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

• ClinicalTrials.gov Identifier: NCT04362059
• Recruitment Status: Completed
• First Posted: April 24, 2020
• Last Update Posted: September 29, 2023
• Sponsor: University Hospital Southampton NHS Foundation Trust
• Collaborators: Bill and Melinda Gates Foundation; University College, London
• Information provided by (Responsible Party): University Hospital Southampton NHS Foundation Trust

Study Description

Brief 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

Condition or disease	Intervention/treatment	Phase
Respiratory Infections	Device: COVSurf Drug Delivery System; Other: Standard of Care	Not Applicable

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Clinical Trial of Nebulized Surfactant for the Treatment of Moderate to Severe COVID-19
• Actual Study Start Date: June 18, 2020
• Actual Primary Completion Date: November 30, 2022
• Actual Study Completion Date: January 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Arm; Patients will be administered surfactant via COVSurf Drug Delivery System	Device: COVSurf Drug Delivery System; Device introduces surfactant to the patients lungs
Active Comparator: Control Arm; Patients shall receive regular Standard of Care treatment	Other: Standard of Care; Standard of care treatment for respiratory illness

Outcome Measures

Primary Outcome Measures :

1. Oxygenation Improvement [ Time Frame: 3 months ]
   To assess the improvement in oxygenation as determined by the PaO2/FiO2 ratio after treatment with study treatment
2. Pulmonary ventilation Improvement [ Time Frame: 3 months ]
   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. IMV Need [ Time Frame: 3 months ]
   Need for invasive mechanical ventilation (IMV) (CPAP/NIV arm only)

Secondary Outcome Measures :

1. Safety Assessment of Frequency and Severity of Adverse Events [ Time Frame: 3 months ]
   To assess safety as judged by the frequency and severity of adverse events and severe adverse events (SAEs).
2. Change in PaO2/FiO2 ratio [ Time Frame: 3 months ]
   Mean change in PaO2/FiO2 ratio at 24 and 48 hours after study initiation.
3. Mean Change in ventilatory index [ Time Frame: 48 hours ]
   Mean change in ventilatory index (VI) at 24 and 48 hours after study initiation
4. Mean Change in pulmonary compliance [ Time Frame: 48 hours ]
   Mean change in pulmonary compliance (L/cmH2O) at 24 and 48 hours after study initiation in the IMV arm
5. Mean Change in PEEP requirement [ Time Frame: 48 Hours ]
   Mean change in PEEP (Positive End-Expiratory Pressure) requirement at 24 and 48 hours after study initiation
6. Clinical Improvement [ Time Frame: 28 days ]
   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
7. Mechanical ventilation duration [ Time Frame: 3 months ]
   Duration of mechanical ventilation
8. Duration of days [ Time Frame: 3 months ]
   Duration of days of IMV or NIV or CPAP
9. IMV free days [ Time Frame: 21 days ]
   Invasive Mechanical Ventilator (IMV) free days at day 21
10. Ventilator support free days [ Time Frame: 21 days ]
    Ventilator support (IMV or NIV or CPAP) free days (VSFD) at day 21
11. Length of ICU stay [ Time Frame: 3 months ]
    Length of intensive care unit stay
12. Number of days hospitalised [ Time Frame: 3 months ]
    Number of days hospitalised
13. Mortality [ Time Frame: 28 days ]
    Mortality at day 28

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United Kingdom

University Hospital Southampton NHS Foundation Trust

Southampton, Hampshire, United Kingdom, SO16 6YD

University College London Hospitals NHS Foundation Trust

London, United Kingdom, NW1 2BU

Sponsors and Collaborators

University Hospital Southampton NHS Foundation Trust

Bill and Melinda Gates Foundation

University College, London

Investigators

• Principal Investigator: Michael P Grocott, MD; University Hospital Southampton NHS Foundation Trust

More Information

Additional Information:

WHO Master Protocol 2020 

Publications of Results:

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 Syndrome Sepsis Study Group. N Engl J Med. 1996 May 30;334(22):1417-21. doi: 10.1056/NEJM199605303342201.

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.

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.

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.

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 May;19(5):797-804. doi: 10.1183/09031936.02.00243302.

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 Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.

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 respiratory distress syndrome in children: a randomized multicenter study. Intensive Care Med. 2003 Mar;29(3):437-46. doi: 10.1007/s00134-003-1650-1. Epub 2003 Feb 15.

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: 10.1165/ajrcmb.20.1.3253.

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.

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.

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.105.073106. Epub 2006 Jan 27.

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 Jul 27;8(1):55. doi: 10.1186/1465-9921-8-55.

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.

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 Feb 24.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dushianthan A, Clark H, Madsen J, Mogg R, Matthews L, Berry L, de la Serna JB, Batchelor J, Brealey D, Hussell T, Porter J, Djukanovic R, Feelisch M, Postle A, Grocott MPW. Nebulised surfactant for the treatment of severe COVID-19 in adults (COV-Surf): A structured summary of a study protocol for a randomized controlled trial. Trials. 2020 Dec 10;21(1):1014. doi: 10.1186/s13063-020-04944-5.

• Responsible Party: University Hospital Southampton NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT04362059
• Other Study ID Numbers: RHM CRI0399
• First Posted: April 24, 2020
• Last Update Posted: September 29, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Respiratory Tract Infections; Infections; Respiratory Tract Diseases