Target Temperature Management 33°C Versus 36°C After Out-of-hospital Cardiac Arrest, a Randomised, Parallel Groups, Assessor Blinded Clinical Trial

Detailed statistical analysis plan for the Target Temperature Management after Out-of-hospital Cardiac Arrest trial

1. Introduction The Target temperature management after out-of-hospital cardiac arrest, a randomised, parallel-group, assessor-blinded clinical trial (the TTM-trial) is the largest trial to date in post-cardiac arrest treatment and in temperature management in the intensive care setting.

To prevent outcome reporting bias and data driven analysis results, the International Conference on Harmonisation of Good Clinical Practice and others have recommended that clinical trials should be analysed according to a pre-specified plan [1]. Leading experts in the critical care community have advocated that this should not only be a recommendation but rather a prerequisite [2]. Here we describe the statistical analysis plan that has been finalised while data collection in the TTM-trial still is on going, and to which all data analyses in the main publication of the TTM-trial results will adhere. The steering group of the TTM-trial unanimously approved the statistical analysis plan December 3rd 2012, patient recruitment at 950 patients was completed January 10th 2013, and the final follow-up is predicted to occur in the beginning of July 2013, after which the database will be locked and then analysed. 2. Trial overview The TTM-trial is a multicentre, multinational, outcome assessor-blinded, parallel group, randomised clinical trial comparing two strict target temperature regimens of 33°C and 36°C in adult patients, who have sustained return of spontaneous circulation and are unconscious after out-of-hospital cardiac arrest, when admitted to hospital. The study background, design, and rationale have previously been published [3, 4]. The TTM-trial protocol (current version 3.3) has been available online on www.ttm-trial.org since the start of the trial. The trial is registered at clinicaltrials.gov NCT01020916 and is endorsed by the European Clinical Research Infrastructure Network and the Scandinavian Critical Care Trials Group. 3. Objective The primary aim of the TTM-trial is to compare the effects of two strict target temperature protocols for the first 36 hours of hospital stay after resuscitation from out-of-hospital cardiac arrest (4 hours for achieving the target temperature, 24 hours of maintenance of target temperature, and 8 hours of rewarming). The null hypothesis is that there is no difference in survival until the end of trial (180 days from randomisation of the last patient) with a target temperature of 33°C compared to 36°C. To demonstrate or reject a Hazard Ratio difference of 20% between the groups, equivalent to approximately one months difference in median survival time assuming proportional hazards in the groups during the observation time, a sample size of 900 patients would be necessary with a type-1 error risk of 5% and a type-2 error risk of 10%. To allow for patients lost-to-follow up the target population is set to 950 patients. 4. Stratification and design variables The only stratification variable used is trial site (hospital). Pre-defined design variables allowing for an adjusted analysis of the primary outcome, and pre-defined subgroup analyses are: age, gender, first presenting cardiac rhythm (shockable or non-shockable), duration of cardiac arrest, and presence of shock at admission. 5. Definition of the efficacy variables The outcomes are defined as primary, secondary and exploratory (tertiary in the trial protocol). Only primary and secondary outcomes will be analysed for the first published report of the TTM-trial due to the complexity of the exploratory outcomes, and thus a need for separate publications.

Primary outcome The primary outcome is survival until end of trial, which will be 180 days from randomisation of the last patient.

Secondary outcomes including adverse events The main secondary outcomes are the composite outcomes of