Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial

Abstract

Background: The Prophylactic hypOthermia to Lessen trAumatic bRain injury-Randomised Controlled Trial (POLAR-RCT) will evaluate whether early and sustained prophylactic hypothermia delivered to patients with severe traumatic brain injury improves patient-centred outcomes.

Methods: The POLAR-RCT is a multicentre, randomised, parallel group, phase III trial of early, prophylactic cooling in critically ill patients with severe traumatic brain injury, conducted in Australia, New Zealand, France, Switzerland, Saudi Arabia and Qatar. A total of 511 patients aged 18-60 years have been enrolled with severe acute traumatic brain injury. The trial intervention of early and sustained prophylactic hypothermia to 33 °C for 72 h will be compared to standard normothermia maintained at a core temperature of 37 °C. The primary outcome is the proportion of favourable neurological outcomes, comprising good recovery or moderate disability, observed at six months following randomisation utilising a midpoint dichotomisation of the Extended Glasgow Outcome Scale (GOSE). Secondary outcomes, also assessed at six months following randomisation, include the probability of an equal or greater GOSE level, mortality, the proportions of patients with haemorrhage or infection, as well as assessment of quality of life and health economic outcomes. The planned sample size will allow 80% power to detect a 30% relative risk increase from 50% to 65% (equivalent to a 15% absolute risk increase) in favourable neurological outcome at a two-sided alpha of 0.05.

Discussion: Consistent with international guidelines, a detailed and prospective analysis plan has been developed for the POLAR-RCT. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses and methods for exploratory analyses. Application of this statistical analysis plan to the forthcoming POLAR-RCT trial will facilitate unbiased analyses of these important clinical data.

Trial registration: ClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235 . Registered on 3 September 2009.

Keywords: Cooling; Critical care; Hypothermia; Outcome; Randomised controlled trials; Traumatic brain injury.

Conflict of interest statement

Ethics approval and consent to participate

Ethics and regulatory approvals of the protocol and related documents were obtained before commencing the trial at each site according to state or national legislation. The list of responsible ethics committees is provided in Additional file 8. The study protocol has been updated on several occasions, with each amendment receiving further ethics and regulatory approval. Version 9 is current from 11 July 2017.

Unconscious patients with severe TBI will not be able to provide informed consent; therefore, this trial uses a deferral of consent procedure. Informed consent will be obtained from each patient’s legal surrogate for data collection as soon as reasonably possible and appropriate after injury. Patients who recover sufficient cognition to understand an explanation of the trial will additionally be asked to consent to continuation in the trial and the use of their data in the trial, if this is required under the ethics committee approval conditions. In France, patients may be enrolled under an ‘Emergency clause’. More details of the trial protocol and participating hospitals are available from the trial registration site [48] as well as from the published study protocol [7].

Competing interests

The authors declare that they have no competing interests.

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