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

Respiratory Infections Clinical Trial

— COVSurf  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04362059
• Other study ID #: RHM CRI0399
• Status: Completed
• Phase: N/A
• Start date: June 18, 2020
• Est. completion date: January 30, 2023

Study information

• Verified date: September 2023
• Source: University Hospital Southampton NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: January 30, 2023
• Est. primary completion date: November 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Respiratory Infections
• Respiratory Tract Infections

Intervention

Device:
• COVSurf Drug Delivery System
Device introduces surfactant to the patients lungs

Other:
• Standard of Care
Standard of care treatment for respiratory illness

Locations

Country	Name	City	State
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton	Hampshire

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital Southampton NHS Foundation Trust	Bill and Melinda Gates Foundation, University College, London

Country where clinical trial is conducted

United Kingdom, 

References & Publications (14)

Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann HP, Raventos AA, Lemaire F, Long W, Zaccardelli DS, Pattishall EN. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndro — View Citation

Dushianthan A, Goss V, Cusack R, Grocott MP, Postle AD. Altered molecular specificity of surfactant phosphatidycholine synthesis in patients with acute respiratory distress syndrome. Respir Res. 2014 Nov 7;15(1):128. doi: 10.1186/s12931-014-0128-8. — View Citation

Goss V, Hunt AN, Postle AD. Regulation of lung surfactant phospholipid synthesis and metabolism. Biochim Biophys Acta. 2013 Feb;1831(2):448-58. doi: 10.1016/j.bbalip.2012.11.009. Epub 2012 Nov 27. — View Citation

Gunther A, Schmidt R, Harodt J, Schmehl T, Walmrath D, Ruppert C, Grimminger F, Seeger W. Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfactant properties. Eur Respir J. 2002 M — View Citation

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibi — View Citation

Moller JC, Schaible T, Roll C, Schiffmann JH, Bindl L, Schrod L, Reiss I, Kohl M, Demirakca S, Hentschel R, Paul T, Vierzig A, Groneck P, von Seefeld H, Schumacher H, Gortner L; Surfactant ARDS Study Group. Treatment with bovine surfactant in severe acute — View Citation

Postle AD, Mander A, Reid KB, Wang JY, Wright SM, Moustaki M, Warner JO. Deficient hydrophilic lung surfactant proteins A and D with normal surfactant phospholipid molecular species in cystic fibrosis. Am J Respir Cell Mol Biol. 1999 Jan;20(1):90-8. doi: — View Citation

Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun. 2020 May 21;526(1):135-140. doi: 10.1016/j.bbrc.2020.03.044. Epub 2020 Mar 19. — View Citation

Rebello CM, Jobe AH, Eisele JW, Ikegami M. Alveolar and tissue surfactant pool sizes in humans. Am J Respir Crit Care Med. 1996 Sep;154(3 Pt 1):625-8. doi: 10.1164/ajrccm.154.3.8810596. — View Citation

Rodriguez-Capote K, Manzanares D, Haines T, Possmayer F. Reactive oxygen species inactivation of surfactant involves structural and functional alterations to surfactant proteins SP-B and SP-C. Biophys J. 2006 Apr 15;90(8):2808-21. doi: 10.1529/biophysj.10 — View Citation

Schmidt R, Markart P, Ruppert C, Wygrecka M, Kuchenbuch T, Walmrath D, Seeger W, Guenther A. Time-dependent changes in pulmonary surfactant function and composition in acute respiratory distress syndrome due to pneumonia or aspiration. Respir Res. 2007 Ju — View Citation

Schwarz KB. Oxidative stress during viral infection: a review. Free Radic Biol Med. 1996;21(5):641-9. doi: 10.1016/0891-5849(96)00131-1. — View Citation

Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, Fan Y, Zheng C. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020 Apr;20(4):425-434. doi: 10.1016/S1473-3099(20)30086-4. Epub 2020 Fe — View Citation

Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial. Collaborative European Multicenter Study Group. Pediatrics. 1988 Nov;82(5):683-91. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Oxygenation Improvement	To assess the improvement in oxygenation as determined by the PaO2/FiO2 ratio after treatment with study treatment	3 months
Primary	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
Primary	IMV Need	Need for invasive mechanical ventilation (IMV) (CPAP/NIV arm only)	3 months
Secondary	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
Secondary	Change in PaO2/FiO2 ratio	Mean change in PaO2/FiO2 ratio at 24 and 48 hours after study initiation.	3 months
Secondary	Mean Change in ventilatory index	Mean change in ventilatory index (VI) at 24 and 48 hours after study initiation	48 hours
Secondary	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
Secondary	Mean Change in PEEP requirement	Mean change in PEEP (Positive End-Expiratory Pressure) requirement at 24 and 48 hours after study initiation	48 Hours
Secondary	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
Secondary	Mechanical ventilation duration	Duration of mechanical ventilation	3 months
Secondary	Duration of days	Duration of days of IMV or NIV or CPAP	3 months
Secondary	IMV free days	Invasive Mechanical Ventilator (IMV) free days at day 21	21 days
Secondary	Ventilator support free days	Ventilator support (IMV or NIV or CPAP) free days (VSFD) at day 21	21 days
Secondary	Length of ICU stay	Length of intensive care unit stay	3 months
Secondary	Number of days hospitalised	Number of days hospitalised	3 months
Secondary	Mortality	Mortality at day 28	28 days

External Links

•   WHO Master Protocol 2020