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

Abstract

BackgroundThe 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.MethodsThe 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.DiscussionConsistent 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 registrationClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235. Registered on 3 September 2009.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2610-y) contains supplementary material, which is available to authorized users.

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

“…We published a statistical analysis plan before completion of the study 19 and an update (Supplement 1) before data lock and unblinding. The planned sample size of 500 patients allowed for withdrawals because of dropouts, loss of consent, and crossover from hypothermia therapy to normothermia (ie, significant bleeding or clinician decision that traumatic brain injury was likely not severe), and also allowed interim analyses.…”

“…Planned analyses were conducted in prespecified perprotocol and as-treated populations 19 (Supplement 1), with both analyses excluding all patients who did not satisfy study inclusion and exclusion criteria. Evaluable patients were then examined for cooling compliance (defined as ≤35°C for >48 hours within 96 hours of randomization) and either excluded from the analysis (per protocol) or transferred to the opposite treatment group (as treated).…”

“…RESULTS Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR,[16][17][18][19][20][21][22][23][24][25][26][27]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI, -9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94).…”

Endoscopic characteristics and management of Subepithelial Lesions in Video-Gastascopie

“…The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) these are larger, and hypothermia is induced as soon as possible after brain injury, regardless of signs of brain swelling. Overall, this trial does not support the practice of prophylactic or therapeutic hypothermia after head injury (36) .…”

A Comprehensive Update of Current Anesthesia Perspectives on Therapeutic Hypothermia

“…The study includes 511 patients in Australia, New Zealand, France, Switzerland, Saudi Arabia, and Qatar enrolled with severe acute TBI. It will determine if prophylactic hypothermia to 33 °C for 72 h will have a larger impact on long-term outcomes compared to normothermic conditions [49]. Current data inconsistently shows its effectiveness.…”