Out-of-hospital Cardiac ArrestTTM-2NCT02908308
Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest
A study testing Targeted temperature management to 33°C in people with Out-of-hospital Cardiac Arrest, run by Helsingborgs Hospital at 60 sites in 14 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Out-of-hospital Cardiac Arrest
- What is being tested?
- Targeted temperature management to 33°C
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,900 participants
- Where
- 60 sitesin 14 countries
- Study dates
- 18 Nov 2017to 31 Dec 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
60 sites in 14 countries.
60 sites in 14 countries
Sweden13 sites
Sahlgrenska University Hospital
Gothenburg
Hallands Hospital
Halmstad, Halland County, 302 33
Helsingborgs Hospital
Helsingborg, 251 87
Centralsjukhuset i Karlstad
Karlstad, 652 30
Linköping University Hospital
Linköping
Skane University Hospital - Lund
Lund, Skåne County, 22185
Skane University Hospital - Malmö
Malmö, Skåne County, 22185
Örebro University Hospital
Örebro
Skaraborgs sjukhus
Skövde
Capio St:Göran
Stockholm
Södersjukhuset
Stockholm
Norra Älvsborgs Länssjukhus (NÄL)
Trollhättan, 461 73
Akademiska Sjukhuset
Uppsala
Australia10 sites
Princess Alexandra Hospital
Brisbane, Queensland
Northern Hospital
Epping, Victoria
The Alfred
Melbourne, Victoria
Austin Hospital
Melbourne
John Hunter Hospital
Newcastle, New South Wales
Concord Repatriation General Hospital
Sydney, New South Wales
Liverpool Hospital
Sydney, New South Wales
St Vincent's Hospital
Sydney, New South Wales
Nepean Hospital
Sydney
Royal North Shore Hospital
Sydney
United Kingdom9 sites
Basildon and Thurrock Hospitals NHS Foundation Trust - Essex CTC
Basildon
Royal Victoria Hospital
Belfast
Birmingham University Hospital
Birmingham
Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
Bournemouth
Bristol Royal Infirmary
Bristol
University Hospital of Wales
Cardiff
Manchester Royal Infirmary
Manchester
Queen Alexandra Hospital
Portsmouth
Royal Berkshire Hospital
Reading
France5 sites
Chu Dupuytren
Limoges
CHU Nantes
Nantes
Cochin University Hospital
Paris
Lariboisière Hospital
Paris
Versailles Hospital
Versailles
Switzerland5 sites
University Hospital Bern, Inselspital
Bern
University Hospital of Lausanne
Lausanne
Cardiocentro Ticino
Lugano
Kantonsspital St.Gallen
Sankt Gallen
Zurich University Hospital
Zurich
Norway4 sites
Sorlandet Hospital
Arendal
Haukeland Hospital
Bergen
Oslo University Hospital
Oslo
St. Olav's University Hospital
Trondheim
Czechia3 sites
Hradec Kralove Hospital
Hradec Králové
Liberec Hospital
Liberec
General University Hospital
Prague
United States2 sites
UPMC-Presbyterian
Pittsburgh, Pennsylvania, 15213
Mayo Clinic Hospital-St. Mary's Campus
Rochester, New York, 55905
New Zealand2 sites
Christchurch Hospital
Christchurch
Wellington Hospital
Wellington, 6021
About this study
Official title: 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.
Read the 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.
- Conditions
- Out-of-hospital Cardiac Arrest
- Being tested
- Targeted temperature management to 33°C, Standard care with early treatment of fever
- Keywords
- Induced hypothermia, Mild induced hypothermia, Therapeutic hypothermia, Cardiac arrest, Out-of-hospital cardiac arrest, Mortality, Neurological function, Randomised clinical trial
- Medical subject headings
- Out-of-Hospital Cardiac Arrest, Heart Arrest
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Targeted temperature management to 33°CProcedure or surgery
Rapid cooling to below 33°C, followed by temperature control at 33°C for up to 28h.
Standard care with early treatment of feverProcedure or surgery
Normothermia and standard care - use of a device for temperature control if temperature is greater than or equal to 37.8°C
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Procedure: Standard care with early treatment of fever |
| Hypothermia | Experimental | Targeted temperature management to 33°C for up to 28h. Receives: Procedure: Targeted temperature management to 33°C |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Landmark mortality at 180 days
Measured: 180 days
Secondary outcomes (5)
Poor functional outcome
Assessed using the modified Rankin Scale (mRS), with a score of 4-6 being a poor outcome.
Measured: 180 days
Days alive outside hospital
Number of days alive within 180 days from initial hospital discharge.
Measured: 180 days.
Quality of Life
Health-related Quality of Life - EQ-5D (VAS scale)
Measured: 180 days
Quality of Life
Health-related Quality of Life - EQ-5D (Index value)
Measured: 180 days
Survival until end of the trial
Mortality.
Measured: 180 days after randmomization of the last patient
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2016 (estimated)
- Study start18 Nov 2017
- Primary completion30 Jun 2022
- Study completion31 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for Out-of-hospital Cardiac ArrestStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 1,900 participants (actual)
Sponsor and investigators
- Lead sponsor
- Helsingborgs Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Lund University, Region Skane, Copenhagen Trial Unit, Center for Clinical Intervention Research, Clinical Studies Sweden, Integrated Biobank of Luxembourg
- Responsible party
- Principal investigator, Niklas Nielsen, Helsingborgs Hospital
- Investigators
- Niklas Nielsen, MD, PhD, Principal investigator, Helsingborgs lasarett, Region Skåne, SwedenHans Friberg, MD, PhD, Principal investigator, Lund University Hospital, Lund, SwedenTobias Cronberg, MD, PhD, Principal investigator, Lund University Hospital, Lund, SwedenJan Hovdenes, MD, PhD, Principal investigator, Oslo University HospitalMatt P Wise, MD, PhD, Principal investigator, University Hospital of Wales, Cardiff, UKClifton W Callaway, MD, PhD, Principal investigator, University of Pittsburgh, Pittsburgh, USAChristian Storm, MD, PhD, Principal investigator, Charité-University Medicine (Berlin, Germany)Alain Cariou, MD, PhD, Principal investigator, Université Paris Descartes, France
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02908308
- Sponsor's protocol ID
- TTM-2
- Acronym
- TTM-2
- Status last verified
- Mar 2023
- First submitted
- 16 Sep 2016
- Last updated
- 3 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 24237006Hultgren M, Blennow Nordstrom E, Ullen S, Nielsen N, Dankiewicz J, Jakobsen JC, Heimburg K, Moseby-Knappe M, Belohlavek J, Bohm M, Cariou A, Eastwood G, Friberg H, Grejs AM, Hammond N, Hanggi M, Hrecko J, Iten M, Keeble TR, Leithner C, Levin H, Mion M, Rylander C, Schrag C, Thomas M, Wise MP, Young P, Cronberg T, Lilja G. Long-Term Outcomes and Recovery Trajectories in Out-of-Hospital Cardiac Arrest: A 2-Year Follow-Up of the Randomized Clinical TTM2 Trial. JAMA Neurol. 2026 Apr 1;83(4):339-347. doi: 10.1001/jamaneurol.2025.5614.
PubMed 41697682Gobel 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.
PubMed 41212202Awad A, Jonsson M, Holgersson J, Jakobsen JC, Hollenberg J, Thomas M, Garcia PDW, Ringh M, Grejs AM, Keeble TR, Belohlavek J, Cariou A, Annoni F, Lilja G, Taccone FS, Rylander C, Nielsen N, Dankiewicz J, Nordberg P. Intravascular vs. surface cooling in out-of-hospital cardiac arrest patients receiving hypothermia after hospital arrival: a post hoc analysis of the TTM2 trial. Intensive Care Med. 2025 Apr;51(4):721-730. doi: 10.1007/s00134-025-07883-4. Epub 2025 Apr 28.
PubMed 40293464Admiraal 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.
PubMed 39933130Taccone 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.
PubMed 39407230Heimburg 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.
PubMed 39368797Battaglini 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.
PubMed 39244144Lang 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.
PubMed 38900283Holgersson 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.
PubMed 38319850Turella S, Dankiewicz J, Friberg H, Jakobsen JC, Leithner C, Levin H, Lilja G, Moseby-Knappe M, Nielsen N, Rossetti AO, Sandroni C, Zubler F, Cronberg T, Westhall E; TTM2-trial investigators. The predictive value of highly malignant EEG patterns after cardiac arrest: evaluation of the ERC-ESICM recommendations. Intensive Care Med. 2024 Jan;50(1):90-102. doi: 10.1007/s00134-023-07280-9. Epub 2024 Jan 3.
PubMed 38172300Lilja 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.
PubMed 37548968Robba 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.
PubMed 36271410Lang 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.
PubMed 36267356During 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.
PubMed 35909163
Study at a glance
From the registry record, last updated by the sponsor on 3 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) - A Randomised Clinical Trial
- ClinicalTrials.gov ID
- NCT02908308
- Acronym / sponsor ID
- TTM-2 / TTM-2
- 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
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,900 participants (actual)
- Lead sponsor
- Helsingborgs HospitalUniversity, hospital or other
- Collaborators
- Lund University, Region Skane, Copenhagen Trial Unit, Center for Clinical Intervention Research, Clinical Studies Sweden, Integrated Biobank of Luxembourg
- Study start
- 18 Nov 2017 (actual)
- Primary completion
- 30 Jun 2022 (actual)
- Study completion
- 31 Dec 2022 (actual)
- First posted
- 20 Sep 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Normothermia | Active comparator | Procedure: Standard care with early treatment of feverStandard 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. |
| Hypothermia | Experimental | Procedure: Targeted temperature management to 33°CTargeted temperature management to 33°C for up to 28h. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Targeted temperature management to 33°CRapid cooling to below 33°C, followed by temperature control at 33°C for up to 28h. | Procedure or surgery | Hypothermia |
| Standard care with early treatment of feverNormothermia and standard care - use of a device for temperature control if temperature is greater than or equal to 37.8°C | Procedure or surgery | Normothermia |
Primary outcome
Mortality
Time frame: 180 days
Landmark mortality at 180 days
5 secondary outcomes
Poor functional outcome
Time frame: 180 days
Days alive outside hospital
Time frame: 180 days.
Quality of Life
Time frame: 180 days
Quality of Life
Time frame: 180 days
Survival until end of the trial
Time frame: 180 days after randmomization of the last patient
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Apr 2023.
- Background: PubMed 24237006Nielsen 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.
- Derived from this study: PubMed 41697682Hultgren M, Blennow Nordstrom E, Ullen S, Nielsen N, Dankiewicz J, Jakobsen JC, Heimburg K, Moseby-Knappe M, Belohlavek J, Bohm M, Cariou A, Eastwood G, Friberg H, Grejs AM, Hammond N, Hanggi M, Hrecko J, Iten M, Keeble TR, Leithner C, Levin H, Mion M, Rylander C, Schrag C, Thomas M, Wise MP, Young P, Cronberg T, Lilja G. Long-Term Outcomes and Recovery Trajectories in Out-of-Hospital Cardiac Arrest: A 2-Year Follow-Up of the Randomized Clinical TTM2 Trial. JAMA Neurol. 2026 Apr 1;83(4):339-347. doi: 10.1001/jamaneurol.2025.5614.
- Derived from this study: PubMed 41212202Gobel 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.
- Derived from this study: PubMed 40293464Awad A, Jonsson M, Holgersson J, Jakobsen JC, Hollenberg J, Thomas M, Garcia PDW, Ringh M, Grejs AM, Keeble TR, Belohlavek J, Cariou A, Annoni F, Lilja G, Taccone FS, Rylander C, Nielsen N, Dankiewicz J, Nordberg P. Intravascular vs. surface cooling in out-of-hospital cardiac arrest patients receiving hypothermia after hospital arrival: a post hoc analysis of the TTM2 trial. Intensive Care Med. 2025 Apr;51(4):721-730. doi: 10.1007/s00134-025-07883-4. Epub 2025 Apr 28.
- Derived from this study: PubMed 39933130Admiraal 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.
- Derived from this study: PubMed 39407230Taccone 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.
- Derived from this study: PubMed 39368797Heimburg 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.
- Derived from this study: PubMed 39244144Battaglini 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.
- Derived from this study: PubMed 38900283Lang 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.
- Derived from this study: PubMed 38319850Holgersson 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.
- Derived from this study: PubMed 38172300Turella S, Dankiewicz J, Friberg H, Jakobsen JC, Leithner C, Levin H, Lilja G, Moseby-Knappe M, Nielsen N, Rossetti AO, Sandroni C, Zubler F, Cronberg T, Westhall E; TTM2-trial investigators. The predictive value of highly malignant EEG patterns after cardiac arrest: evaluation of the ERC-ESICM recommendations. Intensive Care Med. 2024 Jan;50(1):90-102. doi: 10.1007/s00134-023-07280-9. Epub 2024 Jan 3.
- Derived from this study: PubMed 37548968Lilja 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.
- Trial official webpageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Niklas Nielsen, MD, PhD principal investigator
Helsingborgs lasarett, Region Skåne, Sweden
Hans Friberg, MD, PhD principal investigator
Lund University Hospital, Lund, Sweden
Tobias Cronberg, MD, PhD principal investigator
Lund University Hospital, Lund, Sweden
60 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Targeted temperature management to 33°C in people with Out-of-hospital Cardiac Arrest, run by Helsingborgs Hospital at 60 sites in 14 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 60 sites in Sweden, Australia, United Kingdom, France, Switzerland and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: 180 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02908308, which also lists 19 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2023.