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
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Intervention and comparator: Intervention: The study is based on an investigational drug/device combination
product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant
formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled
syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13%
phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5%
cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lysophosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an
investigational device based on the Aerogen® Solo vibrating mesh nebulizer.
The timing and escalation dosing plans for the surfactant are as follows.
Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and
24 hours. 2 controls with no placebo intervention.
Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and
30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention.
Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240
mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention.
Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and
24 hours. 2 controls. 2 controls with no placebo intervention.
The trial steering committee, advised by the data monitoring committee, will review trial progression and dose
escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached)
based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis
of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns.
Comparator: No placebo intervention.
All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated
patients and all other treatments will be left to the discretion of the attending physician.
Main outcomes: The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary
ventilation (Ventilation Index (VI), where VI = [RR x (PIP − PEEP) × PaCO2]/1000) at 48 hours after study initiation.
The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs),
Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance,
change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study
initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the
WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free
days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28.
Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR,
surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate
samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and
cytokine) in plasma and DTAS, and blood oxidative stress markers.
Randomisation: After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the
treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials,
FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting
centre with a unique subject identifier specific to that centre.
Blinding (masking): This is an open-labelled unblinded study.
Numbers to be randomised (sample size): The total sample size is 20 COVID-19 mechanically ventilated patients
(12 intervention; 8 control).
Trial Status: Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and
started on the 14th of October 2020. The anticipated study completion date is November 2021.
Trial registration: ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-
033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).
In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter
serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with
the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Keywords: COVID-19, Randomised controlled trial, protocol, surfactant, Intensive Care, mechanical ventilation,
nebulisation
product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant
formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled
syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13%
phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5%
cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lysophosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an
investigational device based on the Aerogen® Solo vibrating mesh nebulizer.
The timing and escalation dosing plans for the surfactant are as follows.
Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and
24 hours. 2 controls with no placebo intervention.
Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and
30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention.
Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240
mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention.
Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and
24 hours. 2 controls. 2 controls with no placebo intervention.
The trial steering committee, advised by the data monitoring committee, will review trial progression and dose
escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached)
based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis
of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns.
Comparator: No placebo intervention.
All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated
patients and all other treatments will be left to the discretion of the attending physician.
Main outcomes: The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary
ventilation (Ventilation Index (VI), where VI = [RR x (PIP − PEEP) × PaCO2]/1000) at 48 hours after study initiation.
The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs),
Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance,
change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study
initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the
WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free
days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28.
Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR,
surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate
samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and
cytokine) in plasma and DTAS, and blood oxidative stress markers.
Randomisation: After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the
treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials,
FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting
centre with a unique subject identifier specific to that centre.
Blinding (masking): This is an open-labelled unblinded study.
Numbers to be randomised (sample size): The total sample size is 20 COVID-19 mechanically ventilated patients
(12 intervention; 8 control).
Trial Status: Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and
started on the 14th of October 2020. The anticipated study completion date is November 2021.
Trial registration: ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-
033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).
In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter
serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with
the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Keywords: COVID-19, Randomised controlled trial, protocol, surfactant, Intensive Care, mechanical ventilation,
nebulisation
Date Issued
2020-12
Date Acceptance
2020-12-01
Citation
Trials, 2020, 21 (1), pp.1-3
ISSN
1745-6215
Publisher
BioMed Central
Start Page
1
End Page
3
Journal / Book Title
Trials
Volume
21
Issue
1
Copyright Statement
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this article are included in the article's Creative Commons
licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.
License URL
Sponsor
Bill and Melinda Gates Foundation
Identifier
https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04944-5
Grant Number
INV-016631
Subjects
COVID-19
Intensive Care
Randomised controlled trial
mechanical ventilation
nebulisation
protocol
surfactant
Adult
COVID-19
Case-Control Studies
Feasibility Studies
Humans
Intensive Care Units
London
Mortality
Nebulizers and Vaporizers
Respiration, Artificial
Respiratory Insufficiency
SARS-CoV-2
Safety
Surface-Active Agents
Treatment Outcome
Ventilation
Cardiovascular System & Hematology
General & Internal Medicine
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Publication Status
Published
Article Number
1014
Date Publish Online
2020-12-10