A Clinical Trial of Nebulized Surfactant for the Treatment of Moderate to Severe COVID-19

Study Overview
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Brief Summary
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Lung surfactant is present in the lungs. It covers the alveolar surface where it reduces the work of breathing and prevents the lungs from collapsing. In some respiratory diseases and in patients that require ventilation this substance does not function normally. This study will introduce surfactant to the patients lungs via the COVSurf Drug Delivery System

Detailed Description
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The hypothesis behind the proposed trial of surfactant therapy for COVID-19 infected patients requiring ventilator support is that endogenous surfactant is dysfunctional. This could be due to decreased concentration of surfactant phospholipid and protein, altered surfactant phospholipid composition, surfactant protein proteolysis and/or oedema protein inhibition of surfactant surface tension function and/or oxidative inactivation of surfactant proteins. Variations of these dysfunctional mechanisms have been reported in a range of lung diseases, including cystic fibrosis and severe asthma, and in child and adult patients with ARDS. Our studies of surfactant metabolism in adult ARDS patients showed altered percentage composition of surfactant PC, with decreased DPPC and increased surface tension-inactive unsaturated species, and decreased concentrations of both total PC and phosphatidylglycerol (PG) The SARS-CoV-2 virus binds to the angiotensin converting enzyme-2 (ACE2) receptor, which is preferentially expressed in the peripheral lung ATII cells. Consequent viral infection of ATII cells could reduce cell number and impair the capacity of the lungs to synthesise and secrete surfactant. This, however, has not yet been demonstrated empirically in COVID-19 patients. If this is the case, then exogenous surfactant administration to the lungs is potential one treatment option to mitigate disease severity in these patients.

Official Title
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A Clinical Trial of Nebulized Surfactant for the Treatment of Moderate to Severe COVID-19

Conditions
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Respiratory Infections

Intervention / Treatment
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* Device: COVSurf Drug Delivery System
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old Confirmed COVID-19 positive by PCR Within 24 hours of mechanical ventilation (ETI arm) or within 24 hours of needing either CPAP or NIV (CPAP/NIV arm) Assent or professional assent obtained Exclusion Criteria: Imminent expected death within 24 hours Specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary haemorrhage) Known or suspected pregnancy Stage 4 severe chronic kidney disease or requiring dialysis (i.e., eGFR < 30) Liver failure Anticipated transfer to another hospital, which is not a study site within 72 hours. Current participation or participation in another study within the last month that in the opinion of the investigator would prevent enrollment for safety purposes. Consent Declined

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 |
| --- | --- |
| Experimental: Treatment Arm<br>Patients will be administered surfactant via COVSurf Drug Delivery System | Device: COVSurf Drug Delivery System<br>* Device introduces surfactant to the patients lungs<br>|
| Active Comparator: Control Arm<br>Patients shall receive regular Standard of Care treatment | Other: Standard of Care<br>* Standard of care treatment for respiratory illness<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation Improvement | To assess the improvement in oxygenation as determined by the PaO2/FiO2 ratio after treatment with study treatment | 3 months | 
| Pulmonary ventilation Improvement | To assess the improvement in pulmonary ventilation as determined by the Ventilation Index (VI), where VI = (Respiratory rate X PIP X PaCo2 (mmHg)/ 1000 after study treatment. | 3 months | 
| IMV Need | Need for invasive mechanical ventilation (IMV) (CPAP/NIV arm only) | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Assessment of Frequency and Severity of Adverse Events | To assess safety as judged by the frequency and severity of adverse events and severe adverse events (SAEs). | 3 months | 
| Change in PaO2/FiO2 ratio | Mean change in PaO2/FiO2 ratio at 24 and 48 hours after study initiation. | 3 months | 
| Mean Change in ventilatory index | Mean change in ventilatory index (VI) at 24 and 48 hours after study initiation | 48 hours | 
| Mean Change in pulmonary compliance | Mean change in pulmonary compliance (L/cmH2O) at 24 and 48 hours after study initiation in the IMV arm | 48 hours | 
| Mean Change in PEEP requirement | Mean change in PEEP (Positive End-Expiratory Pressure) requirement at 24 and 48 hours after study initiation | 48 Hours | 
| Clinical Improvement | To evaluate clinical improvement defined by time to one improvement point on an ordinal scale, as described in the WHO master protocol (2020) daily while hospitalised and on days 15 and 28 | 28 days | 
| Mechanical ventilation duration | Duration of mechanical ventilation | 3 months | 
| Duration of days | Duration of days of IMV or NIV or CPAP | 3 months | 
| IMV free days | Invasive Mechanical Ventilator (IMV) free days at day 21 | 21 days | 
| Ventilator support free days | Ventilator support (IMV or NIV or CPAP) free days (VSFD) at day 21 | 21 days | 
| Length of ICU stay | Length of intensive care unit stay | 3 months | 
| Number of days hospitalised | Number of days hospitalised | 3 months | 
| Mortality | Mortality at day 28 | 28 days |