Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest

NCT02908308 | Completed DMC

• 1 other identifier: TTM-2
• Study Type: interventional
• Target: 1,900
• Locations: 13 countries
• Sites: 50

Brief Summary

ILCOR guidelines recommend Target Temperature Management (TTM) to between 32°C and 36°C after out-of-hospital cardiac arrest, based on low quality evidence. In a previous trial, TTM at 33°C did not confer a survival benefit or improved neurological function, compared to TTM at 36°C. A lower target temperature might be beneficial compared with normothermia and early treatment of fever. Therefore the primary purpose of the TTM2-trial will be to study any differences in mortality, neurological function and quality of life between a target temperature of 33°C and standard care avoiding fever.

Conditions

Out-of-hospital Cardiac Arrest

Keywords

Induced hypothermia; Mild induced hypothermia; Therapeutic hypothermia; Cardiac arrest; Out-of-hospital cardiac arrest; Mortality; Neurological function; Randomised clinical trial

Outcome Measures

Primary Outcomes (1)

• Mortality

  Landmark mortality at 180 days

  180 days

Secondary Outcomes (5)

• Poor functional outcome

  180 days

• Days alive outside hospital

  180 days.

• Quality of Life

  180 days

• Quality of Life

  180 days

• Survival until end of the trial

  180 days after randmomization of the last patient

Study Arms (2)

Normothermia

ACTIVE COMPARATOR

Standard care with early treatment of fever. Active temperature control with a device will be used if the patient develops a temperature greater than or equal 37.8°C.

Procedure: Standard care with early treatment of fever

Hypothermia

EXPERIMENTAL

Targeted temperature management to 33°C for up to 28h.

Procedure: Targeted temperature management to 33°C

Interventions

Targeted temperature management to 33°C PROCEDURE

Rapid cooling to below 33°C, followed by temperature control at 33°C for up to 28h.

Hypothermia

Standard care with early treatment of fever PROCEDURE

Normothermia and standard care - use of a device for temperature control if temperature is greater than or equal to 37.8°C

Normothermia

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Out-of-hospital cardiac arrest
• Presumed cardiac cause of cardiac arrest
• Unconscious with a FOUR-score \<M4 (not obeying verbal commands)
• Stable return of spontaneous circulation (20 min)
• Eligible for intensive care treatment without restrictions

You may not qualify if:

• Unwitnessed cardiac arrest with an initial rhythm of asystole
• Temperature on admission \<30°C.
• On ECMO prior to ROSC
• Obvious or suspected pregnancy
• Intracranial bleeding
• On ECMO prior to ROSC
• Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy

Sponsors & Collaborators

• Helsingborgs Hospital: lead
• Lund University: collaborator
• Region Skåne - Skånevård SUND: collaborator
• Copenhagen Trial Unit, Center for Clinical Intervention Research: collaborator
• Clinical Trials Sweden, Forum South: collaborator
• Integrated Biobank of Luxembourg: collaborator

Study Sites (60)

Mayo Clinic Hospital-St. Mary's Campus

Rochester, New York, 55905, United States

Location

UPMC-Presbyterian

Pittsburgh, Pennsylvania, 15213, United States

Location

John Hunter Hospital

Newcastle, New South Wales, Australia

Location

Concord Repatriation General Hospital

Sydney, New South Wales, Australia

Location

Liverpool Hospital

Sydney, New South Wales, Australia

Location

St Vincent's Hospital

Sydney, New South Wales, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Location

Northern Hospital

Epping, Victoria, Australia

Location

The Alfred

Melbourne, Victoria, Australia

Location

Austin Hospital

Melbourne, Australia

Location

Nepean Hospital

Sydney, Australia

Location

Royal North Shore Hospital

Sydney, Australia

Location

Innsbruck University Hospital

Innsbruck, Austria

Location

Erasme Hospital

Brussels, Belgium

Location

Ziekenhuis Oost-Limburg

Genk, Belgium

Location

Hradec Kralove Hospital

Hradec Králové, Czechia

Location

Liberec Hospital

Liberec, Czechia

Location

General University Hospital

Prague, Czechia

Location

Aarhus University Hospital

Aarhus, Denmark

Location

Chu Dupuytren

Limoges, France

Location

CHU Nantes

Nantes, France

Location

Cochin University Hospital

Paris, France

Location

Lariboisière Hospital

Paris, France

Location

Versailles Hospital

Versailles, France

Location

Charité, Campus Virchow

Berlin, Germany

Location

San Martino Hospital

Genova, Italy

Location

Modena NOCSAE Hospital

Modena, Italy

Location

Christchurch Hospital

Christchurch, New Zealand

Location

Wellington Hospital

Wellington, 6021, New Zealand

Location

Sorlandet Hospital

Arendal, Norway

Location

Haukeland Hospital

Bergen, Norway

Location

Oslo University Hospital

Oslo, Norway

Location

St. Olav's University Hospital

Trondheim, Norway

Location

Hallands Hospital

Halmstad, Halland County, 302 33, Sweden

Location

Skane University Hospital - Lund

Lund, Skåne County, 22185, Sweden

Location

Skane University Hospital - Malmö

Malmo, Skåne County, 22185, Sweden

Location

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

Helsingborgs Hospital

Helsingborg, 251 87, Sweden

Location

Centralsjukhuset i Karlstad

Karlstad, 652 30, Sweden

Location

Linköping University Hospital

Linköping, Sweden

Location

Örebro University Hospital

Örebro, Sweden

Location

Skaraborgs sjukhus

Skövde, Sweden

Location

Capio St:Göran

Stockholm, Sweden

Location

Södersjukhuset

Stockholm, Sweden

Location

Norra Älvsborgs Länssjukhus (NÄL)

Trollhättan, 461 73, Sweden

Location

Akademiska Sjukhuset

Uppsala, Sweden

Location

University Hospital Bern, Inselspital

Bern, Switzerland

Location

University Hospital of Lausanne

Lausanne, Switzerland

Location

Cardiocentro Ticino

Lugano, Switzerland

Location

Kantonsspital St.Gallen

Sankt Gallen, Switzerland

Location

Zurich University Hospital

Zurich, Switzerland

Location

Basildon and Thurrock Hospitals NHS Foundation Trust - Essex CTC

Basildon, United Kingdom

Location

Royal Victoria Hospital

Belfast, United Kingdom

Location

Birmingham University Hospital

Birmingham, United Kingdom

Location

Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust

Bournemouth, United Kingdom

Location

Bristol Royal Infirmary

Bristol, United Kingdom

Location

University Hospital of Wales

Cardiff, United Kingdom

Location

Manchester Royal Infirmary

Manchester, United Kingdom

Location

Queen Alexandra Hospital

Portsmouth, United Kingdom

Location

Royal Berkshire Hospital

Reading, United Kingdom

Location

Related Publications (16)

• Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Aneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Kober L, Langorgen J, Lilja G, Moller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H; TTM Trial Investigators. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206. doi: 10.1056/NEJMoa1310519. Epub 2013 Nov 17.

  PMID: 24237006 BACKGROUND

• Gobel Andertun S, Wissendorff-Ekdahl A, Ullen S, Cronberg T, Friberg H, Jakobsen JC, Blennow Nordstrom E, Heimburg K, Cariou A, Grejs AM, Haenggi M, Hovdenes J, Robba C, Rylander C, Taccone FS, Wise MP, Young PJ, Nielsen N, Lilja G. Impact of frailty on mortality, functional outcome, and health status after out-of-hospital cardiac arrest: insights from the TTM2-trial. Intensive Care Med. 2025 Dec;51(12):2367-2377. doi: 10.1007/s00134-025-08185-5. Epub 2025 Nov 10.

  PMID: 41212202 DERIVED

• Admiraal MM, Backman S, Annborn M, Borgquist O, Dankiewicz J, During J, Legriel S, Lilja G, Lindehammer H, Nielsen N, Rossetti AO, Unden J, Cronberg T, Westhall E; TTM2-trial investigators. Electrographic and Clinical Determinants of Good Outcome After Postanoxic Status Epilepticus. Neurology. 2025 Mar 11;104(5):e210304. doi: 10.1212/WNL.0000000000210304. Epub 2025 Feb 11.

  PMID: 39933130 DERIVED

• Taccone FS, Cariou A, Zorzi S, Friberg H, Jakobsen JC, Nordberg P, Robba C, Belohlavek J, Hovdenes J, Haenggi M, Aneman A, Grejs A, Keeble TR, Annoni F, Young PJ, Wise MP, Cronberg T, Lilja G, Nielsen N, Dankiewicz J. Hypothermia versus normothermia in patients with cardiac arrest and shockable rhythm: a secondary analysis of the TTM-2 study. Crit Care. 2024 Oct 15;28(1):335. doi: 10.1186/s13054-024-05119-3.

  PMID: 39407230 DERIVED

• Heimburg K, Blennow Nordstrom E, Dankiewicz J, Friberg H, Grejs AM, Hanggi M, Keeble TR, Kirkegaard H, Nielsen N, Rylander C, Tornberg AB, Ullen S, Wise MP, Cronberg T, Lilja G. Low physical activity level in out-of-hospital cardiac arrest survivors with obesity, mobility problems and cognitive impairment: Results from the TTM2 trial. Resuscitation. 2024 Nov;204:110407. doi: 10.1016/j.resuscitation.2024.110407. Epub 2024 Oct 4.

  PMID: 39368797 DERIVED

• Battaglini D, Schiavetti I, Ball L, Jakobsen JC, Lilja G, Friberg H, Wendel-Garcia PD, Young PJ, Eastwood G, Chew MS, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Hammond N, Saxena M, Martin A, Solar M, Taccone FS, Dankiewicz J, Nielsen N, Morten Grejs A, Wise MP, Hangghi M, Smid O, Patroniti N, Robba C; TTM2 trial investigators. Association between early airway intervention in the pre-hospital setting and outcomes in out of hospital cardiac arrest patients: A post-hoc analysis of the Target Temperature Management-2 (TTM2) trial. Resuscitation. 2024 Oct;203:110390. doi: 10.1016/j.resuscitation.2024.110390. Epub 2024 Sep 5.

  PMID: 39244144 DERIVED

• Lang M, Kenda M, Scheel M, Martola J, Wheeler M, Owen S, Johnsson M, Annborn M, Dankiewicz J, Deye N, During J, Friberg H, Halliday T, Jakobsen JC, Lascarrou JB, Levin H, Lilja G, Lybeck A, McGuigan P, Rylander C, Sem V, Thomas M, Ullen S, Unden J, Wise MP, Cronberg T, Wasselius J, Nielsen N, Leithner C, Moseby-Knappe M. Standardised and automated assessment of head computed tomography reliably predicts poor functional outcome after cardiac arrest: a prospective multicentre study. Intensive Care Med. 2024 Jul;50(7):1096-1107. doi: 10.1007/s00134-024-07497-2. Epub 2024 Jun 20.

  PMID: 38900283 DERIVED

• Holgersson J, Meyer MAS, Dankiewicz J, Lilja G, Ullen S, Hassager C, Cronberg T, Wise MP, Belohlavek J, Hovdenes J, Pelosi P, Erlinge D, Schrag C, Smid O, Brunetti I, Rylander C, Young PJ, Saxena M, Aneman A, Cariou A, Callaway C, Eastwood GM, Haenggi M, Joannidis M, Keeble TR, Kirkegaard H, Leithner C, Levin H, Nichol AD, Morgan MPG, Nordberg P, Oddo M, Storm C, Taccone FS, Thomas M, Bro-Jeppesen J, Horn J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher MJ, Friberg H, Nielsen N, Jakobsen JC. Hypothermic versus Normothermic Temperature Control after Cardiac Arrest. NEJM Evid. 2022 Nov;1(11):EVIDoa2200137. doi: 10.1056/EVIDoa2200137. Epub 2022 Jun 15.

  PMID: 38319850 DERIVED

• Lilja G, Ullen S, Dankiewicz J, Friberg H, Levin H, Nordstrom EB, Heimburg K, Jakobsen JC, Ahlqvist M, Bass F, Belohlavek J, Olsen RB, Cariou A, Eastwood G, Fanebust HR, Grejs AM, Grimmer L, Hammond NE, Hovdenes J, Hrecko J, Iten M, Johansen H, Keeble TR, Kirkegaard H, Lascarrou JB, Leithner C, Lesona ME, Levis A, Mion M, Moseby-Knappe M, Navarra L, Nordberg P, Pelosi P, Quayle R, Rylander C, Sandberg H, Saxena M, Schrag C, Siranec M, Tiziano C, Vignon P, Wendel-Garcia PD, Wise MP, Wright K, Nielsen N, Cronberg T. 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. JAMA Neurol. 2023 Oct 1;80(10):1070-1079. doi: 10.1001/jamaneurol.2023.2536.

  PMID: 37548968 DERIVED

• Robba C, Badenes R, Battaglini D, Ball L, Sanfilippo F, Brunetti I, Jakobsen JC, Lilja G, Friberg H, Wendel-Garcia PD, Young PJ, Eastwood G, Chew MS, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Hammond N, Saxena M, Martin A, Solar M, Taccone FS, Dankiewicz J, Nielsen N, Grejs AM, Ebner F, Pelosi P; TTM2 Trial collaborators. Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Crit Care. 2022 Oct 21;26(1):323. doi: 10.1186/s13054-022-04186-8.

  PMID: 36271410 DERIVED

• Lang M, Leithner C, Scheel M, Kenda M, Cronberg T, During J, Rylander C, Annborn M, Dankiewicz J, Deye N, Halliday T, Lascarrou JB, Matthew T, McGuigan P, Morgan M, Thomas M, Ullen S, Unden J, Nielsen N, Moseby-Knappe M. Prognostic accuracy of head computed tomography for prediction of functional outcome after out-of-hospital cardiac arrest: Rationale and design of the prospective TTM2-CT-substudy. Resusc Plus. 2022 Oct 12;12:100316. doi: 10.1016/j.resplu.2022.100316. eCollection 2022 Dec.

  PMID: 36267356 DERIVED

• During J, Annborn M, Cariou A, Chew MS, Dankiewicz J, Friberg H, Haenggi M, Haxhija Z, Jakobsen JC, Langeland H, Taccone FS, Thomas M, Ullen S, Wise MP, Nielsen N. Influence of temperature management at 33 degrees C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial. Crit Care. 2022 Jul 31;26(1):231. doi: 10.1186/s13054-022-04107-9.

  PMID: 35909163 DERIVED

• Robba C, Badenes R, Battaglini D, Ball L, Brunetti I, Jakobsen JC, Lilja G, Friberg H, Wendel-Garcia PD, Young PJ, Eastwood G, Chew MS, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Hammond N, Saxena M, Annborn M, Solar M, Taccone FS, Dankiewicz J, Nielsen N, Pelosi P; TTM2 Trial Collaborators. 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. Intensive Care Med. 2022 Aug;48(8):1024-1038. doi: 10.1007/s00134-022-06756-4. Epub 2022 Jul 2.

  PMID: 35780195 DERIVED

• Robba C, Nielsen N, Dankiewicz J, Badenes R, Battaglini D, Ball L, Brunetti I, Pedro David WG, Young P, Eastwood G, Chew MS, Jakobsen J, Unden J, Thomas M, Joannidis M, Nichol A, Lundin A, Hollenberg J, Lilja G, Hammond NE, Saxena M, Martin A, Solar M, Taccone FS, Friberg HA, Pelosi P. Ventilation management and outcomes in out-of-hospital cardiac arrest: a protocol for a preplanned secondary analysis of the TTM2 trial. BMJ Open. 2022 Mar 3;12(3):e058001. doi: 10.1136/bmjopen-2021-058001.

  PMID: 35241476 DERIVED

• Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullen S, Rylander C, Wise MP, Oddo M, Cariou A, Belohlavek J, Hovdenes J, Saxena M, Kirkegaard H, Young PJ, Pelosi P, Storm C, Taccone FS, Joannidis M, Callaway C, Eastwood GM, Morgan MPG, Nordberg P, Erlinge D, Nichol AD, Chew MS, Hollenberg J, Thomas M, Bewley J, Sweet K, Grejs AM, Christensen S, Haenggi M, Levis A, Lundin A, During J, Schmidbauer S, Keeble TR, Karamasis GV, Schrag C, Faessler E, Smid O, Otahal M, Maggiorini M, Wendel Garcia PD, Jaubert P, Cole JM, Solar M, Borgquist O, Leithner C, Abed-Maillard S, Navarra L, Annborn M, Unden J, Brunetti I, Awad A, McGuigan P, Bjorkholt Olsen R, Cassina T, Vignon P, Langeland H, Lange T, Friberg H, Nielsen N; TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. doi: 10.1056/NEJMoa2100591.

  PMID: 34133859 DERIVED

• Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Belohlavek J, Callaway C, Cariou A, Eastwood G, Erlinge D, Hovdenes J, Joannidis M, Kirkegaard H, Kuiper M, Levin H, Morgan MPG, Nichol AD, Nordberg P, Oddo M, Pelosi P, Rylander C, Saxena M, Storm C, Taccone F, Ullen S, Wise MP, Young P, Friberg H, Nielsen N. Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial-Rationale and design. Am Heart J. 2019 Nov;217:23-31. doi: 10.1016/j.ahj.2019.06.012. Epub 2019 Jun 26.

  PMID: 31473324 DERIVED

Related Links

• Trial official webpage

MeSH Terms

Conditions

Out-of-Hospital Cardiac Arrest; Heart Arrest

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Niklas Nielsen, MD, PhD

  Helsingborgs lasarett, Region Skåne, Sweden

  PRINCIPAL INVESTIGATOR

• Hans Friberg, MD, PhD

  Lund University Hospital, Lund, Sweden

  PRINCIPAL INVESTIGATOR

• Tobias Cronberg, MD, PhD

  Lund University Hospital, Lund, Sweden

  PRINCIPAL INVESTIGATOR

• Jan Hovdenes, MD, PhD

  Oslo University Hospital, Oslo, Norway

  PRINCIPAL INVESTIGATOR

• Matt P Wise, MD, PhD

  University Hospital of Wales, Cardiff, UK

  PRINCIPAL INVESTIGATOR

• Clifton W Callaway, MD, PhD

  University of Pittsburgh, Pittsburgh, USA

  PRINCIPAL INVESTIGATOR

• Christian Storm, MD, PhD

  Charité-University Medicine (Berlin, Germany)

  PRINCIPAL INVESTIGATOR

• Alain Cariou, MD, PhD

  Université Paris Descartes, France

  PRINCIPAL INVESTIGATOR

• David Erlinge, MD, PhD

  Lund University Hospital, Lund, Sweden

  PRINCIPAL INVESTIGATOR

• Christian Rylander, MD, PhD

  Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

• Josef Dankiewicz, MD, PhD

  Skåne University Hospital Lund

  PRINCIPAL INVESTIGATOR

• Mauro Oddo, MD, PhD

  Université de Lausanne, Lausanne, Switzerland

  PRINCIPAL INVESTIGATOR

• Manoj Saxena, MD, PhD

  The George Institute for Global Health (Sydney, Australia)

  PRINCIPAL INVESTIGATOR

• Per Nordberg, MD, PhD

  Södersjukhuset, Stockholm

  PRINCIPAL INVESTIGATOR

• Fabio Taccone, MD, PhD

  Hopital Erasme, Brussles, Belgium

  PRINCIPAL INVESTIGATOR

• Paolo Pelosi, MD, PhD

  San Martino University Hospital, Genoa

  PRINCIPAL INVESTIGATOR

• Michael Ioannidis, MD, PhD

  Innsbruck University Hospital

  PRINCIPAL INVESTIGATOR

• Jan Belholavek, MD, PhD

  Prague University Hospital

  PRINCIPAL INVESTIGATOR

• Paul Young, MD

  Wellington Regional Hospital

  PRINCIPAL INVESTIGATOR

• Hans Kirkegaard, MD,PhD

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

• Alistair Nichol, MD, PhD

  Department of Anaesthesia and Intensive Care Medicine, St Vincent's University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The clinical team responsible for the participant (physicians, nurses and others) and involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention and as temperature is a vital sign required for clinical care. Measures will be taken to ensure that the information about allocation will not disseminate beyond the immediate group of caregivers responsible for patient care. A blinded physician will evaluate the patient at 96 hours after randomisation and make a statement on neurological prognosis.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Associate professor

Study Record Dates

• First Submitted: September 16, 2016
• First Posted: September 20, 2016
• Study Start: November 18, 2017
• Primary Completion: June 30, 2022
• Study Completion: December 31, 2022
• Last Updated: April 3, 2023

Record last verified: 2023-03

Locations

NZ (2); CZ (3); FR (5); CH (5); GB (9); DK (1); BE (2); AU (1); US (2); DE (1); IT (2); NO (4); SE (13)