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.

2nd Department of Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Adult Critical Care University Hospital of Wales Cardiff UK

Australian and New Zealand Intensive Care Research Centre Monash University Melbourne Australia

Bankstown Hospital Clinical School and The George Institute for Global Health University of New South Wales Kensington Australia

Clinical Studies Sweden Skåne University Hospital Lund Sweden

Copenhagen Trial Unit Centre for Clinical Intervention Research Department 7812 Rigshospitalet Copenhagen University Hospital Tagensvej 22 Copenhagen Denmark

Department of Anesthesia and Intensive Care Oslo University Hospital Rikshospitalet Oslo Norway

Department of Anesthesiology and Intensive Care Medicine Institute of Clinical Sciences Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Cardiology Holbæk Hospital Holbæk Denmark

Department of Clinical Sciences Anesthesia and Intensive Care Lund University Skåne University Hospital Lund Sweden

Department of Clinical Sciences Cardiology Lund University Skåne University Hospital Lund Sweden

Department of Clinical Sciences Lund Anesthesia and Intensive Care Lund University Helsingborg Hospital Lund Sweden

Department of Clinical Sciences Neurology Lund University Skåne University Hospital Lund Sweden

Department of Clinical Sciences Research and Education Lund University Skåne University Hospital Lund Sweden

Department of Critical Care Alfred Hospital Melbourne Australia

Department of Emergency Medicine University of Pittsburgh Pittsburgh PA USA

Department of Intensive Care Austin Hospital Heidelberg Australia

Department of Intensive Care Erasme University Hospital Université Libre de Bruxelles Brussels Belgium

Department of Intensive Care Medicine Faculty of Biology and Medicine Centre Hospitalier Universitaire Vaudois University Hospital University of Lausanne Lausanne Switzerland

Department of Medicine Center for Resuscitation Science Karolinska Institute Solna Sweden

Department of Nephrology and Medical Intensive Care Charité Universitätsmedizin Berlin Berlin Germany

Department of Regional Health Research The Faculty of Health Sciences University of Southern Denmark Odense Denmark

Department of Surgical Sciences and Integrated Diagnostics University of Genoa Genoa Italy

Division of Intensive Care and Emergency Medicine Department of Internal Medicine Medical University Innsbruck Innsbruck Austria

Division of Neuroscience Critical Care Department of Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore MD USA

Medical Intensive Care Unit Cochin University Hospital and Paris Descartes University Paris France

Medical Research Institute of New Zealand Wellington New Zealand

Research Center for Emergency Medicine Department of Clinical Medicine Aarhus University Hospital and Aarhus University Aarhus N Denmark

San Martino Policlinico Hospital IRCCS for Oncology and Neurosciences University of Genoa Genoa Italy

Section of Biostatistics Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

University Collage Dublin Clinical Research Centre St Vincent's University Hospital Dublin Ireland

Zobrazit více v PubMed

Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197–2206. doi: 10.1056/NEJMoa1310519. PubMed DOI

Lascarrou JB, Merdji H, Le Gouge A, Colin G, Grillet G, Girardie P, Coupez E, Dequin PF, Cariou A, Boulain T, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019;381(24):2327–2337. doi: 10.1056/NEJMoa1906661. PubMed DOI

Dankiewicz J, Cronberg T, Gisela Lilja G, Jakobsen J, Bělohlávek J, Callaway C, Cariou A, Eastwood G, Erlinge D, Hovdenes J, et al. Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2). A randomised clinical trial – rationale and design. Am Heart J. 2019;217:23–31. PubMed

Ebner F, Harmon MBA, Aneman A, Cronberg T, Friberg H, Hassager C, Juffermans N, Kjaergaard J, Kuiper M, Mattsson N, et al. Carbon dioxide dynamics in relation to neurological outcome in resuscitated out-of-hospital cardiac arrest patients: an exploratory Target Temperature Management Trial substudy. Crit Care. 2018;22(1):196. doi: 10.1186/s13054-018-2119-5. PubMed DOI PMC

Lilja G, Nielsen N, Ullen S, Blennow Nordstrom E, Dankiewicz J, Friberg H, Heimburg K, Jakobsen JC, Levin H, Callaway C, et al. Protocol for outcome reporting and follow-up in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2) Resuscitation. 2020;150:104–112. doi: 10.1016/j.resuscitation.2020.03.004. PubMed DOI

Jakobsen JC, Ovesen C, Winkel P, Hilden J, Gluud C, Wetterslev J. Power estimations for non-primary outcomes in randomised clinical trials. BMJ Open. 2019;9:e027092. doi: 10.1136/bmjopen-2018-027092. PubMed DOI PMC

Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38(3):1091–1096. doi: 10.1161/01.STR.0000258355.23810.c6. PubMed DOI

Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, Swinburn P, Busschbach J. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res. 2013;22(7):1717–1727. doi: 10.1007/s11136-012-0322-4. PubMed DOI PMC

Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, Valsson F, Wanscher M, Friberg H, Hypothermia N. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009;53(7):926–934. doi: 10.1111/j.1399-6576.2009.02021.x. PubMed DOI

Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–563. doi: 10.1056/NEJMoa003289. PubMed DOI

Hypothermia after Cardiac Arrest Study G Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–556. doi: 10.1056/NEJMoa012689. PubMed DOI

Jakobsen JC, Gluud C, Winkel P, Lange T, Wetterslev J. The thresholds for statistical and clinical significance - a five-step procedure for evaluation of intervention effects in randomised clinical trials. BMC Med Res Methodol. 2014;14:34. doi: 10.1186/1471-2288-14-34. PubMed DOI PMC

Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Stat Med. 2011;31:328–340. doi: 10.1002/sim.4431. PubMed DOI

Kahan BC, Morris TP. Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ. 2012;345:e5840. doi: 10.1136/bmj.e5840. PubMed DOI PMC

Montgomery AA, Peters TJ, Little P. Design, analysis and presentation of factorial randomised controlled trials. BMC Med Res Methodol. 2003;3:26. doi: 10.1186/1471-2288-3-26. PubMed DOI PMC

Jakobsen JC, Tamborrino M, Winkel P, Haase N, Perner A, Wetterslev J, Gluud C. Count data analysis in randomised clinical trials. J Biomet Biostat. 2015;6(1):227.

Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol. 2017;17(1):162. doi: 10.1186/s12874-017-0442-1. PubMed DOI PMC

Nielsen EE, Norskov AK, Lange T, Thabane L, Wetterslev J, Beyersmann J, de Una-Alvarez J, Torri V, Billot L, Putter H, et al. Assessing assumptions for statistical analyses in randomised clinical trials. BMJ Evid Based Med. 2019;24(5):185–189. doi: 10.1136/bmjebm-2019-111174. PubMed DOI

Nørskov AK, Lange T, Nielsen EE, Gluud C, Winkel P, Beyersmann J, de Uña-Álvarez J, Torri V, Billot L, Putter H, et al. Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how. BMJ Evid Based Med. 2020;bmjebm-2019-111268. 10.1136/bmjebm-2019-111268. PubMed

Frydenberg SJM. An introduction to Stata for health researchers. 4th ed. College Station: Stata Press; 2014.

Oliveira AG. Biostatistics decoded: Wiley; 2013.

Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–463. doi: 10.1111/j.0006-341X.2000.00455.x. PubMed DOI