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Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: A statistical analysis plan

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  • Janus Christian Jakobsen, University of Copenhagen, University of Southern Denmark
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  • Josef Dankiewicz, Lund University
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  • Theis Lange, University of Copenhagen
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  • Tobias Cronberg, Lund University
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  • Gisela Lilja, Lund University
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  • Helena Levin, Lund University
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  • Jan Bělohlávek, Charles University
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  • Clifton Callaway, University of Pittsburgh
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  • Alain Cariou, Universite Paris 5
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  • David Erlinge, Lund University
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  • Jan Hovdenes, University of Oslo
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  • Michael Joannidis, Innsbruck Medical University
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  • Per Nordberg, Karolinska Institutet
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  • Mauro Oddo, University of Lausanne
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  • Paolo Pelosi, University of Genoa, San Martino Hospital Genoa
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  • Hans Kirkegaard
  • Glenn Eastwood, University of Melbourne
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  • Christian Rylander, University of Gothenburg
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  • Manoj Saxena, University of New South Wales
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  • Christian Storm, Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Division of Neuroscience Critical Care, Johns Hopkins University
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  • Fabio Silvio Taccone, Université Libre de Bruxelles
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  • Matthew P. Wise, Cardiff & Vale University Health Board
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  • Matt P.G. Morgan, Cardiff & Vale University Health Board
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  • Paul Young, Medical Research Institute of New Zealand
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  • Alistair Nichol, University College Dublin, Monash University, Alfred Hospital
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  • Hans Friberg, Lund University
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  • Susann Ullén, Lund University
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  • Niklas Nielsen, Department of Clinical Sciences Lund, Lund University

Background: To date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear. Methods/design: The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33 °C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (≥ 37.8 °C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180 days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4-6) at 180 days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan. Discussion: This SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.

Original languageEnglish
Article number831
JournalTrials
Volume21
Issue1
ISSN1468-6708
DOIs
Publication statusPublished - Oct 2020

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