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

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.

Inclusion Criteria:

- Out-of-hospital cardiac arrest

- Presumed cardiac cause of cardiac arrest

- Unconscious with a FOUR-score
- 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