Cooling Plus Best Medical Treatment Versus Best Medical Treatment Alone for Acute Ischaemic Stroke

Study Overview
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Brief Summary
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The purpose of this study is to determine if systemic cooling to a target temperature of 34 to 35°C, started within 6 hours of symptom onset and maintained for 12 hours, improves functional outcome at 3 months in patients with acute ischaemic stroke.

Official Title
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EuroHYP-1: European Multicentre, Randomised, Phase III Clinical Trial of Therapeutic Hypothermia Plus Best Medical Treatment Versus Best Medical Treatment Alone for Acute Ischaemic Stroke

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Device: Hypothermia
* Drug: Buspirone
* Drug: Pethidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained from the patient or his/her legally acceptable representative or under such other arrangements as may be legally established in participating countries Patients of both sexes aged ≥18 years Estimated body weight of 50 up to and including 120kg Diagnosis of acute ischaemic stroke Possibility to start therapeutic hypothermia within 6 hours after onset of stroke Possibility to start therapeutic hypothermia within 150 minutes after start of alteplase administration in patients receiving thrombolysis at the trial site or within 150 minutes after start of endovascular treatment, if this is later Possibility to start therapeutic hypothermia within 150 minutes after admission to trial site in patients not receiving thrombolysis or in patients who have received thrombolysis at a different site mRS score ≤2 prior to onset of stroke NIHSS score ≥6 GCS motor response subscale score ≥5 Exclusion Criteria: Use of monoamineoxidase inhibitors in the 14 days prior to screening Current use of medication interacting with pethidine or buspirone, i.e., ritonavir, phenytoin, cimetidine, phenothiazines, opioids and partial opioid agonists (e.g., pentazocine, nalbuphine, buprenorphine) Acute alcohol intoxication Opioid addiction Nursing mother or pregnant woman, as verified by a positive urine pregnancy test in females of childbearing potential Known hypersensitivity to the IMPs or any of their formulation ingredients Patient who is imprisoned or is lawfully kept in an institution Employee or direct relative of an employee of the CRO (if applicable), the department of the investigator, or the sponsor Participation in an interventional clinical trial within the last 4 weeks, or be under the exclusion period from another trial Prior participation in this trial Any acutely life-threatening conditions other than acute ischaemic stroke Rapidly resolving stroke symptoms Evidence from CT or MRI of intracranial haemorrhage or tumour or encephalitis or any diagnosis likely to cause the present symptoms other than acute ischaemic stroke. Haemorrhagic transformation of the infarct is not an exclusion criterion, except when there is a parenchymal haematoma covering more than 30% of the infarcted area, with significant space-occupying effect, or when there is a bleeding remote from the infarcted area Known convulsive disorder, acute closed angle glaucoma, myasthenia gravis SPO2 <94% (as measured by pulse oximetry) under nasal oxygen administration Other severe respiratory disorder Bradycardia (<40 bpm) Severe cardiac failure, defined as NYHA classification ≥III Myocardial infarction or angina pectoris in the 3 months prior to screening Vasospastic disorders (e.g., Raynaud's disease) Haematological dyscrasia (e.g., sickle cell disease, cryoglobulinaemia) Known platelet count <100,000/mm3 Known INR >1.7 Skin damage (e.g., inflammation, burns, injuries, ulcerations, hives, rash) at the sites intended to be used for cooling Clinical diagnosis of sepsis Known severe hepatic impairment (serum ALAT and/or ASAT >3 times ULN) Known renal impairment (serum creatinine >2mg/100ml) Addison's disease Any other condition that may interfere with, or be aggravated by, therapeutic hypothermia Any condition that is thought to reduce the compliance to cooperate with the trial procedures

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hypothermia<br>Best medical treatment + hypothermia 34-35°C for 24h | Device: Hypothermia<br>* In patients randomised to therapeutic hypothermia, induction of cooling will be started by infusion of 4°C isotone saline or Ringer's lactate administered over a period of 30 to 60 minutes. A body temperature between 34.0 and 35.0°C will be targeted. Body temperature will be monitored through bladder or rectal thermal probes, and cooling procedures will be adapted to keep body temperature as close as possible to the target. Maintenance of body temperature in the target range will be performed with a surface or endovascular cooling device. After a cooling period of 24h, controlled rewarming to 36°C with a rate of 0.2°C/h will be started. After 36°C have been reached, the device will be disconnected.<br>* Other names: Zoll intravascular temperature management system;Drug: Buspirone<br>* anti-shivering treatment<br>Drug: Pethidine<br>* anti-shivering treatment<br>|
| No Intervention: Control<br>Best medical treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| modified Rankin scale | Analysed with ordinal logistic regression and expressed as a common odds ratio. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality |  | 3 months | 
| Neurological outcome | NIHSS; World Health Organization Disability Assessment Schedule (WHODAS) 2.0 | 3 months | 
| Quality of life | EuroQoL 5-dimensions 5-level questionnaire | 3 months | 
| Cerebral infarct size | Evaluated on CT or MRI imaging | 48±24 hours | 
| Safety of systemic cooling | Number of adverse events and severe adverse events related to the procedure of systemic cooling including induction, maintenance of hypothermia, rewarming, or the administration of anti-shivering medication (pethidine and buspirone) within the first 36h of enrollment. Number of adverse events and severe adverse events until outcome assessment at day 91. | Enrollment - day 91 | 
| Tolerability of systemic cooling | Timing and dose of anti-shivering medication. Bedside shivering assessment scale (BSAS). | 36 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute ischemic stroke, hypothermia