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Trial registered on ANZCTR


Registration number
ACTRN12619001328167p
Ethics application status
Submitted, not yet approved
Date submitted
19/08/2019
Date registered
30/09/2019
Date last updated
30/09/2019
Date data sharing statement initially provided
30/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The BONANZA trial- a randomised controlled trial that is testing whether a management strategy guided by early brain tissue oxygen monitoring in patients in with severe traumatic brain injury improves long term neurological and functional outcomes.
Scientific title
The BONANZA Trial -a randomised controlled trial in patients with severe traumatic brain injury that will determine whether a neuro-intensive care management strategy guided by continuous brain tissue oxygen (PbtO2) monitoring and intracranial pressure (ICP) monitoring will improve neurological and functional outcomes at 6 months measured by the GOSE, when compared to standard care using ICP monitoring alone.
Secondary ID [1] 299023 0
ANZICS-CTG: CTG1718-05
Universal Trial Number (UTN)
U1111-1238-6901
Trial acronym
The BONANZA trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe traumatic brain injury 314034 0
Condition category
Condition code
Injuries and Accidents 312470 312470 0 0
Other injuries and accidents
Neurological 312546 312546 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients in the intervention arm will have continuous PbtO2 and ICP monitoring. Cerebral hypoxic episodes will be treated according to the BONANZA PbtO2 optimisation strategy. The PbtO2 treatment algorithm is a set of physiologic interventions that vary depending on the clinical scenario. The physiological interventions are tiered in a hierarchical fashion, with less aggressive interventions attempted before more aggressive manoeuvres.
Three abnormal clinical scenarios are possible:
1. Isolated intracranial hypertension: PbtO2 is greater than or equal to 20 mmHg and ICP is greater than target.
2. Isolated cerebral hypoxia: PbtO2 is less than 20 mmHg and ICP is within the satisfactory range.
3. Simultaneous cerebral hypoxia and intracranial hypertension: PbtO2 is less than 20 mmHg and ICP is greater than target.
All therapies are administered when the patient is in intensive care.
Tier 1 therapies include sedation and analgesia. A broad range of agents may be used, most commonly Propofol, Midazolam, Morphine and Fentanyl. Vasopressors or drugs that are used to improve blood pressure may also be given in order to improve blood flow to the brain. Commonly used vasopressors are Noradrenaline and Adrenaline. Osmotherapy may also be administered to reduce the water content of the brain and reduce brain swelling. Commonly used osmotics include Mannitol and Hpertonic saline. The doses of all these drugs mentioned are variable and are usually given via an infusion that is titrated according to the patients response.
Tier 2 therapies include the use of neuromuscular blockade agents like Cisatracurium. The dose is variable and may be given intermittently as a bolus or via infusion depending on each patient scenario. Other tier 2 therapies include blood tranfusion, and adjustments to the ventilator in order to optimize levels of oxygen and carbon dioxide in the patients blood.
Tier 3 therapies are largely optional and include lowering the patients temperature, further ventilator adjustments, the use of drugs known as barbiturates that will induce a deep coma in the patient and the consideration of surgery involving the removal of a portion of the skull to relieve pressure on the brain.
These interventions are only delivered when the patient is in intensive care under the supervision of a trained intensivist. The clinical team in intensive care will determine and adjust the therapies according to the patient's clinical scenario and any surgery that may be performed will be undertaken by a neurosurgeon. The number of times an intervention is delivered will vary from patient to patient depending on their individual response and will continue for the duration of PbtO2 monitoring. PbtO2 monitoring will continue until the patient awakens (GCS motor score = 6), or the ICP monitor is removed. Removal of the probe will be at the discretion of the clinical team. The duration of ICP monitoring will be determined by the treating clinicians. Case report forms will capture interventions.
Intervention code [1] 315296 0
Treatment: Devices
Intervention code [2] 315297 0
Treatment: Other
Comparator / control treatment
Patients who are randomized to the control arm will receive standard care (based on ICP driven interventions alone). All patients will be managed according to a clinical standardisation guideline that reflects best international practice.
Control group
Active

Outcomes
Primary outcome [1] 321085 0
Neurological outcomes measured using the Glasgow Outcome Score - Extended (GOS-E)
Timepoint [1] 321085 0
6 months post injury.
Secondary outcome [1] 373931 0
Mortality (all cause).
Timepoint [1] 373931 0
ICU discharge
Hospital discharge
Secondary outcome [2] 373934 0
Quality of life assessments (QOL) using EQ5D.
Timepoint [2] 373934 0
6 months post injury

Eligibility
Key inclusion criteria
Patients >17 years who have suffered a non-penetrating severe TBI and who require ICP monitoring (in the judgement of the treating clinician).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Contraindication to placement of ICP monitor (e.g. uncorrectable coagulopathy).
Pregnancy
Bilaterally absent pupillary response (in the absence of confounders)
Refractory hypotension despite medical attention
Refractory hypoxia despite medical attention
Non-survivable injury in view of treating clinician
Known inability to perform ADLs without assistance prior to injury.
12 hours has elapsed since time of injury.
CNS disease that is likely to impair accurate PbtO2 measurements (prior TBI, SAH, or
neoplasm).

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)
Centralised web-based allocation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The proportion of control participants with a favourable outcome (GOS-E >4) at 6-months in the DECRA study was 49%. In EPO-TBI, in those with a severe head injury (GCS 3-8), 50% of patients in the control arm had favourable outcomes. We consider a clinically relevant effect size to be a 10% absolute (20% relative) increase in favourable outcomes (conservative, given the OR for a favourable outcome (GOS-E >4) was 1.8 in BOOST-2). From a baseline rate of 50% with 80% power, and a two-sided alpha of 0.05, 814 patients are required. Based on a combined withdrawal and loss to follow-up rate of 5%, consistent with our previous trials, we will inflate the sample size to 860 (430 patients in each group).

A detailed statistical analysis plan will be developed and published separately from this trial protocol. This plan defines the intention-to-treat full analysis set, as well as exploratory analyses in “as treated” and “per protocol” subsets, accompanied by an analysis seeking to estimate the average causal effect.
An intention-to-treat analysis will be performed based on all randomly assigned patients except those withdrawing consent for use of all trial 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)
QLD,SA,VIC
Recruitment hospital [1] 14592 0
The Alfred - Melbourne
Recruitment hospital [2] 14593 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 14594 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 14595 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 27611 0
3004 - Melbourne
Recruitment postcode(s) [2] 27612 0
3050 - Parkville
Recruitment postcode(s) [3] 27613 0
5000 - Adelaide
Recruitment postcode(s) [4] 27614 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 303555 0
Government body
Name [1] 303555 0
NHMRC
Address [1] 303555 0
GPO Box 1421
Canberra
ACT 2601
Country [1] 303555 0
Australia
Primary sponsor type
University
Name
Australian and New Zealand Research Centre, School of Public Health and Preventive Medicine, Monash University
Address
553 St Kilda Rd
Melbourne
VIC 3004
Country
Australia
Secondary sponsor category [1] 303690 0
None
Name [1] 303690 0
Address [1] 303690 0
Country [1] 303690 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 304087 0
Alfred Health Ethics Committee
Ethics committee address [1] 304087 0
55 Commercial Rd
Melbourne
VIC 3004
Ethics committee country [1] 304087 0
Australia
Date submitted for ethics approval [1] 304087 0
24/07/2019
Approval date [1] 304087 0
Ethics approval number [1] 304087 0

Summary
Brief summary
Hospital management of patients with severe brain injury focuses on the prevention of additional “secondary” brain injury. Secondary injury plays a large role in the brain damage and death that results from TBI. Secondary injury can result from complications of the injury such as insufficient blood flow, or insufficient oxygen in the brain. These factors can set off a cascade of effects that may cause the brain to swell and lead to further damage to brain cells.

The mainstay of preventing secondary injury has been the management of patients in the intensive care unit (ICU), and the continuous monitoring of pressure inside the brain (called ICP monitoring) with treatment aimed at minimising any rise in ICP along with very close monitoring and treatment of low blood pressure along with supporting the patients breathing on a ventilator.

Some clinicians feel that rises in ICP may be a late indicator of secondary damage to brain cells as the brain depends on an uninterrupted supply of oxygen and glucose to remain viable and have suggested that monitoring the oxygen levels in brain tissue may provide a more useful marker of secondary injury. Several small trials have provided some promising results to support the use of monitoring and optimising brain tissue oxygenation to minimise secondary brain injury. Technology has improved and it is now feasible to monitor oxygen levels so that low levels can be detected and treatments started that might optimize brain tissue oxygenation. This strategy may have the potential to minimize secondary injury and improve long term outcomes

There have been no robust clinical trials to provide evidence to support the use of this technology and it has not been widely adopted in Australasian ICU’s. Clinicians are uncertain about the benefit of monitoring brain tissue oxygen levels. This important question will be answered by a trial testing this strategy compared to the standard management of monitoring ICP alone.

The BONANZA trial will enrol 860 patients who have suffered a severe TBI and require ICP monitoring and subsequent admission to ICU. Each patient will be randomised (like tossing a coin) to either a brain tissue oxygen monitoring strategy (including ICP monitoring) or the standard strategy of ICP monitoring alone. Functional and neurological recovery will be assessed at 6 months post injury to see if there is a difference between both groups of patients.



Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95770 0
Prof Andrew Udy
Address 95770 0
C/O Intensive Care Unit
Alfred Hospital
55 Commercial Rd
Melbourne
VIC 3004
Country 95770 0
Australia
Phone 95770 0
+61 438755568
Fax 95770 0
Email 95770 0
andrew@udy.com
Contact person for public queries
Name 95771 0
Ms Shirley Vallance
Address 95771 0
C/O ANZIC Research Centre
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Rd
Melbourne
VIC 3004
Country 95771 0
Australia
Phone 95771 0
+61 438220852
Fax 95771 0
Email 95771 0
shirley.vallance@monash.edu
Contact person for scientific queries
Name 95772 0
Ms Shirley Vallance
Address 95772 0
C/O ANZIC Research Centre
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Rd
Melbourne
VIC 3004
Country 95772 0
Australia
Phone 95772 0
+61 438220852
Fax 95772 0
Email 95772 0
shirley.vallance@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in this article, after de-identification (texts, tables, figures and appendices).
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following article publication.
Available to whom?
Researchers who provide a methodologically sound proposal.
Available for what types of analyses?
For individual patient data meta-analysis
How or where can data be obtained?
Proposals should be directed to anzicrc@monash.edu. To gain access, data requestors will need to sign a data access agreement
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
How or where can supporting documents be obtained?
Type [1] 4146 0
Study protocol
Citation [1] 4146 0
Link [1] 4146 0
Email [1] 4146 0
anzicrc@monash.edu
Other [1] 4146 0
Attachment [1] 4146 0
Type [2] 4147 0
Statistical analysis plan
Citation [2] 4147 0
Link [2] 4147 0
Email [2] 4147 0
anzicrc@monash.edu
Other [2] 4147 0
Attachment [2] 4147 0
Summary results
No Results