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

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

Tracking Information

• First Submitted Date: April 4, 2013
• First Posted Date: April 16, 2013
• Last Update Posted Date: October 2, 2019
• Study Start Date: July 2013
• Actual Primary Completion Date: July 31, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current
• Change History: Complete list of historical versions of study NCT01833312 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (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: 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: Cooling Plus Best Medical Treatment Versus Best Medical Treatment Alone for Acute Ischaemic Stroke
• 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
• 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Ischemic 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.
  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

• Experimental: Hypothermia
  Best medical treatment + hypothermia 34-35°C for 24h
  Interventions:

  • Device: Hypothermia
  • Drug: Buspirone
  • Drug: Pethidine
• No Intervention: Control
  Best medical treatment

Publications *

• Winkel P, Bath PM, Gluud C, Lindschou J, van der Worp HB, Macleod MR, Szabo I, Durand-Zaleski I, Schwab S; EuroHYP-1 trial investigators. Statistical analysis plan for the EuroHYP-1 trial: European multicentre, randomised, phase III clinical trial of the therapeutic hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke. Trials. 2017 Nov 29;18(1):573. doi: 10.1186/s13063-017-2302-z.
• van der Worp HB, Macleod MR, Bath PM, Demotes J, Durand-Zaleski I, Gebhardt B, Gluud C, Kollmar R, Krieger DW, Lees KR, Molina C, Montaner J, Roine RO, Petersson J, Staykov D, Szabo I, Wardlaw JM, Schwab S; EuroHYP-1 investigators. EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke. Int J Stroke. 2014 Jul;9(5):642-5. doi: 10.1111/ijs.12294. Epub 2014 May 15.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 30, 2019): 98
• Original Estimated Enrollment (submitted: April 12, 2013): 1500
• Actual Study Completion Date: July 31, 2018
• Actual Primary Completion Date: July 31, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT01833312
• Other Study ID Numbers: EuroHYP-1
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: University of Erlangen-Nürnberg Medical School
• Study Sponsor: University of Erlangen-Nürnberg Medical School
• Collaborators: Not Provided

Investigators

• Study Chair: Stefan Schwab, Prof; University of Erlangen-Nürnberg

• PRS Account: University of Erlangen-Nürnberg Medical School
• Verification Date: September 2019