ANZCTR - Registration

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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

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]

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

Condition category

Condition code

Respiratory

Other respiratory disorders / diseases

Infection

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]

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]

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]

Day 28

Secondary outcome [1]

Time to separation from invasive ventilation, censored at Day 28, among survivors. This will be assessed from review of the medical records.

Timepoint [1]

Day 28

Secondary outcome [2]

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]

Day 28

Secondary outcome [3]

Time to separation from ICU, censored at Day 28, among survivors. This will be assessed from review of the medical records.

Timepoint [3]

Day 28

Secondary outcome [4]

Tracheotomy. This will be assessed from review of the medical records.

Timepoint [4]

Day 28

Secondary outcome [5]

Readmission to ICU. This will be assessed from review of the medical records.

Timepoint [5]

Day 28

Secondary outcome [6]

Survival to hospital discharge. This will be assessed from review of the medical records.

Timepoint [6]

Day 60

Secondary outcome [7]

Survival. This will be assessed from review of the medical records.

Timepoint [7]

Day 28
Day 60

Secondary outcome [8]

Place of residence. This will be assessed from review of the medical records and contact with the patient.

Timepoint [8]

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?

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

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

The Northern Hospital - Epping

Recruitment hospital [2]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment postcode(s) [1]

3076 - Epping

Recruitment postcode(s) [2]

3065 - Fitzroy

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Application to Victorian Medical Research Acceleration Fund

Address [1]

Victorian Government Office of Health and Medical Research – The Department of Health and Human Services. 50 Lonsdale Street
Melbourne, 3000 Victoria, AustraliaOHMR@dhhs.vic.gov.au

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincents Hospital Melbourne Australia

Ethics committee address [1]

Research and Ethics 
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

11/05/2020

Approval date [1]

17/06/2020

Ethics approval number [1]

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

Dr Barry Dixon

Address

Department of Critical Care Medicine
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia

Country

Australia

Phone

+613439618815

Fax

+61392884465

barry.dixon@svha.org.au

Contact person for public queries

Name

Barry Dixon

Address

Department of Critical Care Medicine
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia

Country

Australia

Phone

+613439618815

Fax

+61392884465

barry.dixon@svha.org.au

Contact person for scientific queries

Name

Barry Dixon

Address

Department of Critical Care Medicine
St Vincent’s Hospital (Melbourne)
41 Victoria Parade
Fitzroy VIC 3065
Australia

Country

Australia

Phone

+613439618815

Fax

+61392884465

barry.dixon@svha.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Email
7592	Study protocol	barry.dixon@svha.org.au
7593	Statistical analysis plan	barry.dixon@svha.org.au
7594	Informed consent form	barry.dixon@svha.org.au
7595	Clinical study report	barry.dixon@svha.org.au
7596	Ethical approval	barry.dixon@svha.org.au
7597	Analytic code	barry.dixon@svha.org.au

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Nebulised heparin as a treatment for COVID-19: Scientific rationale and a call for randomised evidence.	2020	https://dx.doi.org/10.1186/s13054-020-03148-2
Embase	Prophylactic anticoagulants for people hospitalised with COVID-19.	2020	https://dx.doi.org/10.1002/14651858.CD013739
Embase	Anticoagulants for people hospitalised with COVID-19.	2022	https://dx.doi.org/10.1002/14651858.CD013739.pub2
Dimensions AI	Can 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 studies	2022	https://doi.org/10.1111/bcp.15253

N.B. These documents automatically identified may not have been verified by the study sponsor.

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