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

Jeffrey Presneill, Lorraine Little, Alistair Nichol, Craig French, D James Cooper, Samir Haddad, Jacques Duranteau, Olivier Huet, Markus Skrifvars, Yaseen Arabi, Rinaldo Bellomo, EPO-TBI Investigators, ANZICS Clinical Trials Group, Heather Waddy, Marwan Al Kishi, Sarah Kambire, Serge Camelo, Markus Skrifvars, Stepani Bendel, Carole Schilling, Thomas Kerz, Lynnette Murray, Belinda Howe, Rinaldo Bellomo, Alistair Nichol, Craig French, D James Cooper, Olivier Huet, Lorraine Little, Anne Mak, Ville Pettilä, Jeffrey Presneill, Shirley Vallance, Dinesh Varma, Judy Wills, Colin McArthur, Yan Chen, Lynette Newby, Criona Walshe, James O'Rourke, Carole Schilling, Imogen Mitchell, Frank Van Haren, Helen Rodgers, Seton Henderson, Jan Mehrtens, Sascha Noble, Matthew Bailey, Robyn Hutchinson, Dawn France, Brent Richards, Mandy Tallott, Markus Skrifvars, Heikki Vartiala, Marianne Eliasson, Jean Yves Lefrant, Laurent Muller, Claire Roger, Christian Bengler, Pierre Barbaste, Benoit Veber, Marie Gilles-Baray, Pierre-Gildas Guitard, Helene Braud, Jacques Duranteau, Anatole Harrois, Samy Figueiredo, Sophie Hamada, Didier Payen, Anne Claire Lukaszewicz, Charles Damoisel, Sarah Kambire, Jean François Payen, Pauline Manhes, Gilles Franconey, Perrine Boucheix, Thomas Kerz, Peter Harrigan, Miranda Hardie, Samir Haddad, Yaseen Arabi, Marwan Al Kishi, Ahmad Deeb, Shmeylan Al Harbi, Lolowa Al-Swaidan, Turki Al Moammar, Juliet Lingling, Shella Caliwag, Hanie Richi, Stepani Bendel, Sari Rahikainen, Mikko Myllymaki, Victor Tam, Sharon Micallef, Louise Cole, Leonie Weisbrodt, Richard Strickland, Justine Rivett, Sonya Kloeden, Stephanie O'Connor, David Cooper, Richard McAllister, Nerina Harley, Deborah Barge, Elizabeth Moore, Andrea Jordan, Simon Finfer, Elizabeth Yarad, Simon Bird, Anne O'Connor, Geoffrey Dobb, Jenny Chamberlain, Michelle Barr, Elizabeth Jenkinson, David Gattas, Heidi Buhr, Debra Hutch, Megan Keir, Priya Nair, Claire Reynolds, Serena Knowles, D James Cooper, Jasmin Board, Shirley Vallance, Phoebe McCracken, Geoffrey Gordon, Stephen Reeves, Richard Dinsdale, Lynn Andrews, Dianne Mackle, Sally Hurford, Vineet Nayyar, Christina Whitehead, Jing Kong, Jacques Duranteau, Eric Vicaut, Philippe Gallula, Vidhya Raghavan, Amel Chamam, Sarah Kambire, Jeffrey Presneill, Lorraine Little, Alistair Nichol, Craig French, D James Cooper, Samir Haddad, Jacques Duranteau, Olivier Huet, Markus Skrifvars, Yaseen Arabi, Rinaldo Bellomo, EPO-TBI Investigators, ANZICS Clinical Trials Group, Heather Waddy, Marwan Al Kishi, Sarah Kambire, Serge Camelo, Markus Skrifvars, Stepani Bendel, Carole Schilling, Thomas Kerz, Lynnette Murray, Belinda Howe, Rinaldo Bellomo, Alistair Nichol, Craig French, D James Cooper, Olivier Huet, Lorraine Little, Anne Mak, Ville Pettilä, Jeffrey Presneill, Shirley Vallance, Dinesh Varma, Judy Wills, Colin McArthur, Yan Chen, Lynette Newby, Criona Walshe, James O'Rourke, Carole Schilling, Imogen Mitchell, Frank Van Haren, Helen Rodgers, Seton Henderson, Jan Mehrtens, Sascha Noble, Matthew Bailey, Robyn Hutchinson, Dawn France, Brent Richards, Mandy Tallott, Markus Skrifvars, Heikki Vartiala, Marianne Eliasson, Jean Yves Lefrant, Laurent Muller, Claire Roger, Christian Bengler, Pierre Barbaste, Benoit Veber, Marie Gilles-Baray, Pierre-Gildas Guitard, Helene Braud, Jacques Duranteau, Anatole Harrois, Samy Figueiredo, Sophie Hamada, Didier Payen, Anne Claire Lukaszewicz, Charles Damoisel, Sarah Kambire, Jean François Payen, Pauline Manhes, Gilles Franconey, Perrine Boucheix, Thomas Kerz, Peter Harrigan, Miranda Hardie, Samir Haddad, Yaseen Arabi, Marwan Al Kishi, Ahmad Deeb, Shmeylan Al Harbi, Lolowa Al-Swaidan, Turki Al Moammar, Juliet Lingling, Shella Caliwag, Hanie Richi, Stepani Bendel, Sari Rahikainen, Mikko Myllymaki, Victor Tam, Sharon Micallef, Louise Cole, Leonie Weisbrodt, Richard Strickland, Justine Rivett, Sonya Kloeden, Stephanie O'Connor, David Cooper, Richard McAllister, Nerina Harley, Deborah Barge, Elizabeth Moore, Andrea Jordan, Simon Finfer, Elizabeth Yarad, Simon Bird, Anne O'Connor, Geoffrey Dobb, Jenny Chamberlain, Michelle Barr, Elizabeth Jenkinson, David Gattas, Heidi Buhr, Debra Hutch, Megan Keir, Priya Nair, Claire Reynolds, Serena Knowles, D James Cooper, Jasmin Board, Shirley Vallance, Phoebe McCracken, Geoffrey Gordon, Stephen Reeves, Richard Dinsdale, Lynn Andrews, Dianne Mackle, Sally Hurford, Vineet Nayyar, Christina Whitehead, Jing Kong, Jacques Duranteau, Eric Vicaut, Philippe Gallula, Vidhya Raghavan, Amel Chamam, Sarah Kambire

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.

Discussion: 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.

Trial registration: 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).

Figures

Figure 1
Figure 1
CONSORT flow diagram.

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