Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000730808
Ethics application status
Approved
Date submitted
25/03/2021
Date registered
10/06/2021
Date last updated
25/06/2024
Date data sharing statement initially provided
10/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Methylene Blue in the Assessment of Gain In Cardiac Surgical Post-Operative vasoplegia (MAGIC) trial
Scientific title
A multicentre, parallel group, single-blind, randomised clinical trial investigating the effect of the use of Methylene Blue on days free of vasopressor support in Vasoplegic Patients After Cardiac Surgery.
Secondary ID [1] 303758 0
Nil known
Universal Trial Number (UTN)
Trial acronym
MAGIC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-operative Cardiothroacic surgical vasoplegia 321244 0
Condition category
Condition code
Cardiovascular 319029 319029 0 0
Other cardiovascular diseases
Cardiovascular 319496 319496 0 0
Diseases of the vasculature and circulation including the lymphatic system
Surgery 319497 319497 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous methylene blue infusion at a rate of 1.5mg/kg/hour for one
hour.
Patients will be assessed by research staff for inclusion in the study within 24 hours of admission to ICU immediately following cardiac surgery. The intervention will be provided to the bedside staff and administered within 1 hour of randomisation.
Intervention code [1] 320074 0
Treatment: Drugs
Comparator / control treatment
Intravenous infusion of placebo (1.5ml/kg/hr of 5% dextrose for one
hour)
Patients will be assessed by research staff for inclusion in the study within 24 hours of admission to ICU immediately following cardiac surgery. The intervention will be provided to the bedside staff and administered within 1 hour of randomisation.
Control group
Placebo

Outcomes
Primary outcome [1] 326936 0
The composite outcome of Hours alive and free from vasopressors at day 10 post-randomisation.

This will be assessed by review of both the medication administration records and the medical records.

All patients who die within 90 days prior to hospital discharge will be assigned negative one hours alive and free from vasopressors in order that all patients who die are assigned a worse outcome than all patients who survive.
Timepoint [1] 326936 0
Day 10 post-randomisation
Secondary outcome [1] 393178 0
Hospital mortality censored at 90-days.

This will be assess via review of the hospital census data and medical notes.
Timepoint [1] 393178 0
90 days post-randomisation
Secondary outcome [2] 393179 0
Survival time to hospital discharge censored at 90-days.

This will be assess via review of the hospital census data and medical notes.
Timepoint [2] 393179 0
90 days post-randomisation
Secondary outcome [3] 393180 0
ICU mortality.

This will be assess via review of the hospital census data and medical notes.
Timepoint [3] 393180 0
90 days post-randomisation
Secondary outcome [4] 393181 0
Inotrope-free days (to day 10).

This will be assess via review of the medical notes.
Timepoint [4] 393181 0
10 days post-randomisation
Secondary outcome [5] 393182 0
Mechanical ventilation-free days (to day 10).

This will be assess via review of the medical notes.
Timepoint [5] 393182 0
10 days post-randomisation
Secondary outcome [6] 393183 0
ICU-free days (to day 10).

This will be assess via review of the medical notes.
Timepoint [6] 393183 0
Day 10 post-randomisation
Secondary outcome [7] 393184 0
Hospital-free days (to day 28).

This will be assess via review of the hospital census data and medical notes.
Timepoint [7] 393184 0
Day 28 post-randomisation
Secondary outcome [8] 393185 0
Proportion of patients who receive renal replacement therapy

This will be assess via review of the medical notes.
Timepoint [8] 393185 0
90 days post-randomisation
Secondary outcome [9] 394782 0
Heart rate (hourly for 12 hours and then 6 hourly)

This will be assess via review of the medical notes.
Timepoint [9] 394782 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [10] 394783 0
Mean arterial pressure (hourly for 12 hours and then 6 hourly)

This will be assess via review of the medical notes.
Timepoint [10] 394783 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [11] 394784 0
Arterial lactate (highest daily)

This will be assess via review of the medical notes.
Timepoint [11] 394784 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [12] 394785 0
Methaemoglobin (highest daily)

This will be assess via review of the laboratory data and medical notes.
Timepoint [12] 394785 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [13] 394786 0
Serum creatinine (highest daily)

This will be assess via review of the laboratory data and medical notes
Timepoint [13] 394786 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [14] 394787 0
Bilirubin (highest daily)

This will be assess via review of the laboratory data and medical notes
Timepoint [14] 394787 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [15] 394788 0
Serum ALT (highest daily)

This will be assess via review of the laboratory data and medical notes
Timepoint [15] 394788 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [16] 394789 0
HCO3- (lowest daily)

This will be assess via review of the laboratory data and medical notes
Timepoint [16] 394789 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [17] 394790 0
pH (lowest daily)

This will be assess via review of the laboratory data and medical notes
Timepoint [17] 394790 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [18] 394791 0
Central venous oxygen saturation (lowest daily)

This will be assess via review of the laboratory data and medical notes
Timepoint [18] 394791 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [19] 394792 0
Cardiac index when measured during normal care (lowest and highest daily)

This will be assess via review of the medical notes
Timepoint [19] 394792 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [20] 394793 0
Mean pulmonary pressure when measured during normal care (lowest and highest daily)

This will be assess via review of the medical notes
Timepoint [20] 394793 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [21] 394794 0
Proportion of patients who develop new atrial fibrillation in the ICU.

This will be assess via review of the medical notes
Timepoint [21] 394794 0
Assessed from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [22] 394795 0
Total Vasopressor-dose (converted to nor-adrenaline equivalents).

This will be assess via review of the medication records and medical notes
Timepoint [22] 394795 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [23] 394796 0
Duration of vasopressor therapy

This will be assess via review of the medication records and medical notes
Timepoint [23] 394796 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [24] 394797 0
Proportion of patients who receive glucocorticoid “shock steroids” in the ICU.

This will be assess via review of the medication records and medical notes.
Timepoint [24] 394797 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [25] 394798 0
Daily volume of intravenous fluids administered as boluses.

This will be assess via review of the fluid administration records and medical notes
Timepoint [25] 394798 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [26] 394799 0
ICU length of stay.

This will be assess via review of the medical notes and hospital census data
Timepoint [26] 394799 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [27] 394800 0
Hospital length of stay.

This will be assess via review of the medical notes and hospital census data
Timepoint [27] 394800 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [28] 394801 0
Duration of mechanical ventilation.

This will be assess via review of the medical notes.
Timepoint [28] 394801 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)
Secondary outcome [29] 396711 0
Proportion of patients who receive mineralocorticoid “shock steroids” in the ICU

This will be assess via review of the medication records and medical notes.
Timepoint [29] 396711 0
Recorded from randomisation until day 10, ICU discharge or death (whichever is soonest)

Eligibility
Key inclusion criteria
1) Greater than or equal to 18 years of age
2) Invasively mechanically ventilated in ICU within 24 hours of ICU
admission and receiving greater than or equal to 10mcg/min of noradrenaline to
support mean arterial pressure following cardiac surgery with
cardiopulmonary bypass.
3) The clinician considers that vasoplegia is a significant contributor to the
haemodynamic disturbance AND this impression is supported by
either:
3.1 a cardiac index greater than or equal to 2.5L/min/m2
OR,
3.2 a central venous oxygen saturation greater than or equal to 60%
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Death is deemed to be inevitable as a result of the current acute illness
and either the treating clinician, the patient, or the substitute decision
maker are not committed to full active treatment.
2. The patient has mechanical cause of shock such as cardiac
tamponade or tension pneumothorax.
3. Mechanical support (e.g. IABP, IMPELLA, or ECMO) or post heart
transplant.
4. Enrolment not considered in the patient’s best interest.
5. Patient has an established indication for Methylene Blue
6. Allergy to methylene blue
7. Glucose-6-phosphate dehydrogenase deficiency (risk of haemolytic
anaemia).
8. Usually prescribed an SSRI.
9. Pregnant or breast feeding
10. Has already received methylene blue during this hospital admission
11. Previously enrolled in the MAGIC study

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
The MAGIC trial is a multi-centre, parallel group, single-blind, randomised clinical trial incorporating a nested vanguard pilot phase. The trial is a two-sided superiority trial which will allocate patients with clinically significant vasoplegia in the ICU after cardiac surgery to methylene blue or placebo in a 1:1 ratio. The initial vanguard pilot phase will enrol 60 patients, with the standard deviation for the primary outcome variable then used to determine the ultimate sample size required to detect a 42 hour difference in alive vasopressor-free hours to day 10 between the groups.

The data from these first 60 patients will be reviewed by an independent DSMB after completion of the vanguard phase. The DSMB will advise the management committee if the data indicate overwhelming evidence of benefit or harm from methylene blue.

Assuming that there is no reason to halt the trial and this point, the patients from the vanguard phase will be included in the phase 2 trial and the study management committee will remained masked as to the allocation of treatment for these vanguard patients.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Based on an estimated baseline number of alive vasopressor free hours in
this patient population of 120 hours in the control group and standard
deviation of 90 hours, a sample size of 177 would provide 80% power to
detect a between group difference of 42 hours allowing for a 15% sample size
inflation to account for the expected non-Gaussian distribution of the primary
outcome variable and allowing for a 5% drop-out rate. Because the number
of alive vasopressor free hours for our patient population is uncertain, we will
use pooled data for alive vasopressor free hours from the 60-patient vanguard
pilot phase to more accurately estimate the standard deviation and will update
our provisional sample size calculations following the vanguard phase.

Analysis of Baseline characteristics and primary outcomes:
All data will be assessed for normality and presented by treatment allocation.
Categorical variables will be presented as frequency (%) and compared using chi-squared tests for equal proportion. Continuous variables will be presented as the mean (SD) or median (interquartile range [IQR]) and compared using a student t test for normally distributed variables, and a Wilcoxon rank-sum test otherwise. All statistical analysis will be conducted on an intention-to-treat basis. No imputation will be applied to any missing data for the primary analysis, and the number of observations analysed will be reported. The
primary outcome will be analysed using a Wilcoxon rank-sum test with results reported as median (IQR) and a Hodges–Lehmann estimate of absolute difference reported with 95% confidence interval (CI). Sensitivity to baseline imbalance and known covariates will be performed using quartile regression, while sensitivity to missingness will be determined using multiple imputation.

Analysis of other outcomes:
Binary outcomes will be summarised using the proportions in each treatment group. Continuous outcomes will be summarised using means (SD) or medians (IQR) where appropriate. All “free-hours” variables will be analysed in a similar manner to the primary outcome variable.
A two-tailed P < 0.05 will be used for indicating statistical significance in all analyses. There will be independent blinded and unblinded senior statistical analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/06/2021
Actual
2/02/2022
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/03/2025
Actual
Sample size
Target
177
Accrual to date
20
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment hospital [1] 18986 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 18987 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 33501 0
3084 - Heidelberg
Recruitment postcode(s) [2] 33502 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 23557 0
New Zealand
State/province [1] 23557 0
Wellington

Funding & Sponsors
Funding source category [1] 308166 0
Other Collaborative groups
Name [1] 308166 0
Medical Research Institute of New Zealand
Country [1] 308166 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Medical Research Institute of New Zealand
Address
Suite 1.01, Level 1, 277 Camberwell Road
Camberwell, VIC 3124
Country
New Zealand
Secondary sponsor category [1] 308936 0
None
Name [1] 308936 0
Heart Foundation New Zealand
Address [1] 308936 0
9 Kalmia Street
Ellerslie
Auckland, 1051

Postal Address
PO Box 17-160
Greenlane
Auckland 1546
Country [1] 308936 0
New Zealand
Other collaborator category [1] 281779 0
Hospital
Name [1] 281779 0
The Austin Hospital Intensive Care Unit
Address [1] 281779 0
145 Studley Rd,
Heidelberg VIC 3084,
Australia
Country [1] 281779 0
Australia
Other collaborator category [2] 281780 0
Hospital
Name [2] 281780 0
Fiona Stanley Intensive Care Unit
Address [2] 281780 0
11 Robin Warren Dr,
Murdoch WA 6150,
Australia
Country [2] 281780 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308151 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 308151 0
Ethics committee country [1] 308151 0
New Zealand
Date submitted for ethics approval [1] 308151 0
25/03/2021
Approval date [1] 308151 0
23/07/2021
Ethics approval number [1] 308151 0
21/NTA/51: Provisionally approved with minor changes to PIS. Approval ID pending

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109710 0
Dr Paul Young
Address 109710 0
Wellington Regional Hospital
Riddiford Street, Newtown,
Wellington 6021
New Zealand
Country 109710 0
New Zealand
Phone 109710 0
+64 274552269
Fax 109710 0
Email 109710 0
[email protected]
Contact person for public queries
Name 109711 0
Paul Young
Address 109711 0
Wellington Regional Hospital
Riddiford Street, Newtown,
Wellington 6021
New Zealand
Country 109711 0
New Zealand
Phone 109711 0
+6443855999
Fax 109711 0
Email 109711 0
[email protected]
Contact person for scientific queries
Name 109712 0
Paul Young
Address 109712 0
Wellington Regional Hospital
Riddiford Street, Newtown,
Wellington 6021
New Zealand
Country 109712 0
New Zealand
Phone 109712 0
+6443855999
Fax 109712 0
Email 109712 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Potentially identifiable patient data for the purposes of meta-analysis. This will include demographic information, surgery and physiological data.
When will data be available (start and end dates)?
Beginning 3 months and ending 10 years following main results publication
Available to whom?
Case-by-case basis at the discretion of the Principal Investigator and the Director of ICU research at Wellington Hospital.
Available for what types of analyses?
Meta-analysis
How or where can data be obtained?
Via direct contact with the Principal Investigator
Dr Paul Young
[email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11134Ethical approval  [email protected] Available on request



Results publications and other study-related documents

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