- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00987688
The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR-RCT)
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
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.
Study Overview
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Queensland
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Brisbane, Queensland, Australia
- Princess Alexandra Hospital
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Gold Coast, Queensland, Australia
- Gold Coast University Hospital
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Victoria
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Melbourne, Victoria, Australia
- The Royal Melbourne Hospital
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Prahran, Victoria, Australia, 3004
- Alfred Hospital
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Western Australia
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Perth, Western Australia, Australia
- Royal Perth Hospital
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Brest, France
- Hôpital La Cavale Blanche + CHRU Brest
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Clermont-Ferrand, France
- Hôpital Gabriel Montpied + CHU Clermont-Ferrand
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Nimes, France
- Hôpital Carémeau + CHU de Nimes
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Strasbourg, France
- Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre
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Franche Comte
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Besancon, Franche Comte, France
- Hôpital St Jacques + CHRU Besançon
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North Island
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Auckland, North Island, New Zealand
- Auckland DCCM
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Hamilton, North Island, New Zealand
- Waikato District Health Board
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Doha, Qatar
- Hamad General Hospital
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Riyadh, Saudi Arabia
- King Abdulaziz Medical City
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Bern, Switzerland
- Inselspital, Bern University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Hypothermia
Early and sustained hypothermia.
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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.
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No Intervention: Normothermia
Standard management
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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The proportion of favourable neurological outcomes (Glasgow Outcome Score Extended: GOSE 5 to 8)
Time Frame: 6 months post injury
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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).
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6 months post injury
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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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
Time Frame: 6 months post injury
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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).
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6 months post injury
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Quality of life assessments (QOL) o EQ5D o SF12
Time Frame: 6 months post injury
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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. |
6 months post injury
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Average causal effect of hypothermia on GOSE at 6 months comparing hypothermia and control patients who would survive regardless of treatment assignment.
Time Frame: 6 months post injury
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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.
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6 months post injury
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Mortality
Time Frame: Hospital Discharge and 6 Months post injury
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All Cause Mortality
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Hospital Discharge and 6 Months post injury
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Incidence of adverse events, specifically: o Bleeding o Infection.
Time Frame: Up to study day 10
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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).
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Up to study day 10
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Health economic evaluation
Time Frame: 6 Months post injury
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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.
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6 Months post injury
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Pre-Specified sub group
Time Frame: 6 Months post injury
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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).
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6 Months post injury
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Dose effect / Intensity of cooling
Time Frame: 6 months post injury
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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.
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6 months post injury
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Collaborators and Investigators
Collaborators
Investigators
- Study Chair: Jamie Cooper, BMBS, MD, ANZIC RC
Publications and helpful links
General 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.
- Ridley EJ, Davies AR, Bernard S, McArthur C, Murray L, Paul E, Trapani A, Cooper DJ; ANZICS Clinical Trials Group. Measured energy expenditure in mildly hypothermic critically ill patients with traumatic brain injury: A sub-study of a randomized controlled trial. Clin Nutr. 2021 Jun;40(6):3875-3882. doi: 10.1016/j.clnu.2021.05.012. Epub 2021 May 24.
- Cooper DJ, Nichol AD, Bailey M, Bernard S, Cameron PA, Pili-Floury S, Forbes A, Gantner D, Higgins AM, Huet O, Kasza J, Murray L, Newby L, Presneill JJ, Rashford S, Rosenfeld JV, Stephenson M, Vallance S, Varma D, Webb SAR, Trapani T, McArthur C; POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial. JAMA. 2018 Dec 4;320(21):2211-2220. doi: 10.1001/jama.2018.17075.
- Moore EM, Nichol AD, Bernard SA, Bellomo R. Therapeutic hypothermia: benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury. Injury. 2011 Sep;42(9):843-54. doi: 10.1016/j.injury.2011.03.027. Epub 2011 Apr 9.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- ANZIC-RC/DJC003
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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