Clinical trial NCT02908308: Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest
Official title: Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) - A Randomised Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
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
Lead sponsor: Helsingborgs Hospital
Sponsor class: OTHER
Collaborators: name: Lund University
name: Region Skåne - Skånevård SUND
name: Copenhagen Trial Unit, Center for Clinical Intervention Research
name: Clinical Trials Sweden, Forum South
name: Integrated Biobank of Luxembourg
First posted: 2016-09-20
Enrollment: 1900
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mortality
timeFrame: 180 days
Secondary outcomes:
measure: Poor functional outcome
timeFrame: 180 days
measure: Days alive outside hospital
timeFrame: 180 days.
measure: Quality of Life
timeFrame: 180 days
measure: Quality of Life
timeFrame: 180 days
measure: Survival until end of the trial
timeFrame: 180 days after randmomization of the last patient
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic Hospital-St. Mary's Campus
state: New York
city: Pittsburgh
country: United States
facility: UPMC-Presbyterian
state: Pennsylvania
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Epping
country: Australia
facility: Northern Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred
state: Victoria
city: Melbourne
country: Australia
facility: Austin Hospital
city: Sydney
country: Australia
facility: Nepean Hospital
city: Sydney
country: Australia
facility: Royal North Shore Hospital
city: Innsbruck
country: Austria
facility: Innsbruck University Hospital
city: Brussels
country: Belgium
facility: Erasme Hospital
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
city: Hradec Králové
country: Czechia
facility: Hradec Kralove Hospital
city: Liberec
country: Czechia
facility: Liberec Hospital
city: Prague
country: Czechia
facility: General University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Limoges
country: France
facility: Chu Dupuytren
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Cochin University Hospital
city: Paris
country: France
facility: Lariboisière Hospital
city: Versailles
country: France
facility: Versailles Hospital
city: Berlin
country: Germany
facility: Charité, Campus Virchow
city: Genova
country: Italy
facility: San Martino Hospital
city: Modena
country: Italy
facility: Modena NOCSAE Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Arendal
country: Norway
facility: Sorlandet Hospital
city: Bergen
country: Norway
facility: Haukeland Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Trondheim
country: Norway
facility: St. Olav's University Hospital
city: Halmstad
country: Sweden
facility: Hallands Hospital
state: Halland
city: Lund
country: Sweden
facility: Skane University Hospital - Lund
state: Skåne
city: Malmö
country: Sweden
facility: Skane University Hospital - Malmö
state: Skåne
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Helsingborg
country: Sweden
facility: Helsingborgs Hospital
city: Karlstad
country: Sweden
facility: Centralsjukhuset i Karlstad
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Skövde
country: Sweden
facility: Skaraborgs sjukhus
city: Stockholm
country: Sweden
facility: Capio St:Göran
city: Stockholm
country: Sweden
facility: Södersjukhuset
city: Trollhättan
country: Sweden
facility: Norra Älvsborgs Länssjukhus (NÄL)
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
city: Örebro
country: Sweden
facility: Örebro University Hospital
city: Bern
country: Switzerland
facility: University Hospital Bern, Inselspital
city: Lausanne
country: Switzerland
facility: University Hospital of Lausanne
city: Lugano
country: Switzerland
facility: Cardiocentro Ticino
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St.Gallen
city: Zürich
country: Switzerland
facility: Zurich University Hospital
city: Basildon
country: United Kingdom
facility: Basildon and Thurrock Hospitals NHS Foundation Trust - Essex CTC
city: Belfast
country: United Kingdom
facility: Royal Victoria Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham University Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
Study officials:
affiliation: Helsingborgs lasarett, Region Skåne, Sweden
name: Niklas Nielsen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lund University Hospital, Lund, Sweden
name: Hans Friberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lund University Hospital, Lund, Sweden
name: Tobias Cronberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oslo University Hospital, Oslo, Norway
name: Jan Hovdenes, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Wales, Cardiff, UK
name: Matt P Wise, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh, Pittsburgh, USA
name: Clifton W Callaway, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Charité-University Medicine (Berlin, Germany)
name: Christian Storm, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Université Paris Descartes, France
name: Alain Cariou, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lund University Hospital, Lund, Sweden
name: David Erlinge, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sahlgrenska University Hospital
name: Christian Rylander, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Skåne University Hospital Lund
name: Josef Dankiewicz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Université de Lausanne, Lausanne, Switzerland
name: Mauro Oddo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The George Institute for Global Health (Sydney, Australia)
name: Manoj Saxena, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Södersjukhuset, Stockholm
name: Per Nordberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital Erasme, Brussles, Belgium
name: Fabio Taccone, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: San Martino University Hospital, Genoa
name: Paolo Pelosi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Innsbruck University Hospital
name: Michael Ioannidis, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Prague University Hospital
name: Jan Belholavek, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wellington Regional Hospital
name: Paul Young, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aarhus University Hospital
name: Hans Kirkegaard, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Anaesthesia and Intensive Care Medicine, St Vincent's University Hospital
name: Alistair Nichol, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.