Nebulised Heparin to Reduce COVID-19 Induced Acute Lung Injury

Study Overview
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Brief Summary
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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.

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

Conditions
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Covid19, ARDS, Human, Lung Injury, Acute, Ventilation Perfusion Mismatch

Intervention / Treatment
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* Drug: Nebulised heparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible, a patient must satisfy all these inclusion criteria: Confirmed or suspected COVID-19. Note, if 'suspected', results must be pending or testing intended Ability to obtain informed consent/assent to participate in study Age 18 years or older Requiring high flow nasal oxygen or positive pressure ventilator support or invasive mechanical ventilation for a time period of no greater than 48 hours D-dimers > 200 ng/ml PaO2 to FIO2 ratio less than or equal to 300 Acute opacities on chest imaging affecting at least one lung quadrant. Note 'Acute opacities' do not include effusions, lobar/lung collapse or nodules 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: Enrolled in another clinical trial that is unapproved for co-enrolment Heparin allergy or heparin-induced thrombocytopaenia APTT > 100 seconds Platelet count < 50 x 109 per L Pulmonary bleeding, which is frank bleeding in the trachea, bronchi or lungs with repeated haemoptysis or requiring repeated suctioning Uncontrolled bleeding Pregnant or suspected pregnancy (Urine or serum HCG will be recorded) Receiving or about to commence ECMO or HFOV Myopathy, spinal cord injury, or nerve injury or disease with a likely prolonged incapacity to breathe independently e.g. Guillain-Barre syndrome Usually receives home oxygen Dependent on others for personal care due to physical or cognitive decline (pre-morbid status) Death is imminent or inevitable within 24 hours The clinical team would not be able to set up the study nebuliser and ventilator circuit as required including with active humidification Clinician objection. The use or anticipated use of nebulised tobramycin during this clinical episode Any other specific contraindication to anticoagulation including prophylactic anticoagulation not otherwise listed here Relapse in clinical condition in patient that had fully weaned from advanced respiratory support Any systemic anticoagulation other than prophylactic anticoagulation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard Care<br>Standard care | |
| Experimental: Heparin<br>Standard care plus nebulised unfractionated heparin 25000 units every 6 hours for 10 days | Drug: Nebulised heparin<br>* Nebulised unfractionated heparin 25000 units administered 6 hourly for 10 days<br>|

What is the study measuring?
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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 |