Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001328167
Ethics application status
Approved
Date submitted
19/08/2019
Date registered
30/09/2019
Date last updated
2/09/2024
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
BONANZA-GT
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
The proportion of favourable neurological outcomes, measured using the Glasgow Outcome Score – Extended (GOS-E) at six months following injury, defined as a GOS-E > 4.
Timepoint [1] 321085 0
6 months post injury.
Secondary outcome [1] 373931 0
Mortality (all cause)
Timepoint [1] 373931 0
Assessed at ICU discharge (this timepoint is post randomisation and will be variable for each patient). Assessed at hospital discharge (this timepoint is post randomisation and will be variable for each patient). Assessed at 90 days and 180 days post injury
Secondary outcome [2] 373934 0
Quality of life assessments (QOL) using EQ5D.
Timepoint [2] 373934 0
6 and 12 months post injury
Secondary outcome [3] 410562 0
GOS-E
Timepoint [3] 410562 0
12 months post injury
Secondary outcome [4] 428367 0
The proportion of favourable neurological outcomes in survivors at 6 month following injury.
Timepoint [4] 428367 0
6 months post injury
Secondary outcome [5] 428369 0
Incidence of adverse events recorded by audit of study records.
Timepoint [5] 428369 0
From randomisation until 6-months post injury.
Secondary outcome [6] 428370 0
Direct and indirect costs using data linkage to medical records.
Timepoint [6] 428370 0
Trial completion
Secondary outcome [7] 439311 0
ICU length of stay determined from medical records.
Timepoint [7] 439311 0
Secondary outcome [8] 439312 0
ICU length of stay determined from medical records.
Timepoint [8] 439312 0
6 and 12 months post injury
Secondary outcome [9] 439313 0
Hospital length of stay determined from medical records.
Timepoint [9] 439313 0
6 and 12 months post injury
Secondary outcome [10] 439314 0
Hospital length of stay determined from medical records.
Timepoint [10] 439314 0
6 and 12 months post injury

Eligibility
Key inclusion criteria
Patients = 18 years who have suffered a non-penetrating severe TBI, as defined by:
1. A post resuscitation GCS of 3-8 (motor sub-score less than 6) AND an abnormal CT scan (demonstrating intra-cranial trauma),
OR
2. A post resuscitation GCS of 3-8 (motor sub-score less than 6), in the absence of confounders, AND a high index of suspicion for severe TBI (in the opinion of the treating neurosurgeon).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. Contraindication to placement of ICP and/or PbtO2 monitor (un-correctable coagulopathy).
b. Intra-cranial monitoring is already in situ at the time of neurosurgical assessment.
c. Pregnancy.
d. Bilaterally absent pupillary response (e.g. both pupils must be visible and are fixed and dilated) in the absence of confounders (e.g. traumatic mydriasis, atropine, neuromuscular blockers).
e. Characteristics that preclude accurate optimisation of PbtO2:
- Refractory hypotension (e.g. SBP<90mmHg despite medical intervention)
- Refractory systemic hypoxia (e.g. SaO2 <90% despite medical intervention)
- Active CNS disease that is likely to impair accurate PbtO2 measurements (prior TBI, active CNS disease in vicinity of probe position).
f. Non-survivable injury or no intention of aggressive intervention.
g. Cardiac arrest as part of this traumatic event.
h. Other issues prior to randomization that would preclude appropriate treatment, diagnosis, or follow-up such as known pre-existing neurologic disease with confounding residual deficits or known pre-existing condition resulting in an inability to perform activities of daily living without assistance.
i. At the time of the decision to insert an ICP monitor, 12 or more hours has elapsed since the injury occurred.

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 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
Recruiting
Date of first participant enrolment
Anticipated
1/12/2019
Actual
30/11/2020
Date of last participant enrolment
Anticipated
1/12/2027
Actual
Date of last data collection
Anticipated
1/12/2028
Actual
Sample size
Target
860
Accrual to date
129
Final
Recruitment in Australia
Recruitment state(s)
NT,QLD,SA,WA,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 hospital [5] 22504 0
Royal Perth Hospital - Perth
Recruitment hospital [6] 22505 0
Royal Darwin Hospital - Tiwi
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
Recruitment postcode(s) [5] 37741 0
6000 - Perth
Recruitment postcode(s) [6] 37742 0
0810 - Tiwi
Recruitment outside Australia
Country [1] 24821 0
New Zealand
State/province [1] 24821 0
Wellington
Country [2] 24822 0
Finland
State/province [2] 24822 0
Helsinki
Country [3] 24823 0
Switzerland
State/province [3] 24823 0
Bern
Country [4] 24824 0
New Zealand
State/province [4] 24824 0
Auckland
Country [5] 25928 0
United Kingdom
State/province [5] 25928 0
Brighton
Country [6] 25929 0
United Kingdom
State/province [6] 25929 0
London
Country [7] 26536 0
Germany
State/province [7] 26536 0
Berlin

Funding & Sponsors
Funding source category [1] 303555 0
Government body
Name [1] 303555 0
NHMRC
Country [1] 303555 0
Australia
Funding source category [2] 315120 0
Government body
Name [2] 315120 0
Belgian Health Care Knowledge Centre (INV21-1323)
Country [2] 315120 0
Belgium
Funding source category [3] 315121 0
Government body
Name [3] 315121 0
Irish Health Research Board
Country [3] 315121 0
Ireland
Funding source category [4] 315122 0
Government body
Name [4] 315122 0
Health Research Council of New Zealand (HRC Ref 21/937)
Country [4] 315122 0
New Zealand
Primary sponsor type
University
Name
Australian and New Zealand Intensive Care 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
Approved
Ethics committee name [1] 304087 0
Alfred Health Ethics Committee
Ethics committee address [1] 304087 0
Ethics committee country [1] 304087 0
Australia
Date submitted for ethics approval [1] 304087 0
24/07/2019
Approval date [1] 304087 0
23/11/2019
Ethics approval number [1] 304087 0
Ethics committee name [2] 314057 0
Department of Health, Social Affairs and Integration of the Canton of Bern (GSI) Cantonal Ethics Committee
Ethics committee address [2] 314057 0
Ethics committee country [2] 314057 0
Switzerland
Date submitted for ethics approval [2] 314057 0
15/09/2020
Approval date [2] 314057 0
28/01/2021
Ethics approval number [2] 314057 0
2020-01111
Ethics committee name [3] 314058 0
NHS Health Research Authority
Ethics committee address [3] 314058 0
Ethics committee country [3] 314058 0
United Kingdom
Date submitted for ethics approval [3] 314058 0
15/02/2021
Approval date [3] 314058 0
12/11/2021
Ethics approval number [3] 314058 0
IRAS ID301637

Summary
Brief summary
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
[email protected]
Contact person for public queries
Name 95771 0
Camila Battistuzzo
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 0422020126
Fax 95771 0
Email 95771 0
[email protected]
Contact person for scientific queries
Name 95772 0
Camila Battistuzzo
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 0422020126
Fax 95772 0
Email 95772 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?
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 [email protected]. To gain access, data requestors will need to sign a data access agreement


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
4146Study protocol  [email protected]
4147Statistical analysis plan  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.2022https://dx.doi.org/10.1016/j.jocn.2022.03.017
EmbaseManagement of moderate to severe traumatic brain injury: an update for the intensivist.2022https://dx.doi.org/10.1007/s00134-022-06702-4
EmbaseMonitoring cerebral oxygenation in acute brain-injured patients.2022https://dx.doi.org/10.1007/s00134-022-06788-w
EmbaseThe Impact of Invasive Brain Oxygen Pressure Guided Therapy on the Outcome of Patients with Traumatic Brain Injury: A Systematic Review and Meta-Analysis.2022https://dx.doi.org/10.1007/s12028-022-01613-0
EmbaseTraumatic brain injury over the past 20 years: research and clinical progress.2022https://dx.doi.org/10.1016/S1474-4422%2822%2900307-6
EmbaseIntracranial pressure monitoring with and without brain tissue oxygen pressure monitoring for severe traumatic brain injury in France (OXY-TC): an open-label, randomised controlled superiority trial.2023https://dx.doi.org/10.1016/S1474-4422%2823%2900290-9
EmbaseManagement Strategies Based on Multi-Modality Neuromonitoring in Severe Traumatic Brain Injury.2023https://dx.doi.org/10.1007/s13311-023-01411-2
EmbaseTraumatic brain injury research: homogenising heterogeneity.2023https://dx.doi.org/10.1016/S1474-4422%2823%2900325-3
Dimensions AITemporal Statistical Relationship between Regional Cerebral Oxygen Saturation (rSO2) and Brain Tissue Oxygen Tension (PbtO2) in Moderate-to-Severe Traumatic Brain Injury: A Canadian High Resolution-TBI (CAHR-TBI) Cohort Study2023https://doi.org/10.3390/bioengineering10101124
N.B. These documents automatically identified may not have been verified by the study sponsor.