BACKGROUND: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. METHODS: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control 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 main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4-6) at 180 days after arrest. DISCUSSION: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest.

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 United Kingdom

Clinical Studies Sweden Skåne University Hospital Lund Sweden

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 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 Medical Center Leeuwarden Leeuwarden Netherlands

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

Department of Nephrology and Medical Intensive Care Charité Universitätsmedizin Berlin Germany and Division of Neuroscience Critical Care Department of Anesthesiology and Critical Care Medicin Johns Hopkins University School of Medicine Baltimore MD USA

Department of Research and Education Lund University and Skåne University Hospital

Department of Surgical Sciences and Integrated Diagnostics San Martino Policlinico Hospital IRCCS for Oncology University of Genoa Genoa Italy

Division of Critical Care and Trauma George Institute for Global Health Intensive Care Unit St George Hospital Sydney Australia

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

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

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

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

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

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

Section of Cardiology Stockholm South General Hospital Stockholm Sweden

The Copenhagen Trial Unit Centre for Clinical Intervention Research Copenhagen University Hospital Copenhagen Denmark

University College Dublin Clinical Research Centre St Vincent's University Hospital Dublin Ireland; Australian and New Zealand Intensive Care Research Centre Monash University Melbourne Australia and Dept of Critical Care Alfred Hospital Melbourne Australia

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Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial

Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators

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

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ClinicalTrials.gov
NCT02908308