung Injury; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin
• Other Study ID Numbers: NUIG-2020-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Investigator will consider requests to share anonymised data for the purposes of meta-analysis following discussion with the sponsor.
• IPD Sharing Time Frame: Investigator will consider release of the above data once the study report has been completed.
• IPD Sharing Access Criteria: To be confirmed, prior to enrollment of the first patient.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

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