title: A statistical analysis protocol for the time-differentiated target temperature management after out-of-hospital cardiac arrest (TTH48) clinical trial.
abstract: BACKGROUND
  The TTH48 trial aims to determine whether prolonged duration (48 hours) of targeted temperature management (TTM) at 33 (±1) °C results in better neurological outcomes compared to standard duration (24 hours) after six months in comatose out-of-hospital cardiac arrest (OHCA) patients.
  
  
  METHODS
  TTH48 is an investigator-initiated, multicentre, assessor-blinded, randomised, controlled superiority trial of 24 and 48 hours of TTM at 33 (±1) ° C performed in 355 comatose OHCA patients aged 18 to 80 years who were admitted to ten intensive care units (ICUs) in six Northern European countries. The primary outcome of the study is the Cerebral Performance Category (CPC) score observed at six months after cardiac arrest. CPC scores of 1 and 2 are defined as good neurological outcomes, and CPC scores of 3, 4 and 5 are defined as poor neurological outcomes. The secondary outcomes are as follows: mortality within six months after cardiac arrest, CPC at hospital discharge, Glasgow Coma Scale (GCS) score on day 4, length of stay in ICU and at hospital and the presence of any adverse events such as cerebral, circulatory, respiratory, gastrointestinal, renal, metabolic measures, infection or bleeding. With the planned sample size, we have 80% power to detect a 15% improvement in good neurological outcomes at a two-sided statistical significance level of 5%.
  
  
  CONCLUSIONS
  We present a detailed statistical analysis protocol (SAP) that specifies how primary and secondary outcomes should be evaluated. We also predetermine covariates for adjusted analyses and pre-specify sub-groups for sensitivity analyses. This pre-planned SAP will reduce analysis bias and add validity to the findings of this trial on the effect of length of TTM on important clinical outcomes after cardiac arrest.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT01689077 , 17 September 2012.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark. hanskirkegaard@dadlnet.dk.|Research Center for Emergency Medicine, Aarhus University, Aarhus, Denmark. hanskirkegaard@dadlnet.dk.
authors.forename: Hans
authors.initials: H
authors.lastname: Kirkegaard
authors.affiliation: Hammel Neurorehabilitation Centre and University Research Clinic, Aarhus University, Aarhus, Denmark.
authors.forename: Asger Roer
authors.initials: AR
authors.lastname: Pedersen
authors.affiliation: Division of Intensive Care, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland.|Division of Intensive Care, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University, Helsinki, Finland.|Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Ville
authors.initials: V
authors.lastname: Pettilä
authors.affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hjort
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark.|Department of Clinical Institute, Aalborg University, Aalborg, Denmark.
authors.forename: Bodil Steen
authors.initials: BS
authors.lastname: Rasmussen
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Inge
authors.initials: I
authors.lastname: de Haas
authors.affiliation: Hammel Neurorehabilitation Centre and University Research Clinic, Aarhus University, Aarhus, Denmark.
authors.forename: Jørgen Feldbæk
authors.initials: JF
authors.lastname: Nielsen
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ilkjær
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Kaltoft
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.|Research Center for Emergency Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Anni Nørgaard
authors.initials: AN
authors.lastname: Jeppesen
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.|Research Center for Emergency Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Anders Morten
authors.initials: AM
authors.lastname: Grejs
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.|Research Center for Emergency Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Christophe Henri Valdemar
authors.initials: CH
authors.lastname: Duez
authors.affiliation: Department of Cardiology, Stavanger University Hospital, Stavanger, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Alf Inge
authors.initials: AI
authors.lastname: Larsen
authors.affiliation: Department of Anaesthesiology, Intensive Care and Emergency Medicine, North Estonia Medical Centre, Tallinn, Estonia.
authors.forename: Valdo
authors.initials: V
authors.lastname: Toome
authors.affiliation: Department of Intensive Cardiac Care, North Estonia Medical Centre, Tallinn, Estonia.
authors.forename: Urmet
authors.initials: U
authors.lastname: Arus
authors.affiliation: Department of Intensive Care, Erasmus Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Fabio Silvio
authors.initials: FS
authors.lastname: Taccone
authors.affiliation: Department of Internal Medicine, Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Storm
authors.affiliation: Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland.|Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Laitio
authors.affiliation: Division of Intensive Care, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland.|Division of Intensive Care, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University, Helsinki, Finland.|Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University Melbourne, Monash, Australia.
authors.forename: Markus B
authors.initials: MB
authors.lastname: Skrifvars
authors.affiliation: Department of Anaesthesiology and Intensive Care, Stavanger University Hospital, Stavanger, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Eldar
authors.initials: E
authors.lastname: Søreide
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001831:Body Temperature / Q000502:physiology*; D016887:Cardiopulmonary Resuscitation / Q000379:methods*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D008875:Middle Aged; D058687:Out-of-Hospital Cardiac Arrest / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D016037:Single-Blind Method; D015996:Survival Rate / Q000639:trends; D013696:Temperature; D013997:Time Factors; D055815:Young Adult
keywords: Cardiac arrest; Cerebral performance category; Critical care; Heart arrest; Intensive care; Mortality; Out-of-hospital; Randomised controlled trial; Targeted temperature management