title: Detailed statistical analysis plan for the target temperature management after out-of-hospital cardiac arrest trial.
abstract: BACKGROUND
  Animal experimental studies and previous randomized trials suggest an improvement in mortality and neurological function with temperature regulation to hypothermia after cardiac arrest. According to a systematic review, previous trials were small, had a risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management (TTM) strategy is not known. To prevent outcome reporting bias, selective reporting and data-driven results, we present the a priori defined detailed statistical analysis plan as an update to the previously published outline of the design and rationale for the TTM trial.
  
  
  METHODS
  The TTM trial is an investigator-initiated, multicenter, international, randomized, parallel-group, and assessor-blinded clinical trial of temperature management in 950 adult unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients are randomized to a TTM of either 33°C or 36°C after return of spontaneous circulation. The primary outcome is all-cause mortality at maximal follow-up (until end of the trial and a minimum of 180 days). The main secondary outcomes are the composite outcome of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4, and modified Rankin Scale (mRS) 4 and 5) at hospital discharge and at 180 days; and assessment of safety and harm: bleeding, infections, electrolyte and metabolic disorders, seizures, cardiac arrhythmia, and renal replacement therapy.
  
  
  CONCLUSIONS
  The TTM trial investigates potential benefit and harm of two target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT01020916.
authors.affiliation: Department of Anesthesia and Intensive Care, Helsingborg Hospital, Södra Vallgatan 5, Helsingborg, 253 87, Sweden. niklas.nielsen@telia.com.
authors.forename: Niklas
authors.initials: N
authors.lastname: Nielsen
authors.forename: Per
authors.initials: P
authors.lastname: Winkel
authors.forename: Tobias
authors.initials: T
authors.lastname: Cronberg
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
authors.forename: Hans
authors.initials: H
authors.lastname: Friberg
authors.forename: Yvan
authors.initials: Y
authors.lastname: Gasche
authors.forename: Christian
authors.initials: C
authors.lastname: Hassager
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.forename: Jan
authors.initials: J
authors.lastname: Hovdenes
authors.forename: Jesper
authors.initials: J
authors.lastname: Kjaergaard
authors.forename: Michael
authors.initials: M
authors.lastname: Kuiper
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pellis
authors.forename: Pascal
authors.initials: P
authors.lastname: Stammet
authors.forename: Michael
authors.initials: M
authors.lastname: Wanscher
authors.forename: Matt P
authors.initials: MP
authors.lastname: Wise
authors.forename: Anders
authors.initials: A
authors.lastname: Åneman
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
mesh_terms: D015982:Bias; D001833:Body Temperature Regulation; D002985:Clinical Protocols; D003627:Data Interpretation, Statistical; D004185:Disability Evaluation; D005060:Europe; D006801:Humans; D007036:Hypothermia, Induced / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D058687:Out-of-Hospital Cardiac Arrest / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D010351:Patient Discharge; D020127:Recovery of Function; D012107:Research Design / Q000706:statistics & numerical data*; D012307:Risk Factors; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome
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