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

September 30, 2019 updated by: University of Erlangen-Nürnberg Medical School

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

98

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Erlangen, Germany, 91054
        • Department of Neurology, University Hospital Erlangen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Control
Best medical 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mortality
Time Frame: 3 months
3 months
Neurological outcome
Time Frame: 3 months

NIHSS;

World Health Organization Disability Assessment Schedule (WHODAS) 2.0
3 months
Quality of life
Time Frame: 3 months
EuroQoL 5-dimensions 5-level questionnaire
3 months
Cerebral infarct size
Time Frame: 48±24 hours
Evaluated on CT or MRI imaging
48±24 hours
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.
Enrollment - day 91
Tolerability of systemic cooling
Time Frame: 36 hours

Timing and dose of anti-shivering medication.

Bedside shivering assessment scale (BSAS).
36 hours

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
baseline, 24h, 72h
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).
baseline, 48h
Cost-effectiveness parameters
Time Frame: 3 months

Patient location during stay in hospital.

Destination after discharge from hospital.
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Erlangen-Nürnberg Medical School

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2013

Primary Completion (Actual)

July 31, 2018

Study Completion (Actual)

July 31, 2018

Study Registration Dates

First Submitted

April 4, 2013

First Submitted That Met QC Criteria

April 12, 2013

First Posted (Estimate)

April 16, 2013

Study Record Updates

Last Update Posted (Actual)

October 2, 2019

Last Update Submitted That Met QC Criteria

September 30, 2019

Last Verified

September 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EuroHYP-1

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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