Clinical trial NCT06301412: Combination of Hypothermia and Thrombectomy in Acute Stroke
Official title: Combination of Targeted Temperature Management and Thrombectomy After Acute Ischemic Stroke (COTTIS-2) - a Randomised Controlled Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Ischemic Stroke
Large Vessel Occlusion
Endovascular Treatment
Keywords: hypothermia
neuroprotection
Lead sponsor: University of Freiburg
Sponsor class: OTHER
Collaborators: name: European Union
name: E+E CRO consulting, Vienna, Austria
name: Center for Medical data science, University of Vienna, Austria
First posted: 2024-03-08
Enrollment: 400
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: The goal of this clinical trial is to test the combination of hypothermia and endovascular treatment in acute stroke patients with large vessel occlusion.

The main question it aims to answer is: does an additional cooling to 35°C result in a benefit on clinical outcome ? Participants receive immediate cooling using a noninvasive transnasal cooling technique (RhonoChill) and are maintained at 35°C for 6 hours after reopening of the vessel using surface cooling, and then slowly rewarmed.

Researchers will compare the intervention group (hypothermia and endovascular treatment and best medical treatment including iv thrombolysis) and control group (only endovascular treatment and best medical treatment including iv thrombolysis) to see if additional hypothermia leads to a better outcome after 3 months without relevant complications.

Detailed description: Despite the well-established benefit of endovascular treatment (EVT) for acute ischemic stroke due to large vessel occlusion (LVO), more than half of patients treated with EVT remain functionally dependent despite high reperfusion rates. Thus, new strategies such as additional neuroprotection using hypothermia need to be explored, first to bridge time to reperfusion and second, to attenuate reperfusion injury.

Although therapeutic hypothermia has consistently demonstrated robust neuroprotection in animal ischemic-reperfusion models, randomized trials in acute stroke patients have failed to demonstrate the efficacy of induced hypothermia. The reasons for this treatment failure are diverse and include treatment delay, the unfeasibility of inducing and maintaining hypothermia due to intolerance and shivering in awake patients, the missing recanalization in a large proportion of patients, the heterogeneity of patients included, and too deep (32-34°C) hypothermia associated with an increase in side effects.

In the pilot study COTTIS-1, we could demonstrate the feasibility and safety of immediately induced intraischemic hypothermia to 35°C with non-invasive transnasal cooling by RhinoChill® (BrainCool) followed by surface cooling for 6h after recanalization in sedated and intubated patients with LVO undergoing EVT. By combining this cooling technique with thrombectomy we have tried to address the above mentioned reasons for hypothermia failure. In COTTIS-1, the target temperature of 35°C was reached within 30 min, corresponding to a cooling rate of 2.6°C/h. All patients reached the target temperature, and 86% of the patients had reached ≤35°C at recanalization by thrombectomy. 68% of patients had a good outcome (independency) after 3 months. There were only asymptomatic side effects during hypothermia.

As a consequence, the present COTTIS-2 study is planned to evaluate the efficiency of this cooling protocol in a multicentric, randomized, controlled, end-point-blinded study in Germany.

Eligibility criteria: Inclusion Criteria:

* Pre-stroke modified Rankin Scale (mRS) 0-2 \[7-point scale rating from 0 (no symptoms) to 6 (dead)\]
* Acute ischemic stroke with NIHSS \>5
* Intracranial occlusion of the M1 or M2 segment of the middle cerebral artery (MCA) or internal carotid artery (ICA) or tandem occlusion on CT-angiography or MR-angiography with indication for endovascular treatment:
* Time window 0-24h:

  1. Last seen normal to groin puncture \< 6h: native CT or MRI-DWI with ASPECTS \>5
  2. Last seen normal to groin puncture 6-24h or unknown time window: significant mismatch imaging according to the eligibility criteria of the DEFUSE-3 trial

     * Infarct core \<70ml (DWI oder CBF\<30%)
     * Penumbra \> 15ml (Tmax \>6sec)
     * Ratio penumbra/core \>1.8
* with or without iv thrombolysis with rtPA

Exclusion Criteria:

* Patients with an intranasal obstruction that prevents complete insertion of the nasal cannula should not be treated with the RhinoChill system.
* Known severe hemorrhagic diathesis (International Normalized Ratio (INR) \>3.0, partial thromboplastin time (PTT) \> 70s, platelet count \< 50.000/μl)
* Brain trauma or neurovascular surgery/intervention \<3 months
* Severe infection
* Pregnant women or women of childbearing potential (women of childbearing potential with negative pregnancy test may be included)
* Known cerebral vasculitis
* Proof of bleeding in cerebral CT or MRI (cerebral microbleeds in MRI \[hypertensive or in the context of cerebral amyloid angiopathy\] is permitted).
* Known life expectancy \< 6 months

Primary outcomes:
measure: functional outcome
timeFrame: 3 months
Secondary outcomes:
measure: infarction volume
timeFrame: 24 hours
measure: increase in infarction
timeFrame: 24 hours
measure: recanalization result
timeFrame: after thrombectomy and 24 hours
measure: neurological improvement
timeFrame: 48 hours
measure: outcome at discharge
timeFrame: up to 3 months
measure: shift in functional outcome
timeFrame: 3 months
measure: very good clinical outcome
timeFrame: 3 months
measure: mortality
timeFrame: 3 months
measure: Length of ventilation
timeFrame: 3 months
measure: Length of stay
timeFrame: 3 months
measure: body temperature
timeFrame: 24 hours
measure: time to groin puncture
timeFrame: baseline, pre-intervention
measure: time to recanalization
timeFrame: periprocedurally
Other outcomes:
measure: Occurrence of intracerebral haemorrhage (ICH)
timeFrame: 24 hours
measure: Complications associated with hypothermia
timeFrame: 24hours
Locations:
city: Freiburg
country: Germany
facility: University of Freiburg, Department of Neurology
Study officials:
affiliation: University of Freiburg, Department of Neurology, Germany
name: Juergen Bardutzky, Prof.
role: PRINCIPAL_INVESTIGATOR
References: