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

Out-of-hospital Cardiac Arrest Clinical Trial

— TTM-2  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02908308
• Other study ID #: TTM-2
• Status: Completed
• Phase: N/A
• Start date: November 18, 2017
• Est. completion date: December 31, 2022

Study information

• Verified date: March 2023
• Source: Helsingborgs Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1900
• Est. completion date: December 31, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Arrest
• Hypothermia
• Out-of-hospital Cardiac Arrest

Intervention

Procedure:
• Targeted temperature management to 33°C
Rapid cooling to below 33°C, followed by temperature control at 33°C for up to 28h.
• 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

Locations

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

Sponsors (6)

Lead Sponsor	Collaborator
Helsingborgs Hospital	Clinical Trials Sweden, Forum South, Copenhagen Trial Unit, Center for Clinical Intervention Research, Integrated Biobank of Luxembourg, Lund University, Region Skåne - Skånevård SUND

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Czechia,  Denmark,  France,  Germany,  Italy,  New Zealand,  Norway,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

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

External Links

•   Trial official webpage