title: Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.
abstract: BACKGROUND
  The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.
  
  
  METHODS
  EPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled. Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission. The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05.
  
  
  CONCLUSIONS
  A detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses. Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data.
  
  
  BACKGROUND
  Australian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012).
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. intensive@fastmail.com.au.|Department of Intensive Care, Mater Health Services, Raymond Terrace, South Brisbane, 4101, Australia. intensive@fastmail.com.au.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Presneill
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. lorraine.little@monash.edu.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Little
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. alistair.nichol@monash.edu.|Department of Anaesthesia and Intensive Care Medicine, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. alistair.nichol@monash.edu.|School of Medicine and Medical Sciences, University College, Elm Park, Dublin 4, Ireland. alistair.nichol@monash.edu.|Department of Intensive Care Medicine, The Alfred, Commercial Road, Melbourne, 3004, Australia. alistair.nichol@monash.edu.
authors.forename: Alistair
authors.initials: A
authors.lastname: Nichol
authors.affiliation: Department of Intensive Care, Western Health, Gordon Street, Footscray, 3011, Australia. craig.french@wh.org.au.|The University of Melbourne, Grattan Street, Parkville, 3052, Australia. craig.french@wh.org.au.
authors.forename: Craig
authors.initials: C
authors.lastname: French
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. jamie.cooper@monash.edu.|Department of Intensive Care Medicine, The Alfred, Commercial Road, Melbourne, 3004, Australia. jamie.cooper@monash.edu.
authors.forename: D James
authors.initials: DJ
authors.lastname: Cooper
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. haddads55@yahoo.com.|Intensive Care Department, King Abdulaziz Medical City, PO Box 22490, Riyadh, 11426, Kingdom of Saudi Arabia. haddads55@yahoo.com.
authors.forename: Samir
authors.initials: S
authors.lastname: Haddad
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. jacques.duranteau@bct.aphp.fr.|Service d'Anesthésie-Réanimation, Hôpitaux universitaires Paris Sud, Assistance Publique des Hôpitaux de Paris, Hôpital de Bicêtre, 78, rue du Général Leclerc, Paris, 94275, Le Kremlin Bicêtre, France. jacques.duranteau@bct.aphp.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Duranteau
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, CHRU La Cavale Blanche Université de Bretagne Ouest, Brest, Cedex, 29609, France. olivier.huet@chu-brest.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Huet
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, P.O. Box 266, Helsinki, FIN-00029, Finland. Markus.Skrifvars@hus.fi.
authors.forename: Markus
authors.initials: M
authors.lastname: Skrifvars
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. Arabi@NGHA.MED.SA.|Intensive Care Department, College of Medicine King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, PO Box 22490, Riyadh, 11426, Kingdom of Saudi Arabia. Arabi@NGHA.MED.SA.
authors.forename: Yaseen
authors.initials: Y
authors.lastname: Arabi
authors.affiliation: Australian and New Zealand Intensive Care Research Centre, Monash University School of Public Health and Preventive Medicine, 99 Commercial Road, Melbourne, 3004, Australia. Rinaldo.Bellomo@austin.org.au.|The University of Melbourne, Grattan Street, Parkville, 3052, Australia. Rinaldo.Bellomo@austin.org.au.|Department of Intensive Care, Austin Health, Studley Road, Heidelberg, 3084, Australia. Rinaldo.Bellomo@austin.org.au.
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001315:Australia; D001930:Brain Injuries / Q000175:diagnosis / Q000188:drug therapy* / Q000191:economics / Q000401:mortality; D002985:Clinical Protocols; D003362:Cost-Benefit Analysis; D016638:Critical Illness; D003627:Data Interpretation, Statistical; D004185:Disability Evaluation; D004334:Drug Administration Schedule; D016527:Drug Costs; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects / Q000191:economics; D005060:Europe; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D015601:Injury Severity Score; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000191:economics; D009520:New Zealand; D011446:Prospective Studies; D011788:Quality of Life; D020127:Recovery of Function; D012107:Research Design / Q000706:statistics & numerical data*; D012529:Saudi Arabia; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018696:Neuroprotective Agents; D004921:Erythropoietin