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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

Tracking Information
First Submitted Date  ICMJE April 4, 2013
First Posted Date  ICMJE April 16, 2013
Last Update Posted Date October 2, 2019
Study Start Date  ICMJE July 2013
Actual Primary Completion Date July 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2013)
modified Rankin scale [ Time Frame: 3 months ]
Analysed with ordinal logistic regression and expressed as a common odds ratio.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2013)
  • Mortality [ Time Frame: 3 months ]
  • Neurological outcome [ Time Frame: 3 months ]
    NIHSS; World Health Organization Disability Assessment Schedule (WHODAS) 2.0
  • Quality of life [ Time Frame: 3 months ]
    EuroQoL 5-dimensions 5-level questionnaire
  • Cerebral infarct size [ Time Frame: 48±24 hours ]
    Evaluated on CT or MRI imaging
  • 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.
  • Tolerability of systemic cooling [ Time Frame: 36 hours ]
    Timing and dose of anti-shivering medication. Bedside shivering assessment scale (BSAS).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 12, 2013)
  • 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).
  • 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).
  • Cost-effectiveness parameters [ Time Frame: 3 months ]
    Patient location during stay in hospital. Destination after discharge from hospital.
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Cooling Plus Best Medical Treatment Versus Best Medical Treatment Alone for Acute Ischaemic Stroke
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Ischemic Stroke
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Hypothermia
    Best medical treatment + hypothermia 34-35°C for 24h
    • Device: Hypothermia
    • Drug: Buspirone
    • Drug: Pethidine
  • No Intervention: Control
    Best medical treatment
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 30, 2019)
Original Estimated Enrollment  ICMJE
 (submitted: April 12, 2013)
Actual Study Completion Date  ICMJE July 31, 2018
Actual Primary Completion Date July 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01833312
Other Study ID Numbers  ICMJE EuroHYP-1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party University of Erlangen-Nürnberg Medical School
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Erlangen-Nürnberg Medical School
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Stefan Schwab, Prof University of Erlangen-Nürnberg
PRS Account University of Erlangen-Nürnberg Medical School
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP