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Cooling Plus Best Medical Treatment Versus Best Medical Treatment Alone for Acute Ischaemic Stroke (EuroHYP-1)

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ClinicalTrials.gov Identifier: NCT01833312
Recruitment Status : Terminated (Slow recruitment, cessation of funding)
First Posted : April 16, 2013
Last Update Posted : October 2, 2019
Information provided by (Responsible Party):
University of Erlangen-Nürnberg Medical School

Brief 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.

Condition or disease Intervention/treatment Phase
Acute Ischemic Stroke Device: Hypothermia Drug: Buspirone Drug: Pethidine Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 98 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : July 2013
Actual Primary Completion Date : July 31, 2018
Actual Study Completion Date : July 31, 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Hypothermia
Best medical treatment + hypothermia 34-35°C for 24h
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.
Other Names:
  • EMCOOLS Brain.Pad
  • Arctic Sun and ArcticGel Pads
  • CritiCool and CureWrap 3500
  • Zoll intravascular temperature management system

Drug: Buspirone
anti-shivering treatment

Drug: Pethidine
anti-shivering treatment

No Intervention: Control
Best medical treatment

Primary Outcome Measures :
  1. modified Rankin scale [ Time Frame: 3 months ]
    Analysed with ordinal logistic regression and expressed as a common odds ratio.

Secondary Outcome Measures :
  1. Mortality [ Time Frame: 3 months ]
  2. Neurological outcome [ Time Frame: 3 months ]


    World Health Organization Disability Assessment Schedule (WHODAS) 2.0

  3. Quality of life [ Time Frame: 3 months ]
    EuroQoL 5-dimensions 5-level questionnaire

  4. Cerebral infarct size [ Time Frame: 48±24 hours ]
    Evaluated on CT or MRI imaging

  5. Safety of systemic cooling [ Time Frame: Enrollment - day 91 ]

    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.

  6. Tolerability of systemic cooling [ Time Frame: 36 hours ]

    Timing and dose of anti-shivering medication.

    Bedside shivering assessment scale (BSAS).

Other Outcome Measures:
  1. Selected biomarkers [ Time Frame: baseline, 24h, 72h ]
    • 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).

  2. Other imaging parameters [ Time Frame: baseline, 48h ]
    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).

  3. Cost-effectiveness parameters [ Time Frame: 3 months ]

    Patient location during stay in hospital.

    Destination after discharge from hospital.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01833312

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Department of Neurology, University Hospital Erlangen
Erlangen, Germany, 91054
Sponsors and Collaborators
University of Erlangen-Nürnberg Medical School
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Study Chair: Stefan Schwab, Prof University of Erlangen-Nürnberg
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Erlangen-Nürnberg Medical School
ClinicalTrials.gov Identifier: NCT01833312    
Other Study ID Numbers: EuroHYP-1
First Posted: April 16, 2013    Key Record Dates
Last Update Posted: October 2, 2019
Last Verified: September 2019
Keywords provided by University of Erlangen-Nürnberg Medical School:
acute ischemic stroke
Additional relevant MeSH terms:
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Ischemic Stroke
Cerebral Infarction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Receptor Agonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Analgesics, Opioid
Sensory System Agents