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

Acute Ischemic Stroke Clinical Trial

— EuroHYP-1  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01833312
• Other study ID #: EuroHYP-1
• Status: Terminated
• Phase: Phase 3
• Start date: July 2013
• Est. completion date: July 31, 2018

Study information

• Verified date: September 2019
• Source: University of Erlangen-Nürnberg Medical School
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 98
• Est. completion date: July 31, 2018
• Est. primary completion date: July 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Cerebral Infarction
• Ischemia
• Stroke

Intervention

Device:
• Hypothermia
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.

Drug:
• Buspirone
anti-shivering treatment
• Pethidine
anti-shivering treatment

Locations

Country	Name	City	State
Germany	Department of Neurology, University Hospital Erlangen	Erlangen

Sponsors (1)

Lead Sponsor	Collaborator
University of Erlangen-Nürnberg Medical School

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Selected biomarkers	MMPs including gelatinases (MMP-2 and MMP-9), collagenases (MMP-1, MMP-8 and MMP-13) and stromelysins (MMP-3 and MMP-10) using multiplex ELISA [SearchLight technology].; MMP endogen inhibitors (TIMP-1 and TIMP-2) using multiplex ELISA [SearchLight technology].; H-FABP, UFD-1, RNABP, NDKA, GSTP-1 and Pro-BNP using standard ELISA.; Cerebral Array I & II containing BDNF, GFAP, NSE, NGAL, sTNFRI, D-dimer and CRP using biochip analysers [Randox].; Pro-ANP, Copeptin, IL6, IL8, IL10, mannose-binding lectin (MBL), mHLA-DR, monocytotic cytokine-secretion ex vivo stimulation, C5a in plasma, ultrasensitive PCT, lipopolysaccharide-binding protein (LBP).	baseline, 24h, 72h
Other	Other imaging parameters	Presence, location and extent of any visible infarct, early infarct swelling, hyperdense artery, leukoaraiosis, atrophy and prior infarct on the scan performed at screening assessment (within 90 minutes before the start of the treatment) will be tested for any interaction with early (infarct swelling, haemorrhagic transformation, neurological deterioration, death) and late (NIHSS and mRS scores, death) neurological and functional outcome variables at day 8 or day of discharge from hospital, whichever occurs firs, and at outcome assessment (day 91±14).	baseline, 48h
Other	Cost-effectiveness parameters	Patient location during stay in hospital.; Destination after discharge from hospital.	3 months
Primary	modified Rankin scale	Analysed with ordinal logistic regression and expressed as a common odds ratio.	3 months
Secondary	Mortality		3 months
Secondary	Neurological outcome	NIHSS; World Health Organization Disability Assessment Schedule (WHODAS) 2.0	3 months
Secondary	Quality of life	EuroQoL 5-dimensions 5-level questionnaire	3 months
Secondary	Cerebral infarct size	Evaluated on CT or MRI imaging	48±24 hours
Secondary	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
Secondary	Tolerability of systemic cooling	Timing and dose of anti-shivering medication.; Bedside shivering assessment scale (BSAS).	36 hours

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