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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00987688




Registration number
NCT00987688
Ethics application status
Date submitted
29/09/2009
Date registered
1/10/2009
Date last updated
22/08/2018

Titles & IDs
Public title
The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury
Scientific title
Multi-centre Randomised Trial to Evaluate the Effect of Early Hypothermia on Neurological Function in Patients With Severe Traumatic Brain Injury. Including Renal Sub Study
Secondary ID [1] 0 0
ANZIC-RC/DJC003
Universal Trial Number (UTN)
Trial acronym
POLAR-RCT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Brain Injuries, Traumatic 0 0
Condition category
Condition code
Injuries and Accidents 0 0 0 0
Other injuries and accidents
Neurological 0 0 0 0
Other neurological disorders
Skin 0 0 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Hypothermia

Experimental: Hypothermia - Early and sustained hypothermia.

No Intervention: Normothermia - Standard management


Other interventions: Hypothermia
exposure: Early and sustained hypothermia. Hypothermia will initially be induced by infusion of up to 2L ice cold saline. Following a safety assessment the patient will be rapidly cooled to 33C using surface temperature control equipment. They will be maintained at 33C for 72 hours. Rewarming will occur at a rate of 1C/4hrs and will be titrated to intracranial pressure (ICP) control and BP.

Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
The proportion of favourable neurological outcomes (Glasgow Outcome Score Extended: GOSE 5 to 8) - The Glasgow Outcome Scale Extended (GOSE) is an ordinal rating scale. The 8 scores in the scale are: Dead (1), Vegetative State (2), Lower Severe Disability (3), Upper Severe Disability (4), Lower Moderate Disability (5), Upper Moderate Disability (6), Lower Good Recovery (7), and Upper Good Recovery (8).
Timepoint [1] 0 0
6 months post injury
Secondary outcome [1] 0 0
Probability of an equal or greater GOSE level at 6 months compared to the probability of a lesser GOSE level, using a proportional odds model or partial proportional odds model - The Glasgow Outcome Scale Extended (GOSE) is an ordinal rating scale. The 8 scores in the scale are: Dead (1), Vegetative State (2), Lower Severe Disability (3), Upper Severe Disability (4), Lower Moderate Disability (5), Upper Moderate Disability (6), Lower Good Recovery (7), and Upper Good Recovery (8).
Timepoint [1] 0 0
6 months post injury
Secondary outcome [2] 0 0
Quality of life assessments (QOL) o EQ5D o SF12 - Quality of life assessments using the EQ-5D-3L and SF12. The EQ-5D-3L descriptive system that comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems.
The SF-12® Health Survey (SF-12) is a 12-item questionnaire used to assess health outcomes from the patient's perspective.
Timepoint [2] 0 0
6 months post injury
Secondary outcome [3] 0 0
Average causal effect of hypothermia on GOSE at 6 months comparing hypothermia and control patients who would survive regardless of treatment assignment. - This complier average causal effect (CACE) analysis will be conducted to estimate the average effect of cooling treatment on the primary outcome for patients who would comply with whichever cooling group they were assigned to, considering both the binary and continuous definitions of compliance with cooling.
Timepoint [3] 0 0
6 months post injury
Secondary outcome [4] 0 0
Mortality - All Cause Mortality
Timepoint [4] 0 0
Hospital Discharge and 6 Months post injury
Secondary outcome [5] 0 0
Incidence of adverse events, specifically: o Bleeding o Infection. - The incidence of adverse events will be measured up to day 10 in both groups. The principle adverse events of interest will be bleeding (intracranial or extracranial) and infection (by site).
Timepoint [5] 0 0
Up to study day 10
Secondary outcome [6] 0 0
Health economic evaluation - Cost-effectiveness from the health-care payer perspective will be calculated as a cost per additional patient with a favourable neurological outcome at 6 months following randomisation (defined as GOSE 5-8) and the cost per additional quality-adjusted life year, with quality-adjusted life years calculated using utility scores derived from the EQ-5D-3L conducted at 6 months post randomisation. Costs will be determined based on resource use during the intensive care, acute and post-acute periods up to six months post-randomisation. Where available, total costs of care provided by the state government through the relevant compensation scheme will be obtained for the subgroup of road trauma patients, and this data will be used to determine the cost per additional QALY and cost per additional favourable neurological outcome in this subgroup.
Timepoint [6] 0 0
6 Months post injury
Secondary outcome [7] 0 0
Pre-Specified sub group - The primary and secondary outcomes will be evaluated according to (i) the presence of surgically evacuated intracranial mass lesions (Marshall score V); and (ii) the presence of any intracranial mass lesion whether or not surgically evacuated (Marshall V or VI).
Timepoint [7] 0 0
6 Months post injury
Secondary outcome [8] 0 0
Dose effect / Intensity of cooling - Intensity of cooling in intervention arm patients will be categorised according to the time after randomization to first reach one of two core temperature thresholds, being 35°C and also 34°C. Cooling intensity categories are defined as never achieving hypothermia and tertiles of time in those reaching hypothermia. Primary and secondary outcomes of patients in these intensity categories will be compared across categories and to standard care patients.
Timepoint [8] 0 0
6 months post injury

Eligibility
Key inclusion criteria
- Blunt trauma with clinical diagnosis of severe TBI and GCS <9

- Estimated age = 18 and < 60 years of age

- The patient is intubated or intubation is imminent
Minimum age
18 Years
Maximum age
60 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Pre-hospital:

- Clinical diagnosis of drug or alcohol intoxication as predominant cause of coma

- Randomisation unable to be performed within 3 hrs of estimated time of injury

- Estimated transport time to study hospital >2.5hrs

- Able to be intubated without drugs

- Systolic BP <90mmHg

- Heart rate > 120bpm

- GCS=3 + un-reactive pupils

- Penetrating neck/torso injury

- Known or obvious pregnancy

- Receiving hospital is not a study site

- Evidence of current anti-coagulant treatment

- Emergency Dept:

- Clinical diagnosis of drug or alcohol intoxication as predominant cause of coma

- Randomisation unable to be performed within 3 hrs of estimated time of injury

- Able to be intubated without drugs

- GCS=3 + un-reactive pupils

- Persistent Systolic BP <90mmHg

- Clinically significant bleeding likely to require haemostatic intervention, for
example:

- Bleeding into the chest, abdomen or retro-peritoneum likely to require
surgery +/- embolisation

- Pelvic fracture likely to require surgery +/- embolisation

- More than two long bone fractures requiring operative fixation

- Penetrating neck/torso injury

- Positive urine or blood pregnancy test

- Evidence of current anti-coagulant treatment

- In the treating clinician's opinion, "cooling" is not in the patient's best
interest

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
Blinded (masking used)
Who is / are masked / blinded?


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

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
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,VIC,WA
Recruitment hospital [1] 0 0
Princess Alexandra Hospital - Brisbane
Recruitment hospital [2] 0 0
Gold Coast University Hospital - Gold Coast
Recruitment hospital [3] 0 0
The Royal Melbourne Hospital - Melbourne
Recruitment hospital [4] 0 0
Alfred Hospital - Prahran
Recruitment hospital [5] 0 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 0 0
- Brisbane
Recruitment postcode(s) [2] 0 0
- Gold Coast
Recruitment postcode(s) [3] 0 0
- Melbourne
Recruitment postcode(s) [4] 0 0
3004 - Prahran
Recruitment postcode(s) [5] 0 0
- Perth
Recruitment outside Australia
Country [1] 0 0
France
State/province [1] 0 0
Franche Comte
Country [2] 0 0
France
State/province [2] 0 0
Brest
Country [3] 0 0
France
State/province [3] 0 0
Clermont-Ferrand
Country [4] 0 0
France
State/province [4] 0 0
Nimes
Country [5] 0 0
France
State/province [5] 0 0
Strasbourg
Country [6] 0 0
New Zealand
State/province [6] 0 0
North Island
Country [7] 0 0
Qatar
State/province [7] 0 0
Doha
Country [8] 0 0
Saudi Arabia
State/province [8] 0 0
Riyadh
Country [9] 0 0
Switzerland
State/province [9] 0 0
Bern

Funding & Sponsors
Primary sponsor type
Other
Name
Australian and New Zealand Intensive Care Research Centre
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Australian and New Zealand Intensive Care Society Clinical Trials Group
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
National Health and Medical Research Council, Australia
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Transport Accident Commision, Victoria
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Monash University
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
Délégation à la Recherche Clinique et à l'Innovation (DRCI) CHU Besançon
Address [5] 0 0
Country [5] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Traumatic brain injury (TBI) is a leading cause of death and long term disability,
particularly in young adults. Studies from Australia have shown that approximately half of
those with severe traumatic brain injury will be severely disabled or dead 6 months post
injury. Given the young age of many patients with severe TBI and the long term prevalence of
major disability, the economic and more importantly the social cost to the community is very
high.

Pre-hospital and hospital management of patients with severe brain injury focuses on
prevention of additional injury due primarily to lack of oxygen and insufficient blood
pressure. This includes optimising sedation and ventilation, maintaining the fluid balance
and draining Cerebrospinal Fluid (CSF) and performing surgery where appropriate. In recent
years there has been a research focus on specific pharmacologic interventions, however, to
date, there has been no treatment that has been associated with improvement of neurological
outcomes.

One treatment that shows promise is the application of hypothermia (cooling). This treatment
is commonly used in Australia to decrease brain injury in patients with brain injury
following out-of-hospital cardiac arrest. Cooling is thought to protect the brain using a
number of mechanisms. There have been a number of animal studies that have looked at how
cooling is protective and also some clinical research that suggests some benefit. However at
the current time there is insufficient evidence to provide enough proof that cooling should
be used routinely for patients with brain injury and like all treatments there can be some
risks and side effects.

The POLAR trial has been developed to investigate whether early cooling of patients with
severe traumatic brain injury is associated with better outcomes. It is a randomised
controlled trial, which is a type of trial that provides the highest quality of evidence.

The null hypothesis is that there is no difference in the proportion of favourable
neurological outcomes six months after severe traumatic brain injury in patients treated with
early and sustained hypothermia, compared to standard normothermic management.
Trial website
https://clinicaltrials.gov/show/NCT00987688
Trial related presentations / publications
Nichol A, Gantner D, Presneill J, Murray L, Trapani T, Bernard S, Cameron P, Capellier G, Forbes A, McArthur C, Newby L, Rashford S, Rosenfeld JV, Smith T, Stephenson M, Varma D, Walker T, Webb S, Cooper DJ. Protocol for a multicentre randomised controlled trial of early and sustained prophylactic hypothermia in the management of traumatic brain injury. Crit Care Resusc. 2015 Jun;17(2):92-100.
Presneill J, Gantner D, Nichol A, McArthur C, Forbes A, Kasza J, Trapani T, Murray L, Bernard S, Cameron P, Capellier G, Huet O, Newby L, Rashford S, Rosenfeld JV, Smith T, Stephenson M, Varma D, Vallance S, Walker T, Webb S, James Cooper D; POLAR investigators and the ANZICS Clinical Trials Group. Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial. Trials. 2018 Apr 27;19(1):259. doi: 10.1186/s13063-018-2610-y.
Public notes

Contacts
Principal investigator
Name 0 0
Jamie Cooper, BMBS, MD
Address 0 0
ANZIC RC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications