The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury (POLAR-RCT)

August 20, 2018 updated by: David James Cooper, Australian and New Zealand Intensive Care Research Centre

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

Status

Completed

Intervention / Treatment

Detailed Description

Eligible patients will be randomised in the pre-hospital setting or on admission to the Emergency Department. POLAR study trained paramedics and physicians will screen patients in the pre-hospital setting. Eligible patients will be randomised if they fulfil the inclusion criteria with no pre-hospital exclusion criteria. Those randomised to the normothermia group will follow standard care. For those randomised to the "cooling arm", pre-hospital prophylactic hypothermia will be induced by exposure and by infusing up to 2 litres intravenous cold (4°C) 0.9% sodium chloride aiming for a core temperature of 35°C during transport. In the emergency department the "cooling arm" patients will be assessed to exclude significant bleeding and, once significant bleeding has been excluded, surface cooling vests/wraps will be applied to reach the target core temperature of 33°C. The patient will be then maintained at this temperature for a further 72 hours. Patients with significant bleeding will have cooling withheld until it is safe to decrease the temperature to the target core temperature of 33°C. Patients who have not been randomised pre-hospital will be re-screened in the ED. Eligible patients will be randomised if they fulfil the inclusion criteria with no ED exclusion criteria. Hypothermia will be induced by administration of up to 2L intravenous ice-cold (4°C) 0.9% sodium chloride followed by application of the surface cooling vests/wraps to achieve the target core temperature of 33°C. Patients allocated to standard 'normothermic' care will be maintained at a core temperature of 37°C ± 0.5°C.

Study Type

Interventional

Enrollment (Actual)

511

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Queensland
      • Brisbane, Queensland, Australia
        • Princess Alexandra Hospital
      • Gold Coast, Queensland, Australia
        • Gold Coast University Hospital
    • Victoria
      • Melbourne, Victoria, Australia
        • The Royal Melbourne Hospital
      • Prahran, Victoria, Australia, 3004
        • Alfred Hospital
    • Western Australia
      • Perth, Western Australia, Australia
        • Royal Perth Hospital
      • Brest, France
        • Hôpital La Cavale Blanche + CHRU Brest
      • Clermont-Ferrand, France
        • Hôpital Gabriel Montpied + CHU Clermont-Ferrand
      • Nimes, France
        • Hôpital Carémeau + CHU de Nimes
      • Strasbourg, France
        • Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre
    • Franche Comte
      • Besancon, Franche Comte, France
        • Hôpital St Jacques + CHRU Besançon
    • North Island
      • Auckland, North Island, New Zealand
        • Auckland DCCM
      • Hamilton, North Island, New Zealand
        • Waikato District Health Board
      • Doha, Qatar
        • Hamad General Hospital
      • Riyadh, Saudi Arabia
        • King Abdulaziz Medical City
      • Bern, Switzerland
        • Inselspital, Bern University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 58 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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
Experimental: Hypothermia
Early and sustained 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.
No Intervention: Normothermia
Standard management

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The proportion of favourable neurological outcomes (Glasgow Outcome Score Extended: GOSE 5 to 8)
Time Frame: 6 months post injury
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).
6 months post injury

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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).
6 months post injury
Quality of life assessments (QOL) o EQ5D o SF12
Time Frame: 6 months post injury

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
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
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.
6 months post injury
Mortality
Time Frame: Hospital Discharge and 6 Months post injury
All Cause Mortality
Hospital Discharge and 6 Months post injury
Incidence of adverse events, specifically: o Bleeding o Infection.
Time Frame: Up to study day 10
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).
Up to study day 10
Health economic evaluation
Time Frame: 6 Months post injury
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.
6 Months post injury
Pre-Specified sub group
Time Frame: 6 Months post injury
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).
6 Months post injury
Dose effect / Intensity of cooling
Time Frame: 6 months post injury
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.
6 months post injury

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2010

Primary Completion (Actual)

November 10, 2017

Study Completion (Actual)

June 15, 2018

Study Registration Dates

First Submitted

September 29, 2009

First Submitted That Met QC Criteria

September 30, 2009

First Posted (Estimate)

October 1, 2009

Study Record Updates

Last Update Posted (Actual)

August 22, 2018

Last Update Submitted That Met QC Criteria

August 20, 2018

Last Verified

August 1, 2018

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

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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