Journal: Trials

Article Title: 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

doi: 10.1186/s13063-017-2302-z

Figure Lengend Snippet: Overview of patient schedule and data collection in the EuroHYP-1 trial ( grey tone only for the experimental group). 1 Re-warming: hypothermia group only. 2 Previous medication including alteplase. 3 Includes sodium, potassium, magnesium, creatinine, urea, gamma-glutamyl transpeptidase, ASAT, ALAT, alkaline phosphatase, blood glucose; haemoglobin, haematocrit, erythrocytes, leukocytes, platelets, INR. Further samples may be taken throughout the study at the discretion of the investigator. 4 Body temperature will be assessed according to local clinical practice with tympanic, bladder, or rectal temperature measurement, except in patients randomised to therapeutic hypothermia from start of treatment phase (TP, beginning of hour 1) until end of re-warming period, when bladder or rectal thermal probes will be used. During TP, body temperature will be assessed every 15 min during the first 3 hours (except at time points t = 0 min and t = 15 min) and every 60 min thereafter in patients randomised to therapeutic hypothermia, every 60 min (except at time point t = 0 min) in patients randomised to best medical treatment alone, subsequently in all patients at 8-hour intervals until A6 (day 8 or day of discharge from hospital, whichever occurs first). 5 The mRS assessment at outcome assessment (A7) will be recorded using a digital video camera. The clip will then be transferred to the EuroHYP-1 outcome adjudication web portal. 6 Anti-shivering medication: induction: buspirone 10 mg p.o./pethidine 50 mg i.v. (2 min); repeat doses of 10 mg buspirone p.o. may be administered as long as a maximum dose of 30 mg/24 h is respected; a bolus of pethidine 25 mg i.v. may be given as long as an interval of at least 30 min is respected and a maximum dose of 500 mg/24 h is not exceeded. 24 h-doses include induction bolus. For the prevention and treatment of opioid-induced nausea and vomiting, a 5HT3RA may be administered as support medication. 7 Induction of cooling: 20 ml/kg estimated bodyweight 4 °C isotone saline or Ringer´s lactate over a period of 30–60 min; EMCOOLS Brain.Pad, if available. 8 IMDs permitted for cooling: EMCOOLS Brain.Pad (for induction of cooling only); Medivance/Bard Arctic Sun temperature management system with heat exchange control unit Arctic Sun 2000 or Arctic Sun 5000 and ArcticGel Pads; MTRE CritiCool temperature management system with heat exchange control unit CritiCool, accessoires and CureWrap; Zoll IVTM system with heat exchange control unit CoolGard 3000 or Thermogard XP, CoolGard start-up kit and intravascular temperature management catheters ICYy 3893 AE or ICY 3893 CO. 9 If endovascular cooling is performed, the catheter insertion site must be visually inspected for detection of bleeding/haematoma in 3-hour intervals during TP and once 3 hours after removal of the intravascular catheter. 10 Monitoring for pneumonia includes monitoring of oxygen saturation and body temperature, physical examination (auscultation, percussion) and, if clinically indicated, chest X-ray. Monitoring for signs of pneumonia must be performed from screening assessment (A1, within 90 minutes before the start of the treatment phase TP) until A6 (day 8 or day of discharge from hospital, whichever occurs first). 11 Patient location during stay in hospital must be assessed at 12:00 hours on each day in hospital. 12 WHODAS 2.0 questionnaire and EQ-5D questionnaire must be filled in by the patient or his/her relative/carer at outcome assessment (A7). 13 Health Recovery Guide and Diary: Section 6: filled in by the patient every day from discharge to V7; Section 7: filled in by the carer/relative prior to V7. 14 For participation in the biomarker sub-study a special informed consent form must be filled in by the patient or his/her legal representative. Assessment at End of Hour 24 ± 2 hours. 15 Only selected study sites. 16 Informed consent will be obtained in accordance with national regulatory requirements. 17 NIHSS assessment at End of Hour 24 ± 2 hours. 18 Starting at t = 30 min. 19 Every 60 minutes only. 20 Prior to intended repeat administration of pethidine. CT computed tomography, ECG electrocardiogram, EQ-5D-5 L EuroQoL quality-of-life scale, GCS Glasgow coma scale, MRI magnetic resonance imaging, NIHSS National Institutes of Health Stroke Score, SAE serious adverse event, WHODAS World Health Organization Disability Assessment Schedule

Article Snippet: 8 IMDs permitted for cooling: EMCOOLS Brain.Pad (for induction of cooling only); Medivance/Bard Arctic Sun temperature management system with heat exchange control unit Arctic Sun 2000 or Arctic Sun 5000 and ArcticGel Pads; MTRE CritiCool temperature management system with heat exchange control unit CritiCool, accessoires and CureWrap; Zoll IVTM system with heat exchange control unit CoolGard 3000 or Thermogard XP, CoolGard start-up kit and intravascular temperature management catheters ICYy 3893 AE or ICY 3893 CO. 9 If endovascular cooling is performed, the catheter insertion site must be visually inspected for detection of bleeding/haematoma in 3-hour intervals during TP and once 3 hours after removal of the intravascular catheter.

Techniques: Saline, Control, Biomarker Discovery, Computed Tomography, Magnetic Resonance Imaging