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Trial registered on ANZCTR


Registration number
ACTRN12620000101987
Ethics application status
Approved
Date submitted
6/12/2019
Date registered
5/02/2020
Date last updated
5/02/2020
Date data sharing statement initially provided
5/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Biomarker Use in Evidence of Neuronal Damage in Response to Anaesthesia and Surgery (The BOUNDARY Study)
Scientific title
Biomarker Use in Evidence of Neuronal Damage in Response to Anaesthesia and Surgery (The BOUNDARY Study)
Secondary ID [1] 300027 0
NIL
Universal Trial Number (UTN)
Trial acronym
BOUNDARY
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Delirium 315529 0
Postoperative Cognitive Dysfunction 315530 0
Condition category
Condition code
Anaesthesiology 313808 313808 0 0
Anaesthetics
Neurological 313809 313809 0 0
Dementias
Surgery 313810 313810 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants involved in the study will be randomly assigned to either a sevoflurane or propofol maintenance anaesthesia group before undergoing major elective non-cardiac surgery. We will quantitate the change in two blood biomarkers of neurological damage (neurofilament light and tau) to further investigate preliminary evidence that sevoflurane protects against neuronal damage. No further alterations or additions to anaesthetic or surgical technique are required.

Characteristics of both types of anaesthesia are as follows:

TIVA Anaesthesia (Propofol): intravenous remifentanyl infusion 0.3mcgs/kg or 4 nanograms/ml or appropriate dose titrated to effect; propofol TCI 4mcg/ml or titrated to effect; oxygen and air.

Volatile Anaesthesia (Sevoflurane): intravenous midazolam up to 5 mg, fentanyl 100 micrograms or as required, induction intravenous propofol 2 mg/kg or as required; inspired sevoflurane concentration at MAC or as required in air and oxygen.

General anaesthesia is always administered prior to the commencement of surgery. Specific time frames cannot be provided as this is contingent on the type of surgery, but it generally occurs 10-15 minutes before surgical incision.
Intervention code [1] 316300 0
Prevention
Comparator / control treatment
Control data will be obtained from a non-surgical group previously recruited throughout various investigations run in the department. This bank of data has been amassed between 2006 and 2018.
As there is some preliminary evidence which suggests sevoflurane protects against neuronal injury, propofol can be considered the comparator in this study.
Impairment or decline in the study participants is calculated against the controls, and then the two anaesthetic groups are compared to each other for incidence of impairment at baseline or decline over time.
Control group
Active

Outcomes
Primary outcome [1] 322214 0
Fluctuating levels of neurofilament light.
Timepoint [1] 322214 0
Blood samples will be taken prior to anaesthetic induction as a baseline measurement and again at 30 minutes following surgical incision and at 6, 24 and 48 hours following surgery. Where possible a 6-week sample will also be taken.
Primary outcome [2] 322272 0
Incidence of postoperative cognitive dysfunction as measured by a neuropsychological test battery. The components of the battery are as follows: memory (CERAD word learning test - immediate and delayed recall); attention (Trail Making A); executive function (Trail Making B, Digit Symbol Substitution Test, Clock Drawing Test); semantic fluency (controlled oral word association); verbal fluency (FAS); and motor function (Grooved Pegboard - dominant and non-dominant). We will also administer the Montreal Cognitive Assessment as part of the neuropsychological test battery (composite primary outcome).
Timepoint [2] 322272 0
3 months postoperatively.
Primary outcome [3] 322273 0
Fluctuating levels of tau proteins.
Timepoint [3] 322273 0
Blood samples will be taken prior to anaesthetic induction as a baseline measurement and again at 30 minutes following surgical incision and at 6, 24 and 48 hours following surgery. Where possible a 6-week sample will also be taken.
Secondary outcome [1] 377758 0
Postoperative delirium.
Timepoint [1] 377758 0
Postoperative delirium will be assessed once daily up to 5 days following surgery or until discharge. Delirium assessments will be conducted by trained research staff using the 3 minute Diagnostic Confusion Assessment Method (3D-CAM), who will be blinded to group allocation (i.e. sevoflurane vs propofol maintenance anaesthesia).

Eligibility
Key inclusion criteria
1. 65 years of age
2. Scheduled for elective non-cardiac surgery
3. Undergoing a procedure equally suited to intravenous (TIVA) or volatile anaesthetic management
4. Have no contraindication to neuropsychological testing (e.g. language, visual or hearing impairment)
5. Reside in an accessible proximity to the hospital for neuropsychological testing
Minimum age
65 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pre-existing neurological or clinically evident neurovascular disease (e.g. stroke)
2. Dementia of any aetiology
3. Received a general anaesthetic in previous 6 months
4. Associated medical problems that may lead to significant complications and loss to follow-up

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be randomised by computer generated random-permuted block sequence to receive either sevoflurane or propofol general anaesthesia; all other aspects of clinical management of the patient will be the standard of care. All postoperative assessments will be conducted by researchers blinded to treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
An external person to the study will set up the computer generated random-permuted block sequence for randomisation. Half of the patients recruited will recieve sevoflurane and the other half are to recieve propofol. Assignment for each patient will be in a sealed envelope and only made known to the treating anaesthetist. Research staff will be blind for the entirety of the process.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis

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)
VIC
Recruitment hospital [1] 15428 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 28756 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 304479 0
Other Collaborative groups
Name [1] 304479 0
Alzheimer's Association
Address [1] 304479 0
225 N. Michigan Ave. Floor 17 Chicago, IL 60601
Country [1] 304479 0
United States of America
Primary sponsor type
Hospital
Name
St Vincent's Hospital
Address
PO Box 2900
Fitzroy
VIC 3065
Country
Australia
Secondary sponsor category [1] 304749 0
None
Name [1] 304749 0
Address [1] 304749 0
Country [1] 304749 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304913 0
St Vincent's Hospital HREC-A
Ethics committee address [1] 304913 0
PO Box 2900
Fitzroy
VIC 3065
Ethics committee country [1] 304913 0
Australia
Date submitted for ethics approval [1] 304913 0
Approval date [1] 304913 0
04/12/2018
Ethics approval number [1] 304913 0

Summary
Brief summary
This study aims to investigate if markers of neuronal damage (neurofilament light and tau) are associated with general anesthesia and surgery. Specifically, we wish to confirm and expand our recent preliminary findings that this damage is associated with anesthetic type and with clinical outcomes of delirium and postoperative cognitive dysfunction. To establish this, patients undergoing major elective non-cardiac surgery will be randomly allocated to receive sevoflurane maintenance anaesthesia or propofol maintenance anaesthesia. Cognitive and memory testing will take place prior to surgery, at 7 days after surgery and at 3 months after surgery. Tests for delirium and collection of blood samples will also be conducted during the participants' time in hospital.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98622 0
A/Prof Lisbeth Evered
Address 98622 0
St Vincent's Hospital
PO Box 2900
Fitzroy
VIC 3065
Country 98622 0
Australia
Phone 98622 0
+61 03 9231 2251
Fax 98622 0
Email 98622 0
lis.evered@svha.org.au
Contact person for public queries
Name 98623 0
Miss Erika Fortunato
Address 98623 0
St Vincent's Hospital
PO Box 2900
Fitzroy
VIC 3065
Country 98623 0
Australia
Phone 98623 0
+61 03 9288 2072
Fax 98623 0
Email 98623 0
erika.fortunato@svha.org.au
Contact person for scientific queries
Name 98624 0
A/Prof Lisbeth Evered
Address 98624 0
St Vincent's Hospital
PO Box 2900
Fitzroy
VIC 3065
Country 98624 0
Australia
Phone 98624 0
+61 03 9231 2251
Fax 98624 0
Email 98624 0
lis.evered@svha.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
It is intended that the IPD will be made available for this trial but specific details have not yet been ascertained.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Analytic code
How or where can supporting documents be obtained?
Type [1] 6076 0
Study protocol
Citation [1] 6076 0
Link [1] 6076 0
Email [1] 6076 0
lis.evered@svha.org.au
Other [1] 6076 0
Attachment [1] 6076 0
Type [2] 6077 0
Statistical analysis plan
Citation [2] 6077 0
Link [2] 6077 0
Email [2] 6077 0
lis.evered@svha.org.au
Other [2] 6077 0
Attachment [2] 6077 0
Type [3] 6078 0
Informed consent form
Citation [3] 6078 0
Link [3] 6078 0
Email [3] 6078 0
lis.evered@svha.org.au
Other [3] 6078 0
Attachment [3] 6078 0
Type [4] 6079 0
Clinical study report
Citation [4] 6079 0
Link [4] 6079 0
Email [4] 6079 0
lis.evered@svha.org.au
Other [4] 6079 0
Attachment [4] 6079 0
Type [5] 6080 0
Ethical approval
Citation [5] 6080 0
Link [5] 6080 0
Email [5] 6080 0
lis.evered@svha.org.au
Other [5] 6080 0
Attachment [5] 6080 0
Type [6] 6081 0
Analytic code
Citation [6] 6081 0
Link [6] 6081 0
Email [6] 6081 0
lis.evered@svha.org.au
Other [6] 6081 0
Attachment [6] 6081 0
Summary results
No Results