- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04362059
A Clinical Trial of Nebulized Surfactant for the Treatment of Moderate to Severe COVID-19 (COVSurf)
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Danny B Pratt
- Phone Number: 3943 02381204989
- Email: danny.pratt@uhs.nhs.uk
Study Locations
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-
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London, United Kingdom, NW1 2BU
- University College London Hospitals NHS Foundation Trust
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Hampshire
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Southampton, Hampshire, United Kingdom, SO16 6YD
- University Hospital Southampton NHS Foundation Trust
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment Arm
Patients will be administered surfactant via COVSurf Drug Delivery System
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Device introduces surfactant to the patients lungs
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Active Comparator: Control Arm
Patients shall receive regular Standard of Care treatment
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Standard of care treatment for respiratory illness
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Oxygenation Improvement
Time Frame: 3 months
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To assess the improvement in oxygenation as determined by the PaO2/FiO2 ratio after treatment with study treatment
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3 months
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Pulmonary ventilation Improvement
Time Frame: 3 months
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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
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IMV Need
Time Frame: 3 months
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Need for invasive mechanical ventilation (IMV) (CPAP/NIV arm only)
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3 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety Assessment of Frequency and Severity of Adverse Events
Time Frame: 3 months
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To assess safety as judged by the frequency and severity of adverse events and severe adverse events (SAEs).
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3 months
|
Change in PaO2/FiO2 ratio
Time Frame: 3 months
|
Mean change in PaO2/FiO2 ratio at 24 and 48 hours after study initiation.
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3 months
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Mean Change in ventilatory index
Time Frame: 48 hours
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Mean change in ventilatory index (VI) at 24 and 48 hours after study initiation
|
48 hours
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Mean Change in pulmonary compliance
Time Frame: 48 hours
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Mean change in pulmonary compliance (L/cmH2O) at 24 and 48 hours after study initiation in the IMV arm
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48 hours
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Mean Change in PEEP requirement
Time Frame: 48 Hours
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Mean change in PEEP (Positive End-Expiratory Pressure) requirement at 24 and 48 hours after study initiation
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48 Hours
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Clinical Improvement
Time Frame: 28 days
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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
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28 days
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Mechanical ventilation duration
Time Frame: 3 months
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Duration of mechanical ventilation
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3 months
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Duration of days
Time Frame: 3 months
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Duration of days of IMV or NIV or CPAP
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3 months
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IMV free days
Time Frame: 21 days
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Invasive Mechanical Ventilator (IMV) free days at day 21
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21 days
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Ventilator support free days
Time Frame: 21 days
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Ventilator support (IMV or NIV or CPAP) free days (VSFD) at day 21
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21 days
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Length of ICU stay
Time Frame: 3 months
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Length of intensive care unit stay
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3 months
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Number of days hospitalised
Time Frame: 3 months
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Number of days hospitalised
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3 months
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Mortality
Time Frame: 28 days
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Mortality at day 28
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28 days
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Collaborators and Investigators
Investigators
- Principal Investigator: Michael P Grocott, MD, University Hospital Southampton NHS Foundation Trust
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- RHM CRI0399
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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