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

Overview

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.

Interventions

• Device hypothermia
  hypothermia is started after intubation for endovascular treatment and induced by transnasal cooling (RhinoChill) to a target temperature of 35°C and hypothermia is then maintained at 35°C for 6 hours after recanalisation by surface cooling followed by slow rewarming by 0.2°C per hour to 36.5°C

Primary outcome measures

• functional outcome [Time frame: 3 months]

Secondary outcome measures (12)

• infarction volume [Time frame: 24 hours]
• increase in infarction [Time frame: 24 hours]
• recanalization result [Time frame: after thrombectomy and 24 hours]
• neurological improvement [Time frame: 48 hours]
• outcome at discharge [Time frame: up to 3 months]
• shift in functional outcome [Time frame: 3 months]
• very good clinical outcome [Time frame: 3 months]
• mortality [Time frame: 3 months]
• Length of ventilation [Time frame: 3 months]
• Length of stay [Time frame: 3 months]
• body temperature [Time frame: 24 hours]
• time to groin puncture [Time frame: baseline, pre-intervention]

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:

• Last seen normal to groin puncture < 6h: native CT or MRI-DWI with ASPECTS >5
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Germany · 1 center

• University of Freiburg, Department of Neurology — Freiburg im Breisgau

Identifiers

NCT: NCT06301412 · COTTIS-2_Version4.0-13Nov23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗