Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000517976
Ethics application status
Approved
Date submitted
11/04/2020
Date registered
27/04/2020
Date last updated
28/09/2023
Date data sharing statement initially provided
27/04/2020
Date results information initially provided
28/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
COVID-19: Can Nebulised HepArin Reduce Time to Extubation in SARS-CoV-2 patients requiring mechanical ventilation (CHARTER Study)
Scientific title
A randomised controlled trial of Nebulised Heparin in critically ill mechanically ventilated patients with COVID-19 to assess the effect on the duration of mechanical ventilation.
Secondary ID [1] 300989 0
None
Universal Trial Number (UTN)
Trial acronym
Can Nebulised HepArin Reduce Time to Extubation in SARS-CoV-2 (CHARTER Study)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 Respiratory Failure 317028 0
Condition category
Condition code
Respiratory 315193 315193 0 0
Other respiratory disorders / diseases
Infection 315350 315350 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Nebulised (Vibrating mesh nebuliser) heparin sodium 25,000 IU in 5 ml 6-hourly to day 10 while invasively ventilated in addition to standard care.
The medication will be prescribed and administration documented in the medical record.
Intervention code [1] 317312 0
Treatment: Drugs
Comparator / control treatment
Standard care represents the treatments routinely provided by the medical team managing the patient. Standard care will be at the discretion of the medical team.
Control group
Active

Outcomes
Primary outcome [1] 323448 0
Time to separation from invasive ventilation, censored at Day 28, with non-survivors treated as though never separated from the ventilator. This will be assessed from review of the medical records.
Timepoint [1] 323448 0
Day 28
Secondary outcome [1] 381971 0
Time to separation from invasive ventilation, censored at Day 28, among survivors. This will be assessed from review of the medical records.
Timepoint [1] 381971 0
Day 28
Secondary outcome [2] 381972 0
Time to separation from ICU, censored at Day 28, with non-survivors treated as though not separated from the ICU. This will be assessed from review of the medical records.
Timepoint [2] 381972 0
Day 28
Secondary outcome [3] 381973 0
Time to separation from ICU, censored at Day 28, among survivors. This will be assessed from review of the medical records.
Timepoint [3] 381973 0
Day 28
Secondary outcome [4] 381974 0
Tracheotomy. This will be assessed from review of the medical records.
Timepoint [4] 381974 0
Day 28
Secondary outcome [5] 381975 0
Readmission to ICU. This will be assessed from review of the medical records.
Timepoint [5] 381975 0
Day 28
Secondary outcome [6] 381976 0
Survival to hospital discharge. This will be assessed from review of the medical records.
Timepoint [6] 381976 0
Day 60
Secondary outcome [7] 381977 0
Survival. This will be assessed from review of the medical records.
Timepoint [7] 381977 0
Day 28
Day 60
Secondary outcome [8] 381978 0
Place of residence. This will be assessed from review of the medical records and contact with the patient.
Timepoint [8] 381978 0
Day 60

Eligibility
Key inclusion criteria
Age 18 years or older
In ICU or scheduled for transfer to ICU
Endotracheal tube in place
Intubated yesterday or today
PaO2 to FIO2 ratio less than or equal to 300 while intubated
Acute opacities not fully explained by effusions, lobar/lung collapse and nodules, affecting at least one lung quadrant on chest X-ray or CT
The acute opacities on chest X-ray or CT are most likely due to COVID-19
There is a PCR positive sample for SARS-CoV-2 within the past 21 days or there are results pending or further testing is planned
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Enrolled in another clinical trial that is unapproved for co-enrolment
Heparin allergy or heparin-induced thrombocytopaenia
APTT > 120 seconds and this is not due to anticoagulant therapy
Platelet count < 20 x 10^9 per L
Pulmonary bleeding
Uncontrolled bleeding
Pregnant or might be pregnant
Receiving or about to commence ECMO or HFOV
Myopathy, spinal cord injury, or nerve injury or disease with a likely prolonged incapacity to breathe independently e.g. Guillain-Barre syndrome
Acute brain injury that may result in long-term disability
Usually receives home oxygen
Dependent on others for personal care due to physical or cognitive decline
Death is imminent or inevitable within 24 hours
The clinical team would not be able to set up the study nebuliser and ventilator circuit as required including with active humidification
Clinician objection

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated blocks of variable size and random seed will be used to generate the random sequence.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary outcome (time to separation from invasive ventilation to Day 28, where non-survivors to Day 28 are treated as though not separated from invasive ventilation) is unchanged, but the effect estimate used in the sample size calculation has been changed from the difference in mean days to separation to the hazard ratio. Data from a recently published large trial that inform the hypothesised treatment effect have been added. The Day 28 mortality assumption in the sample size calculation has been changed from 50% to 20%. Inflation of the sample size based on the assumption that 20% of enrolments would be found not to have COVID-19 has been revised. There is now 5% inflation of the sample size to account for withdrawals. The sample size has been amended from 206 to 270. The trial protocol was amended with these changes (Protocol Version 4, dated 01 September 2021) and approved by the HREC on 23 September 2021).

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
21/05/2020
Actual
9/07/2020
Date of last participant enrolment
Anticipated
26/05/2021
Actual
29/01/2022
Date of last data collection
Anticipated
25/07/2021
Actual
17/08/2022
Sample size
Target
270
Accrual to date
Final
50
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 16425 0
The Northern Hospital - Epping
Recruitment hospital [2] 16427 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 29968 0
3076 - Epping
Recruitment postcode(s) [2] 29970 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 305435 0
Government body
Name [1] 305435 0
Application to Victorian Medical Research Acceleration Fund
Country [1] 305435 0
Australia
Primary sponsor type
Hospital
Name
St Vincents Hospital Melbourne
Address
Department of Critical Care Medicine
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia
Country
Australia
Secondary sponsor category [1] 305830 0
None
Name [1] 305830 0
Address [1] 305830 0
Country [1] 305830 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305754 0
St Vincents Hospital Melbourne Australia
Ethics committee address [1] 305754 0
Research and Ethics
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia
Ethics committee country [1] 305754 0
Australia
Date submitted for ethics approval [1] 305754 0
11/05/2020
Approval date [1] 305754 0
17/06/2020
Ethics approval number [1] 305754 0

Summary
Brief summary
The search for an effective treatment for COVID-19 is underway around the world.

A trial of nebulised heparin is warranted.

A recent (not yet published; still under journal review) pre-pandemic double-blind multi-centre randomised study of 256 mechanically ventilated patients with or at risk of developing the Acute Respiratory Distress Syndrome (ARDS) of which 47% had ARDS, led by our group, found important pre-specified secondary outcomes were significantly improved with nebulised heparin. There was no evidence of harm.

COVID-19 is associated with the development of ARDS displaying the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. The anticoagulant actions of nebulised heparin limit fibrin deposition. Serendipitously, unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents its entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. For these reasons we believe a trial of nebulised heparin in patients with COVID-19 is warranted.

Our hypothesis is that nebulised heparin will reduce the time to separation from invasive ventilation at Day 28.

Nebulised heparin sodium 25,000 Units, will be administered 6-hourly with a vibrating mesh nebuliser while patients are receiving invasive mechanical ventilation up to Day 10. The dose and methodology of nebulisation were established in previous clinical trials by our group. The intervention is given in addition to standard care.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101478 0
Dr Barry Dixon
Address 101478 0
Department of Critical Care Medicine
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia
Country 101478 0
Australia
Phone 101478 0
+613439618815
Fax 101478 0
+61392884465
Email 101478 0
[email protected]
Contact person for public queries
Name 101479 0
Dr Barry Dixon
Address 101479 0
Department of Critical Care Medicine
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia
Country 101479 0
Australia
Phone 101479 0
+613439618815
Fax 101479 0
+61392884465
Email 101479 0
[email protected]
Contact person for scientific queries
Name 101480 0
Dr Barry Dixon
Address 101480 0
Department of Critical Care Medicine
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia
Country 101480 0
Australia
Phone 101480 0
+613439618815
Fax 101480 0
+61392884465
Email 101480 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7592Study protocol  [email protected]
7593Statistical analysis plan  [email protected]
7594Informed consent form  [email protected]
7595Clinical study report  [email protected]
7596Ethical approval  [email protected]
7597Analytic code  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAnticoagulants for people hospitalised with COVID-19.2022https://dx.doi.org/10.1002/14651858.CD013739.pub2
EmbaseNebulised heparin as a treatment for COVID-19: Scientific rationale and a call for randomised evidence.2020https://dx.doi.org/10.1186/s13054-020-03148-2
EmbaseProphylactic anticoagulants for people hospitalised with COVID-19.2020https://dx.doi.org/10.1002/14651858.CD013739
Dimensions AICan nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies2022https://doi.org/10.1111/bcp.15253
N.B. These documents automatically identified may not have been verified by the study sponsor.