Combination of Hypothermia and Thrombectomy in Acute Stroke (COTTIS-2)

Combination of Targeted Temperature Management and Thrombectomy After Acute Ischemic Stroke (COTTIS-2) - a Randomised Controlled Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Ischemic Stroke; Large Vessel Occlusion; Endovascular Treatment
• Intervention / Treatment: Device: hypothermia

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.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Juergen Bardutzky, Prof.; Phone Number: +49-15237729739; Email: juergen.bardutzky@uniklinik-freiburg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: EVT group; standard endovascular treatment (EVT) for large vessel occlusion (LVO) without hypothermia
Active Comparator: EVT group plus hypothermia group; standard endovascular treatment (EVT) for large vessel occlusion (LVO) combined with hypothermia	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
functional outcome	The presence of patients with good neurological outcome after 3 months as defined by modified Rankin Scale (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) of 0-2	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
infarction volume	Infarction volume assessed in the standard CT 24 hours after thrombectomy	24 hours
increase in infarction	increase of the infarct core based on imaging at the time of admission (DWI-MRI or CBF<30% of contralateral side at CT-Perfusion) and CT after 24 hours	24 hours
recanalization result	Recanalization result (by mTICI score: successful recanalization mTICI 2b-3) after thrombectomy (based on angiography during/after thrombectomy) and 24 hours after thrombectomy (based on ultrasound of the cerebral vessels)	after thrombectomy and 24 hours
neurological improvement	Change of at least 8 points on the National Institutes of Health Stroke Scale (NIHSS; on which scores range from 0 to 42, with higher scores indicating a greater deficit) at 48 hours after thrombectomy	48 hours
outcome at discharge	modified Rankin Score (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death) upon discharge/transfer in rehabilitation	up to 3 months
shift in functional outcome	ordinal shift across the range of modified Rankin Score (mRS; on which scores range from 0 to 6, with 0 means no symptoms and 6 means death)	3 months
very good clinical outcome	Presence of patients with very good clinical outcome after 3 months (mRS 0-1)	3 months
mortality	Mortality during acute hospitalisation and after 3 months	3 months
Length of ventilation	Length of mechanical ventilation	3 months
Length of stay	Length of ICU stay and hospital stay	3 months
body temperature	Temperature at admission, at recanalization, and first 6 hours after recanalization, and at 24 hours	24 hours
time to groin puncture	Time from arrival until groin puncture	baseline, pre-intervention
time to recanalization	Time from arrival until recanalization	periprocedurally

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of intracerebral haemorrhage (ICH)	Any ICH (subarachnoid, intraparenchymal, intraventricular) on the CT after 24 hours; Symptomatic ICH (defined according to SITS-MOST criteria): Hematoma >30% of initial infarction volume associated with a clinical deterioration in NIHSS score of at least 4 points within 24 hours after thrombectomy	24 hours
Complications associated with hypothermia	Nosebleed and pailing of the nose; Periorbital emphysema; Pneumocephalus (in 24-hour control CT); Blood pressure, heart rate, oxygen saturation SO2; Episodes with severe hypotension with systolic blood pressure <110mmHg; Incidence of pneumonia (defined as: any new pulmonary infiltrate on radiographic imaging occurring <48hrs after admission combined with at least one of the subsequent findings: fever >38°C, leukopenia/leucocytosis, purulent secretions with positive cultures); Disturbances in electrolytes, renal function, coagulation (potassium, sodium, chloride, creatinine, INR, pTT, thrombocytes measured on admission before hypothermia and at 24 hours)	24hours

Collaborators and Investigators

• Sponsor: University of Freiburg
• Collaborators: European Union; E+E CRO consulting, Vienna, Austria; Center for Medical data science, University of Vienna, Austria
• Investigators: Principal Investigator: Juergen Bardutzky, Prof., University of Freiburg, Department of Neurology, Germany

Publications and helpful links

Helpful Links

• Results of the pilot study COTTIS-1 on feasibility and safety

Study record dates

Study Major Dates

• Study Start (Estimated): March 18, 2024
• Primary Completion (Estimated): March 18, 2026
• Study Completion (Estimated): June 18, 2026

Study Registration Dates

• First Submitted: February 22, 2024
• First Submitted That Met QC Criteria: March 3, 2024
• First Posted (Actual): March 8, 2024

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 3, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: hypothermia; neuroprotection
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: COTTIS-2_Version4.0-13Nov23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual patient data (after anonymization), on which the results of the present study are based, can be made available to scientists upon request (methodologically meaningful evaluation proposal approved by a committee specifically appointed for this evaluation proposal) (6 months to 36 months after publication of the study)
• IPD Sharing Time Frame: 6 months to 36 months after publication of the study
• IPD Sharing Access Criteria: upon request of scientists with methodologically meaningful evaluation proposal approved by a committee specifically appointed for this evaluation proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No