Dataset Information

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial.

ABSTRACT:

Introduction

We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke.

Patients and methods

In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0-35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression.

Results

The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48-2.13; p = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65-1.94; p = 0.52).

Discussion

In this trial, cooling to a target of 34.0-35.0°C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes.

Conclusion

Before new trials are launched, the feasibility of cooling needs to be improved.

SUBMITTER: van der Worp HB

PROVIDER: S-EPMC6960691 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial.

van der Worp H Bart HB Macleod Malcolm R MR Bath Philip Mw PM Bathula Raj R Christensen Hanne H Christensen Hanne H Colam Bridget B Cordonnier Charlotte C Demotes-Mainard Jacques J Durand-Zaleski Isabelle I Gluud Christian C Jakobsen Janus Christian JC Kallmünzer Bernd B Kollmar Rainer R Krieger Derk W DW Lees Kennedy R KR Michalski Dominik D Molina Carlos C Montaner Joan J Roine Risto O RO Petersson Jesper J Perry Richard R Sprigg Nikola N Staykov Dimitre D Szabo Istvan I Vanhooren Geert G Wardlaw Joanna M JM Winkel Per P Schwab Stefan S

European stroke journal 20190420 3

<h4>Introduction</h4>We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke.<h4>Patients and methods</h4>In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0-35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , vers ...[more]

PMID: 31984233

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Project description:BackgroundCooling 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/designThe 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).DiscussionMajor 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 registrationClinicaltrials.gov, identifier: NCT01833312 . 4 April 2013.

Project description:Background and objectivesSovateltide (Tycamzzi™), an endothelin-B (ET-B) receptor agonist, increases cerebral blood flow, has anti-apoptotic activity, and promotes neural repair following cerebral ischaemic stroke. The objectives of this study were to evaluate the efficacy and safety of sovateltide in adult participants with acute cerebral ischaemic stroke.MethodsThis was a randomised, double-blind, placebo-controlled, multicentre, Phase III clinical trial of sovateltide in participants with cerebral ischaemic stroke receiving standard of care (SOC) in India. Patients aged 18-78 years presenting up to 24 h after the onset of symptoms with radiologic confirmation of ischaemic stroke and a National Institutes of Health Stroke Scale score (NIHSS) of ≥ 6 were enrolled. Patients with recurrent stroke, receiving endovascular therapy, or with intracranial haemorrhage were excluded. The study drug (saline or sovateltide [0.3 µg/kg] was administered intravenously in three doses at 3 ± 1 h intervals on Days 1, 3, and 6, and follow-up was 90 days). The Multivariate Imputation by Chained Equations (MICE) was used to impute the missing assessments on the endpoints. An unpaired t-test, two-way analysis of variance with Tukey's multiple comparison test, and the Chi-square test were used for the statistical analysis. The objective was to determine at Day 90 (1) the number of patients with a modified Rankin Scale score (mRS) 0-2, and (2) the number of patients with an NIHSS 0-5 at 90 days.ResultsPatients were randomised with 80 patients in the sovateltide and 78 in the control group. Patients received the investigational drug at about 18 h of stroke onset in both control and sovateltide groups. The median NIHSS at randomisation was 10.00 (95% CI 9.99-11.65) in the control group and 9.00 (95% CI 9.11-10.46) in the sovateltide group. Seventy patients completed the 90-day follow-up in the control group and 67 in the sovateltide group. The proportion of intention-to-treat (ITT) patients with mRS 0-2 score at Day 90 post-randomisation was 22.67% higher (odds ratio [OR] 2.75, 95% CI 1.37-5.57); similarly, the proportion of patients with NIHSS score of 0-5 at Day 90 was 17.05% more (OR 2.67, 95% CI 1.27-5.90) in the sovateltide group than in the control group. An improvement of ≥ 2 points on the mRS was observed in 51.28% and 72.50% of patients in the control and sovateltide groups, respectively (OR 2.50, 95% CI 1.29-4.81). Seven of 78 patients (8.97%) in the control group and 7 of 80 (8.75%) in the sovateltide group developed intracranial haemorrhage (ICH). The adverse events were not related to sovateltide.ConclusionsThe sovateltide group had a greater number of cerebral ischaemic stroke patients with lower mRS and NIHSS scores at 90 days post-treatment than the control group. This trial supported the regulatory approval of sovateltide in India, but a multinational RESPECT-ETB trial will be conducted for US approval.Trial registrationClinical Trials Registry, India (CTRI/2019/09/021373) and the United States National Library of Medicine, ClinicalTrials.gov (NCT04047563).

Project description:ObjectivesTo compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death.DesignMulticentre, randomised, open label trial.Setting106 hospitals in China between 13 June 2018 and 10 July 2022.Participants4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg.InterventionsPatients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg).Main outcome measuresThe primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted.Results2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups.ConclusionsAmong patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days.Trial registrationClinicalTrials.gov Identifier NCT03479554.

Project description:BackgroundIntraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome.MethodsIn this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134.FindingsBetween Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar.InterpretationIn patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.FundingNational Institute of Neurological Disorders and Stroke.

Dataset Information

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial.

Introduction

Patients and methods

Results

Discussion

Conclusion

Publications

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial.

Similar Datasets

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