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

Abstract

Background: Cooling may reduce infarct size and improve neurological outcomes in patients with ischaemic stroke. In phase II trials, cooling awake patients with ischaemic stroke has been shown to be feasible and safe, but the effects in functional outcomes has not yet been investigated in an adequately sized randomised clinical trial.

Methods/design: The EuroHYP-1 trial is a multinational, randomised, superiority phase III clinical trial with masked outcome assessment testing the benefits and harms of therapeutic cooling in awake adult patients with acute ischaemic stroke. The outcomes dealt with here include the primary outcome the Rankin score (mRS) at day 91 +/-14 days after randomisation. The secondary and exploratory outcomes at day 91 +/-14 days unless otherwise stated encompassing: (1) death or dependency, defined as mRS score > 2; (2) death; (3) National Institutes of Health Stroke Score; (4) brain infarct size at 48 +/-24 hours; (5) EQ-5D-5 L score, and (6) WHODAS 2.0 score. Other outcomes are: the primary safety outcome serious adverse events; and the incremental cost-effectiveness, and cost utility ratios. The analysis sets include (1) the intention-to-treat population, and (2) the per protocol population. The sample size is estimated to 800 patients (5% type 1 and 20% type 2 errors). All analyses are adjusted for the protocol-specified stratification variables (nationality of centre), and the minimisation variables. In the analysis, we use ordinal regression (the primary outcome), logistic regression (binary outcomes), general linear model (continuous outcomes), and the Poisson or negative binomial model (rate outcomes).

Discussion: Major adjustments compared with the original statistical analysis plan encompass: (1) adjustment of analyses by nationality; (2) power calculations for the secondary outcomes; (3) to address the multiplicity problem using of a fixed-sequence testing procedure starting with the primary outcome followed by the secondary outcomes ordered according to falling power; (4) assignment of worst possible score to patients who are not alive at the planned date of measurement of the continuous scores; (5) improved imputations; (6) outline of a supplementary exploratory analysis of the temperature measurements and time to death; and (7) substantial reduction of sample size.

Trial registration: Clinicaltrials.gov, identifier: NCT01833312 . 4 April 2013.

Keywords: Acute ischaemic stroke; Cooling; Cost-effectiveness; Modified Ranking scale; Quality of life; Randomised clinical trial.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

All included participants have provided verbal and written consent before inclusion in the trial. The trial has been approved by the relevant ethics committees in all participating countries (Belgium (AZ Sint Jan Brugge–Oostende AV Ethics Committee OG 065, ref no. 1759, 7 May 2015), Denmark (Regional Ethics Committee for Region Hovedstaden, ref no. 30113713, 10 Oct 2013), Finland (Hospital District of South-West Finland, ref no. 161/1800/2014, 28 Jun 2016), France (Comité de Protection des Personnes Nord Ouest IV, ref no. CPP 14/21, 13 Jun 2014), Germany (Ethik-Kommission der FAU, Erlangen, ref no 63_13 Az and 67_13 Mz, 7 Jun 2013), Ireland (SJH/AMNCH Research Ethics Committee, ref no. 2015-11 List 43 (4), 26 Nov 2915), Italy (Comitato Etico Dell' Universita' "Sapienza", ref no. 161 SA/2016, 8 May 2015), Lithuania (Lietuvos Bioetikos Komitetas, ref no. L-15-04/1, 18 Feb 2015), Poland (Instytut Psychiatrii I Neurologii Komisja Bioetyczna, ref no. 8/2014, 12 Jun 2014), Spain (CEIC del Hospital Universitari Vall d’Hebrón, 4 Apr 2014), Sweden (Regionala Etikprovningsnamden Lund, ref no. 2016/1088, 2 Feb 2017), Turkey (Hacettepe Universitesi Klinik Arastirmalar Etik Kurulu Karar Formu, ref no. KA 14039, 19 Mar 2015), UK England (North East - Newcastle & North Tyneside 2 Research Ethics Committee, ref no. 3/NE/0299, 2 Dec 2013), UK Scotland (Scotland A Research Ethics Committee, ref no. 13/SS/0194, 9 Dec 2013).

Consent for publication

Not applicable (no individual details will be published based from the EuroHYP-1 trial, only summary data will be used, thus assuring the anonymity of the trial participants).

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

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

Fig. 2

Flow of participants in the EuroHYP-1 trial