TY - JOUR

T1 - Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest

T2 - a statistical analysis plan

AU - Jakobsen, Janus Christian

AU - Dankiewicz, Josef

AU - Lange, Theis

AU - Cronberg, Tobias

AU - Lilja, Gisela

AU - Levin, Helena

AU - Bělohlávek, Jan

AU - Callaway, Clifton

AU - Cariou, Alain

AU - Erlinge, David

AU - Hovdenes, Jan

AU - Joannidis, Michael

AU - Nordberg, Per

AU - Oddo, Mauro

AU - Pelosi, Paolo

AU - Kirkegaard, Hans

AU - Eastwood, Glenn

AU - Rylander, Christian

AU - Saxena, Manoj

AU - Storm, Christian

AU - Taccone, Fabio Silvio

AU - Wise, Matthew P

AU - Morgan, Matt P G

AU - Young, Paul

AU - Nichol, Alistair

AU - Friberg, Hans

AU - Ullén, Susann

AU - Nielsen, Niklas

PY - 2020/10/7

Y1 - 2020/10/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85092309127&partnerID=8YFLogxK

U2 - 10.1186/s13063-020-04654-y

DO - 10.1186/s13063-020-04654-y

M3 - Journal article

VL - 21

SP - 831

JO - Trials

JF - Trials

SN - 1745-6215

IS - 1

M1 - 831

ER -