Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM-2)

Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) - A Randomised Clinical Trial

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.

Study Overview

• Status: Completed
• Conditions: Out-of-hospital Cardiac Arrest
• Intervention / Treatment: Procedure: Standard care with early treatment of fever; Procedure: Targeted temperature management to 33°C

Detailed Description

The TTM2 trial is a continuation of the collaboration that resulted in the previous Targeted Temperature Management after out-of-hospital cardiac arrest trial (hereafter: TTM1). With its planned size with it will supersede the TTM1 trial as the largest trial on temperature management as a post-cardiac arrest treatment.

The TTM1 trial (NCT01020916) was a multicenter, multinational, outcome assessor-blinded, parallel group, randomised clinical trial comparing two strict target temperature regimens of 33°C and 36°C in adult patients, who have sustained return of spontaneous circulation and are unconscious after out-of-hospital cardiac arrest, when admitted to hospital. The trial did not demonstrate any difference in survival until end of trial (Hazard Ratio with a point estimate in favour of 36°C of 1.06 (95% confidence interval 0.89-1.28; P=0.51) or neurologic function at six months after the arrest, measured with CPC and mRS.

The planned study is a international, multicenter, parallel group, non-commerical, randomized, superiority trial in which a target temperature om 33°C after cardiac arrest will be compared to normothermia and early treatment of fever.

Patients eligible for inclusion will be unconscious adult patients with OHCA of a presumed cardiac cause with stable return of spontaneous circulation. Randomization will be performed by a physician in the emergency department, in the angiography suite or in the intensive care unit via web-based application using permuted blocks with varying sizes, stratified by site. Due to the nature of the intervention, health care staff will not be blinded to the intervention. However, the physicians who will assess outcomes will be blinded to temperature allocation, as will those who perform prognostication.

The intervention period will commence at the time of randomization. Cooling in the hypothermia group will achieved by means of cold fluids and state-of-the-art cooling devices (intravascular or body-surface applied closed loop systems). The initial aim will be to achieve a body temperature of 33.0°C. When this has been achieved, the target temperature will be 33°C until 28 hours after randomisation. When 28 hours have passed, gradual rewarming at a rate of 1/3°C per hour will commence, this will allow 12 hours for rewarming.

In the normothermia arm the aim will be to avoid a temperature greater than or equal to 37.8°C using conservative measures. If a single temperature of 37.8° or greater is measured, active cooling with a device should be initiated and maintained until 40 hours after randomization.

All participants will be sedated, mechanically ventilated and hemodynamically supported throughout the intervention period of 40 hours. Participants in both arms who remain comatose after 40h should be kept at a normothermic level (36.5 - 37.7°C) until 72h after randomization and active warming should be avoided.

Participants who remain unconscious four days after randomization will be assessed according to a conservative protocol based on the European Resuscitation Council's recommendations for withdrawal of life sustaining therapies.

Follow up will be performed at:

1 month (face-to-face or telephone), Assessment according to the modified Rankin scale (mRS)

6 moths (face-to-face), Assessment according to the mRS-scale. Assessment of health-related quality of life using EQ5D-5L.

• Study Type: Interventional
• Enrollment (Actual): 1900
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia
    • Austin Hospital
  • Sydney, Australia
    • Nepean Hospital
  • Sydney, Australia
    • Royal North Shore Hospital
  • New South Wales
    • Newcastle, New South Wales, Australia
      • John Hunter Hospital
    • Sydney, New South Wales, Australia
      • Concord Repatriation General Hospital
    • Sydney, New South Wales, Australia
      • Liverpool Hospital
    • Sydney, New South Wales, Australia
      • St Vincent's Hospital
  • Queensland
    • Brisbane, Queensland, Australia
      • Princess Alexandra Hospital
  • Victoria
    • Epping, Victoria, Australia
      • Northern Hospital
    • Melbourne, Victoria, Australia
      • The Alfred
• Austria
  • Innsbruck, Austria
    • Innsbruck University Hospital
• Belgium
  • Brussels, Belgium
    • Erasme hospital
  • Genk, Belgium
    • Ziekenhuis Oost-Limburg
• Czechia
  • Hradec Králové, Czechia
    • Hradec Kralove Hospital
  • Liberec, Czechia
    • Liberec Hospital
  • Prague, Czechia
    • General University Hospital
• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital
• France
  • Limoges, France
    • CHU Dupuytren
  • Nantes, France
    • CHU Nantes
  • Paris, France
    • Lariboisière Hospital
  • Paris, France
    • Cochin University Hospital
  • Versailles, France
    • Versailles Hospital
• Germany
  • Berlin, Germany
    • Charité, Campus Virchow
• Italy
  • Genova, Italy
    • San Martino Hospital
  • Modena, Italy
    • Modena NOCSAE Hospital
• New Zealand
  • Christchurch, New Zealand
    • Christchurch Hospital
  • Wellington, New Zealand, 6021
    • Wellington Hospital
• Norway
  • Arendal, Norway
    • Sorlandet hospital
  • Bergen, Norway
    • Haukeland Hospital
  • Oslo, Norway
    • Oslo University Hospital
  • Trondheim, Norway
    • St. Olav's University Hospital
• Sweden
  • Gothenburg, Sweden
    • Sahlgrenska University Hospital
  • Helsingborg, Sweden, 251 87
    • Helsingborgs Hospital
  • Karlstad, Sweden, 652 30
    • Centralsjukhuset i Karlstad
  • Linköping, Sweden
    • Linköping University hospital
  • Skövde, Sweden
    • Skaraborgs sjukhus
  • Stockholm, Sweden
    • Södersjukhuset
  • Stockholm, Sweden
    • Capio St:Göran
  • Trollhättan, Sweden, 461 73
    • Norra Älvsborgs Länssjukhus (NÄL)
  • Uppsala, Sweden
    • Akademiska Sjukhuset
  • Örebro, Sweden
    • Orebro University Hospital
  • Halland
    • Halmstad, Halland, Sweden, 302 33
      • Hallands hospital
  • Skåne
    • Lund, Skåne, Sweden, 22185
      • Skane University Hospital - Lund
    • Malmö, Skåne, Sweden, 22185
      • Skane University Hospital - Malmö
• Switzerland
  • Bern, Switzerland
    • University Hospital Bern, Inselspital
  • Lausanne, Switzerland
    • University Hospital of Lausanne
  • Lugano, Switzerland
    • Cardiocentro Ticino
  • Saint Gallen, Switzerland
    • Kantonsspital St.Gallen
  • Zürich, Switzerland
    • Zurich University Hospital
• United Kingdom
  • Basildon, United Kingdom
    • Basildon and Thurrock Hospitals NHS Foundation Trust - Essex CTC
  • Belfast, United Kingdom
    • Royal Victoria Hospital
  • Birmingham, United Kingdom
    • Birmingham University Hospital
  • Bournemouth, United Kingdom
    • Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
  • Bristol, United Kingdom
    • Bristol Royal Infirmary
  • Cardiff, United Kingdom
    • University Hospital of Wales
  • Manchester, United Kingdom
    • Manchester Royal Infirmary
  • Portsmouth, United Kingdom
    • Queen Alexandra Hospital
  • Reading, United Kingdom
    • Royal Berkshire Hospital
• United States
  • New York
    • Rochester, New York, United States, 55905
      • Mayo Clinic Hospital-St. Mary's Campus
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC-Presbyterian

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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
• Inclusion within 180 minutes of ROSC

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normothermia; 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; Normothermia and standard care - use of a device for temperature control if temperature is greater than or equal to 37.8°C
Experimental: Hypothermia; Targeted temperature management to 33°C for up to 28h.	Procedure: Targeted temperature management to 33°C; Rapid cooling to below 33°C, followed by temperature control at 33°C for up to 28h.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Landmark mortality at 180 days	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Poor functional outcome	Assessed using the modified Rankin Scale (mRS), with a score of 4-6 being a poor outcome.	180 days
Days alive outside hospital	Number of days alive within 180 days from initial hospital discharge.	180 days.
Quality of Life	Health-related Quality of Life - EQ-5D (VAS scale)	180 days
Quality of Life	Health-related Quality of Life - EQ-5D (Index value)	180 days
Survival until end of the trial	Mortality.	180 days after randmomization of the last patient

Collaborators and Investigators

• Sponsor: Helsingborgs Hospital
• Collaborators: Lund University; Region Skåne - Skånevård SUND; Copenhagen Trial Unit, Center for Clinical Intervention Research; Clinical Trials Sweden, Forum South; Integrated Biobank of Luxembourg
• Investigators: Principal Investigator: 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, Gothenburg, Sweden; Principal Investigator: Josef Dankiewicz, MD, PhD, Skane 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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Trial official webpage

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2017
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: September 16, 2016
• First Submitted That Met QC Criteria: September 19, 2016
• First Posted (Estimate): September 20, 2016

Study Record Updates

• Last Update Posted (Actual): April 3, 2023
• Last Update Submitted That Met QC Criteria: March 30, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Cardiac arrest; Therapeutic hypothermia; Mortality; Induced hypothermia; Mild induced hypothermia; Out-of-hospital cardiac arrest; Neurological function; Randomised clinical trial
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Body Temperature Changes; Heart Arrest; Hypothermia; Out-of-Hospital Cardiac Arrest
• Other Study ID Numbers: TTM-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No