Nebulised Heparin to Reduce COVID-19 Induced Acute Lung Injury

Phase 1

Completed

• Conditions: ARDS, Human; Lung Injury, Acute; Ventilation Perfusion Mismatch; Covid19
• Interventions: Drug: Nebulised heparin

• Registration Number: NCT04511923
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-08-10
• Study First Submitted QC: 2020-08-11
• Study First Posted: 2020-08-13
• Study Start: 2020-12-23
• Primary Completion: 2021-12-31
• Study Completion: 2022-02-28
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-23
• Last Update Posted: 2024-07-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Heparin	Nebulised heparin	Standard care plus nebulised unfractionated heparin 25000 units every 6 hours for 10 days

Primary Outcome Measures

Name	Time	Method
Frequenccy of Severe Adverse Outcomes	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.
D-dimer profile	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.

Secondary Outcome Measures

Name	Time	Method
Oxygenation Index	Up to day 10	Determine the impact of nebulised heparin on oxygenation index
Ratios of Indices of Inflammation	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.
Time to separation from advanced respiratory support	Up to day 28	Time to separation from advanced respiratory support, where non survivors are treated as though not separated from advanced respiratory support.
Indices of Inflammation	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)
Number treated with Prone positioning	Up to day 10	Number treated with prone positioning instituted after enrolment
Number treated with extra-corporeal membrane oxygenation	Up to day 10	Number treated with extra-corporeal membrane oxygenation instituted after enrolment
Discharge to ward in survivors	Up to day 28	Time to discharge from the ICU to day 28, among survivors
Patient Survival	Up to day 60	Survival to day 28; Survival to day 60; and Survival to hospital discharge, censored at day 60
Number of surviving patients residing at home or in a community	Up to day 60	Number residing at home or in a community setting at day 60, among survivors
Number treated with awake prone positioning	Up to day 10	Number of patients treated with awake prone positioning
Indices of Coagulation	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).
Number treated with neuromuscular blockers	Up to day 10	Number treated with neuromuscular blockers instituted after enrolment
Discharge to ward	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
Number of patients residing at home or in a community setting at day 60	Up to day 60	Number residing at home or in a community setting at day 60
Quasi-Static Lung Compliance	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.
Number requiring Tracheostomy	Up to day 28	Number tracheotomised
Time to separation from invasive ventilation among survivors	Up to day 28	Time to separation from invasive ventilation among survivors
Ventilatory ratio	Up to day 10	Effect of nebulised heparin on ventilatory ratio measured every 6 hours

Trial Locations

Locations (1)

University Hospital Galway; 🇮🇪 Galway, Ireland