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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Out-of-hospital Cardiac Arrest

Intervention / Treatment
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* Procedure: Targeted temperature management to 33°C
* Procedure: Standard care with early treatment of fever


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Induced hypothermia, Mild induced hypothermia, Therapeutic hypothermia, Cardiac arrest, Out-of-hospital cardiac arrest, Mortality, Neurological function, Randomised clinical trial