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Trial registered on ANZCTR


Registration number
ACTRN12620000137998
Ethics application status
Approved
Date submitted
17/01/2020
Date registered
12/02/2020
Date last updated
12/02/2020
Date data sharing statement initially provided
12/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II
Scientific title
20% Human Albumin Solution Fluid Bolus Administration Therapy in Patients after Cardiac Surgery-II (HAS FLAIR-II): a phase II multicentre randomised controlled trial to determine whether fluid resuscitation with 20% albumin (Albumex®20) in patients after cardiac surgery decreases the duration of vasopressor requirement compared to usual care.
Secondary ID [1] 299594 0
None
Universal Trial Number (UTN)
U1111-1242-2469
Trial acronym
HAS FLAIR-II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiac Surgery
314881 0
Critical illness 314882 0
Condition category
Condition code
Anaesthesiology 313232 313232 0 0
Anaesthetics
Surgery 313233 313233 0 0
Other surgery
Cardiovascular 314313 314313 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous fluid bolus therapy (FBT)* with 20% albumin will administered by the treating team until one of the following criteria for treatment cessation is met:
- Initial (index) vasopressor dependence resolves

[The resolution of vasopressor dependence is defined as the patient being alive and all vasopressors being discontinued for at least 4 consecutive hours in the presence of a MAP>65 mmHg, or a target MAP set by the clinician in charge of the patient’s care, during the index vasopressor period (subsequent vasopressor periods will not contribute to the primary outcome)]

- Patient is discharged from ICU
- 7 days have passed since randomisation
- Contraindications to 20% albumin or crystalloid therapy arise
- Death occurs
- Serious adverse events suspected to be related to a study medication develops

*FBT will be defined as a volume of at least 100 mL of intravenous fluid administered over one hour or less at a rate of 2 ml/min or greater to increase or maintain intravascular volume. The FBT would be in addition to maintenance fluids, or specific fluids used to replace non-physiological fluid losses.

N.B FBT is a common intervention for the optimisation of cardiac output and the treatment of hypotension after cardiac surgery. However there are no consensus diagnostic criteria to identify whether a patient is appropriate for FBT after being admitted to ICU following cardiac surgery. Thus, the decision to administer FBT is based on clinical judgment.
Intervention code [1] 315850 0
Treatment: Other
Intervention code [2] 315851 0
Treatment: Drugs
Comparator / control treatment
The control will be ‘standard care’ which is fluid bolus therapy with a crystalloid solution for at least the first 1000 mL followed by whatever other fluids clinicians consider appropriate and no use of 20% albumin in the first 7 days post randomisation.


Control group
Active

Outcomes
Primary outcome [1] 321728 0
Duration of vasopressor therapy (in hours) censored at day 7. Defined by discontinuation of all vasopressors for at least 4 consecutive hours in the presence of a MAP>65mmHg or target MAP set by the clinician in charge of the patient’s care for the same 24-hour period.
Timepoint [1] 321728 0
at day 7
Secondary outcome [1] 376014 0
Volume of resuscitation fluid per calendar day as documented on the ICU fluid balance chart
Timepoint [1] 376014 0
Until discharge from ICU or day 7 post randomisation whichever occurs first
Secondary outcome [2] 376015 0
Volume of study and non-study fluid administered, but not as fluid bolus therapy, censored per calendar day as documented on the ICU fluid balance chart
Timepoint [2] 376015 0
Until discharge from ICU or day 7 post randomisation whichever occurs first
Secondary outcome [3] 376016 0
Total intravenous fluid input censored per calendar day as documented on the ICU fluid balance chart
Timepoint [3] 376016 0
Until discharge from ICU or day 7 post randomisation whichever occurs first
Secondary outcome [4] 376017 0
Fluid output (mediastinal drain(s) and urine output) censored per calendar day as documented on the ICU fluid balance chart
Timepoint [4] 376017 0
Cumulative fluid balance censored per calendar day while in ICU
Secondary outcome [5] 376018 0
Number of FBTs administered per calendar day while in ICU as documented on the ICU fluid balance chart
Timepoint [5] 376018 0
Until discharge from ICU or day 7 post randomisation whichever occurs first
Secondary outcome [6] 376019 0
Duration and cumulative dose of vasopressor therapy by type (e.g. noradrenaline, vasopressin) in the first 7 days as documented on the ICU observation chart
Timepoint [6] 376019 0
at day 7
Secondary outcome [7] 376020 0
Change in serum creatinine from baseline to peak level in the first 7 days
Timepoint [7] 376020 0
at day 7
Secondary outcome [8] 376021 0
Incidence of acute kidney injury (KDIGO classification) in the first 7 days after randomisation
Timepoint [8] 376021 0
at day 7
Secondary outcome [9] 376022 0
Proportion of patients newly treated with renal replacement therapy during index hospital admission as documented in the patient notes
Timepoint [9] 376022 0
at day 30 or discharge from hospital whichever occurs first
Secondary outcome [10] 376023 0
Ventilator free hours at day 7 as calculated from the patient observation chart
Timepoint [10] 376023 0
at day 7
Secondary outcome [11] 376024 0
Days at home up to 30 days after surgery (DAH30) as ascertained through patient level data linkage to the recruitment sites admission databases and the Australian & New Zealand Society of Cardiac & Thoracic Surgeons dataset
Timepoint [11] 376024 0
at day 30

Eligibility
Key inclusion criteria
The treating clinician wishes to administer fluid bolus therapy (FBT) after cardiac surgery.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Age less than 18 years
Pregnancy
Patients who have previously received a FBT prescribed in the ICU after cardiac surgery (NB patients who have received FBT in the ICU prior to surgery remain eligible).
Contraindication to study fluid e.g. patients with known or suspected allergy to albumin or crystalloid fluid
Documented refusal of any study fluid (i.e. a patient may refuse to receive Human Albumin Solution which is in 20% and 4% albumin)
Death is deemed to be imminent or inevitable during this admission, and either the attending physician, patient or substitute decision-maker is not committed to active treatment
Off pump cardiac surgery
Patient who have previously been enrolled in this 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)
ICU patients will be enrolled as soon as possible after fulfilling the criteria for randomisation. A permuted block randomisation method with variable block sizes of 2, 4 and 6 and stratified by site and the presence of a vasopressor at the time of randomisation will be used to allocate eligible patients to either the treatment or usual care group in a 1:1 ratio. Randomisation will be performed by the randomisation module in Research Electronic Data Capture (REDCap), which is a secure web application for managing online data collection.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The random allocation sequence is generated using a computer software program by coordinating investigators at the coordinating centre and embedded into the REDCap system. Site investigators, site research coordinators, or statisticians in co-ordinating centre do not have access to the allocation sequence.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Our sample size calculation is based on the pilot study (HAS FLAIR) where the median time to suspension of noradrenaline in the control group was 28 hours with a standard deviation of 30 hours. To have 90% power at a two-sided alpha level of 0.05 to identify a clinically relevant reduction of 30% (from 28 to 19.6 hours) in the duration of noradrenaline infusion in those patients requiring a fluid bolus for comparison between the two groups by t-test, we estimate that a sample size of 438 patients (219 per group) would be required.
To mitigate the possible effect of non-parametric distribution, we will compare the median time to cessation of noradrenaline using the Wilcoxon test. Under the same assumptions used for the t-test, the sample size will require adjustment to 458 patients. Finally, to account for a withdrawal of consent to use data (event rate: 1 in 100 patients randomised), we estimate that a rounded sample size of 470 patients would be needed.

Statistical analysis will be performed by a statistician. Data will be presented as n (95% CI), mean (SD) or median [IQR] as appropriate. The main analyses will be conducted on an intention to treat basis using standard statistical methods for categorical and continuous data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 15009 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 15011 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 15012 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 15013 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [5] 15015 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 28294 0
3084 - Heidelberg
Recruitment postcode(s) [2] 28296 0
3050 - Parkville
Recruitment postcode(s) [3] 28297 0
3168 - Clayton
Recruitment postcode(s) [4] 28298 0
3220 - Geelong
Recruitment postcode(s) [5] 28300 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 304074 0
Hospital
Name [1] 304074 0
Austin Health
Address [1] 304074 0
Intensive Care Unit
Austin Campus
145 Studley Road
Heidelberg
VIC 3084
Country [1] 304074 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country
Australia
Secondary sponsor category [1] 304277 0
Individual
Name [1] 304277 0
Professor Rinaldo Bellomo
Address [1] 304277 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg VIC 3084
Country [1] 304277 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304566 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 304566 0
Ethics and Research Governance Unit
Level 8, Harold Stokes Building
Austin Health
PO Box 5555
Heidelberg
Victoria
3084
Ethics committee country [1] 304566 0
Australia
Date submitted for ethics approval [1] 304566 0
16/10/2019
Approval date [1] 304566 0
05/12/2019
Ethics approval number [1] 304566 0
HREC/57780/Austin-2019

Summary
Brief summary
HAS FLAIR-II is a multi-centre, randomised controlled trial, looking at patients who require fluid bolus therapy (FBT) after cardiac surgery. FBT after cardiac surgery is a common intervention used to correct hypotension +/- optimise cardiac function.

There are several types of intravenous fluid used for fluid resuscitation, which are broadly classified into crystalloids and colloids. After cardiac surgery, patients receive a combination of crystalloid and the colloid albumin in the form of 4% albumin. 20% albumin corrects low blood volume more rapidly and requires less volume to do so than crystalloid fluids and 4% albumin, and by doing so reduces the amount of chloride and fluid the body receives. This
may avoid harm associated with chloride and large fluid administrations.

Participants will be allocated in a 1:1 ratio to either the treatment group (FBT with 20% albumin) or to usual care (FBT with whatever fluid the treating clinicians consider appropriate and no use of 20% albumin in the first 7 days). We will evaluate the duration of vasopressor use in those who received 20% albumin compared to those that received usual care. We plan to enroll 470 patients post cardiac surgery from Intensive Care Units in Australia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97406 0
Dr Geoffrey Wigmore
Address 97406 0
Department of Intensive Care
Austin Health
Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country 97406 0
Australia
Phone 97406 0
+61 3 9496 5000
Fax 97406 0
Email 97406 0
geoffrey.wigmore@austin.org.au
Contact person for public queries
Name 97407 0
Dr Glenn Eastwood
Address 97407 0
Department of Intensive Care
Austin Health
Austin Campus
145 Studley Road
Heidelberg
VIC 3084
Country 97407 0
Australia
Phone 97407 0
+61 3 9496 4835
Fax 97407 0
+61 3 9496 3932
Email 97407 0
glenn.eastwood@austin.org.au
Contact person for scientific queries
Name 97408 0
Dr Geoffrey Wigmore
Address 97408 0
Department of Intensive Care
Austin Health
Austin Campus
145 Studley Road
Heidelberg
VIC 3084

Country 97408 0
Australia
Phone 97408 0
+61 3 9496 5000
Fax 97408 0
Email 97408 0
geoffrey.wigmore@austin.org.au

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?
Statistical analysis plan
How or where can supporting documents be obtained?
Type [1] 5412 0
Statistical analysis plan
Citation [1] 5412 0
Link [1] 5412 0
Email [1] 5412 0
Other [1] 5412 0
Will be published in a peer review journal, details will be provided once published.
Attachment [1] 5412 0
Summary results
No Results