European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND

Abstract

Rationale and hypothesis

Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is an effective and approved therapy for acute ischemic stroke within 4.5 h of onset except for USA, Canada, Croatia, and Moldovia with a current 3 h label. We hypothesized that ischemic stroke patients selected with significant penumbral mismatch on magnetic resonance imaging (MRI) at 4.5–9 h after onset of stroke will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo.

Study design

ECASS-4: ExTEND is an investigator driven, phase 3, randomized, multi-center, double-blind, placebo-controlled study. Ischemic stroke patients presenting within 4.5 and 9 h of stroke onset, who fulfil clinical requirements (National Institutes of Health Stroke Score (NIHSS) 4–26 and pre-stroke modified Rankin Scale (mRS) 0–1) will undergo MRI. Patients who meet imaging criteria (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml) additionally will be randomized to either rt-PA or placebo.

Study outcome

The primary outcome measure will be the categorical shift in the mRS at day 90. Clinical secondary outcomes will be disability at day 90 dichotomized as favorable outcome mRS 0–1 at day 90. Tertiary endpoints include reduction in the NIHSS by 11 or more points or reaching 0–1 at day 90, reperfusion and recanalization at 24 h post stroke as well as depression, life quality, and cognitive impairment at day 90. Safety endpoints will include symptomatic intracranial hemorrhage (ICH) and death.

Keywords

clinical trial ischemic stroke acute stroke therapy thrombolytic therapy recombinant tissue plasminogen activator magnetic resonance imaging

Introduction and trial rationale

Recent randomized clinical trials^1–5 demonstrated the efficacy of intra-arterial thrombectomy for patients with ischemic stroke due to large artery occlusions, mainly within a 6-h time window. Nevertheless only a minority of stroke patients meets the criteria of these successful thrombectomy trials regarding major vessel occlusion, severity of stroke, and admission in a thrombectomy specialized center within the required time window. Thus intravenous thrombolysis with rt-PA still remains the most important treatment of acute ischemic stroke. When administered within 4.5 h from stroke onset based on plain computed tomography (CT)-imaging, rt-PA improves outcome.^6,7 The benefit of thrombolytic therapy up to 4.5 h from stroke onset has been initially confirmed by the European Cooperative Acute Stroke Study (ECASS) III trial.⁸ Despite the efficacy and effectiveness of rt-PA therapy, only about 5% to 20% of eligible patients receive therapy.⁹ Beside the diffidence of rt-PA inexperienced physicians, the extremely short approved time window for rt-PA administration is one main reason for this. Thus extension of the time window for therapy is the most logical way to increase the number of patients eligible to receive rt-PA. The evidence that potentially viable brain tissue (ischemic penumbra) may exist up to 48 h^10,11 from onset of ischemic stroke underlines the plausibility of this approach. MRI allows the identification of ischemic penumbra^12,13 by depicting the mismatch between the hypoperfused perfusion weighted image (PWI) and the infarct core seen on the diffusion weighted image (DWI) and may be present in up to 50% of patients presenting within 24 h from stoke onset.¹⁰

Improved imaging based pre-selection of stroke patients might allow a further extension of the time window and include patients with unknown stroke onset for thrombolysis.¹⁴ Depiction of penumbral mismatch by means of MR DWI/PWI imaging might help to identify a trial population with an improved probability of therapeutic success.¹⁵

A series of phase 2 clinical trials have been conducted to further investigate the relationship between MR DWI/PWI mismatch, thrombolytic therapy and surrogate MR-based outcomes. In the open label non-randomized diffusion and perfusion imaging evaluation for understanding stroke evolution study, patients who received rt-PA within a 3–6-h time window had MR DWI/PWI and magnetic resonance angiography (MRA) performed at study enrollment and after 24 h.^16,17 DWI expansion showed a strong relationship between recanalization, reperfusion, and attenuation of infarct growth. Furthermore a subset of patients with “malignant mismatch” corresponding to a DWI volume greater than 100 ml and high risk of symptomatic intracerebral hemorrhage was identified.

In addition, the echoplanar imaging thrombolytic evaluation trial (EPITHET) showed an absolute improvement of 15% in clinical outcome measures (mRS 0–1) in the penumbral population. The desmoteplase in acute stroke studies DIAS I and II using the bat venom derived thrombolytic agent desmoteplase underline two further aspects concerning patient selection. Patients presenting within 3–9 h from stroke onset were selected on the basis of at least a 20% DWI/PWI mismatch and randomized to placebo or increasing doses of desmoteplase.^18–20 An excellent dose response relationship between desmoteplase and reperfusion seen on PWI as a surrogate outcome measure was shown. The desmoteplase group showed no improvement of outcome compared to the placebo group. Reasons for this failure include a low baseline NIHSS (<10), (which complicates proof of a positive outcome in the therapeutic arm because of the ceiling effect of improving neurological outcomes), very small diffusion lesions, and low vessel occlusion rates. In addition, the choice of CT perfusion (performed in 20% of patients at study entry) as a selection modality was inferior to MR DWI/PWI.

Based on the EPITHET data, we have been able to refine the optimal perfusion parameters as well as the mismatch definition, which may optimize the selection of patients with optimal response to therapy. It has been concluded that a time-to-maximum (Tmax) of plus 4–6 s as the PWI parameter most accurately predicts final infarct volume, and a perfusion volume to infarct core ratio of 1.2 is most likely to predict optimal rt-PA responsiveness.

Based on these informations, we have designed the ECASS-4: ExTEND phase 3, double-blind study of thrombolysis enrolling patients in the 4.5–9-h time window to receive either intravenous rt-PA or placebo in a 1:1 ratio.

Study objectives

To assess whether ischemic stroke patients selected with significant penumbral mismatch have improved clinical outcomes when treated with intravenous rt-PA (alteplase) compared to placebo at 4.5–9 h post onset of stroke.

As a secondary objective explorative data about depression and cognitive impairment will be collected and analyzed regarding the effect of thrombolysis.

Methods

Design

ECASS-4 is a randomized, multi-center, double-blinded, placebo-controlled phase 3 trial (2 arms with 1:1 randomization). Patients randomized to treatment will be stratified for time of randomization after stroke to within <6 h vs. 6–9 h and for the NIHSS prior randomization (NIHSS ≤8, 9–13, ≥14). Data and results will be pooled with the Australian/Asian START-ExTEND trial.²¹

Patient population – inclusion and exclusion criteria

Patients will be randomized in equal numbers to either rt-PA or placebo arms. Randomization will be stratified based on initial stroke severity (NIHSS ≤8, 9–13, ≥14) and time between symptom onset and treatment (<6 vs. 6–9 h). To have an 80% power demonstrating a beneficial effect of rt-PA the number of patients has been calculated to be 125 in the verum and 125 in the placebo group. Assuming a drop-out rate of 5%, a total of 264 patients (132 per group) will be included in the study in order to have 250 evaluable patients.

Inclusion criteria

Patients presenting with acute ischemic stroke;

Patient, family member, or legally responsible person depending on local ethics requirements has given informed consent;

Patient’s age is ≥18 years;

Treatment onset within ≥4.5–9 h after stroke onset;

Patients who wake with stroke may be included if neurological and other exclusion criteria are satisfied. These “wake up” strokes are defined as having no symptoms at sleep onset, but stroke symptoms on waking;

NIHSS score of 4 to 26 with clinical signs of hemispheric infarction;

Penumbral imaging with a perfusion volume (PWI) to infarct core (DWI) ratio of 1.2, and a perfusion lesion minimum volume of 20 ml. Images will be reviewed centrally.

Exclusion criteria

ICH identified by CT or MRI;

Rapidly improving symptoms, particularly if in the judgment of the managing clinician the improvement is likely to result in the patient having an NIHSS score of <4 at randomization;

Pre-stroke mRS score of more than 1 (indicating previous disability);

Contra indication to imaging with MR;

Infarct core >1/3 middle cerebral artery (MCA) territory qualitatively or >100 ml quantitatively (determined by DWI lesion on MRI);

Participation in any investigational study in the previous 30 days;

A life expectancy of less than three months;

Any condition that could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study (this applies to patients with severe microangiopathy such as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura). The judgment is left to the discretion of the investigator;

Pregnant women (clinically evident) or breastfeeding women;

Previous stroke within last three months;

Recent past history or clinical presentation of ICH, subarachnoid hemorrhage, arterio-venous malformation, aneurysm, or cerebral neoplasm. The judgment is left to the discretion of the investigator;

Use of oral anticoagulants within 48 h prior to randomization (including, but not limited to Rivaroxaban, Apixaban, or Edoxaban) or a prolonged prothrombin time (INR > 1.6) or any activated partial thromboplastin time exceeding 1.5 times the normal range or prolonged Thrombin-Time, indicating the potential use of Dabigatran-Etexilate;

Use of heparin, except for low dose subcutaneous heparin, in the previous 48 h;

Use of glycoprotein IIb-IIIa inhibitors within the past 72 h;

Platelet count < 100.000/µl (<100 g/L);

Blood glucose < 50 mg/dl (2.8 mmol/l) or >400 mg/dl (22.2 mmol/l);

Uncontrolled hypertension defined by a blood pressure >185 mmHg systolic or >110 mmHg diastolic on at least two separate occasions at least 10 min apart, or requiring aggressive treatment to reduce the blood pressure to within these limits. The definition of “aggressive treatment” is left to the discretion of the responsible investigator;

Hereditary or acquired hemorrhagic diathesis;

Gastrointestinal or urinary bleeding within the preceding 21 days;

Manifest or recent acute pancreatitis;

Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis;

Major surgery within 14 days prior to randomization which poses a risk in the opinion of the investigator;

Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel;

Exposure to a thrombolytic agent within the previous 72 h.

Randomization

The randomization system for investigational product will be based on computer-generated randomization lists, with stratification for time from onset of stroke to randomization (4.5–6 h or 6–9 h) and for the NIHSS prior randomization (≤8, 9–13, ≥14).

Clinical assessment

Neurological impairment and functional scores will be measured by a neurologist or health care professional trained in their administration and blinded to the imaging results and treatment designation. The NIHSS will be performed before randomization at 12–24 h, day 3, day 7 ± 1, and day 90 ± 7. At day 90 ± 7, clinical assessments will also include the Barthel Index (BI) and the mRS as well as secondary outcomes of depression and quality of life. Cognitive impairment will be assessed using the Montreal Cognitive Assessment (MoCA).²² Assessments of depressive symptoms/disorder and quality of life using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Stroke Impact Scale (Version 3.0),²³ respectively, at day 90 are optional but recommended.

Imaging assessment

Patients will have standardized DWI, PWI, and MRA sequences performed prior to treatment and eligible patients enrolled into the study will have the second scan performed using the same parameters 12–24 h after the first scan. Penumbral mismatch will be defined as PWI:DWI ratio of ≥1.2 and PWI minimum volume will be 20 ml. The MRI protocol will follow current international consensus guidelines.²⁴

An initial scout view will be followed by isotropic DWI (created from DWI images obtained with diffusion sensitizing gradients applied in three orthogonal planes) using b values between 0 sec/mm², equivalent to a T2-weighted image, and 1000 sec/mm². Whole brain imaging will use 15 contiguous axial slices each 5 mm in thickness. Perfusion images will be derived from the concentration-time course obtained after the administration of intravenous gadolinium (0.1 mmol/kg) given over 3–5 s with gradient-echo images acquired every 2 s for 100 s (12 axial slices at each time point). The imaging times for PWI and DWI are each approximately 2 min. Time of flight MRA will be obtained to determine the presence or absence of MCA stem or major branch occlusion. A gradient echo (T2*) sequence will be performed to assess for presence of ICH. A flair sequence is also acquired to identify lesion expansion to the sub-acute imaging time point. This protocol is identical between the acute and sub-acute (24 h) imaging.

The presence and degree of reperfusion will be determined as the difference between the 24 h and acute PWI lesion volumes (percentage change and cm³). Recanalization will be determined based on initial and 24 h MRA and classified according to the thrombolysis in myocardial infarction (TIMI) system. The presence of symptomatic hemorrhagic transformation will be graded by volume (cm³) of hemorrhagic tissue on MRI (repeated study within 24 h or if later clinical deterioration occurs).

To quality assure the MRI-based decision making at the recruiting centers, all imaging data will be electronically transferred and read at the imaging center on a weekly basis. The imaging center will be kept blinded to the clinical information and will perform the analysis of the secondary, radiological outcome measures, prior to unblinding. Analysis of the MRI data is performed using the Olea Sphere® software (Olea Medical, La Ciotat, France).²⁵ Thresholds for calculation of mismatch volume are 100 < ADC < 600mm²/s for the Apparent Diffusion Coefficient (ADC) and Tmax >6 s for the Tmax of the residue function.

Investigational product

The investigational product (rt-PA (alteplase) or placebo) is supplied by Boehringer Ingelheim, Ingelheim Germany as 50 mg lyophilized powder in glass vials. The dose of rt-PA to be administered is 0.9 mg/kg (maximum 90 mg), given as 10% of total dose bolus over 1 min, then the remaining 90% as an infusion over 60 min. No other anticoagulants or antiplatelet agents are to be given within 24 h of administration of the investigational product.

Blinding

All those involved in the conduct of the study will be blinded to treatment allocation (double blind). Members of the data safety monitoring committee will have access to data that is grouped, but not unblinded in terms of treatment allocation.

Study endpoints

Primary endpoint

Categorical shift in mRS at day 90.

Secondary endpoints

Disability at day 90, dichotomized as a favorable outcome (mRS) 0–1 vs. 2–6;

Change in ≥11 NIHSS or reaching 0 or 1 on this scale at day 1 and day 90;

Reperfusion at 12–24 h after treatment;

Recanalization at 12–24 h after treatment;

Infarct growth measured by DWI within 12–24 hrs after treatment;

NIHSS score at day 7;

BI at day 90;

Cognitive impairment: MoCA at day 90.

Tertiary endpoints

Depression: MADRS score at day 90.

These endpoints will be evaluated in selected centers and not for the entire cohort.

Safety endpoints

Death due to any cause;

Neurological death;

Symptomatic ICH according to the ECASS-3 definition.

Data collection/data safety monitoring

All data are recorded in the case record form (CRF). The monitor will review the CRF and evaluate them for completeness and consistency. Data management and handling will be conducted in accordance with ICH guidelines and by standard operating procedures of a representative of the sponsor clinical research organization (CRO). Data entry, validation, and data queries will be handled by the CRO’s team. Before database closure, a reconciliation will be performed between the serious adverse event (SAEs) entered in the safety database and the study database. After database closure, the database will be exported as SAS® data sets.

Table 1.

Schedule of Assessments

Procedure	Detail	Baseline	Treatment	12–24 h	3 days	7 ± 1 days	90 ± 7 days
Demographics		X
IC/EC criteria		X
Informed consent		X
Demographics	Years of education, work status				X
Medical history		X
Concomitant medication		X			X
Imaging	MRI – penumbra, perfusion lesion, DWI, PWI, MRA, T2*, FLAIR	X		X
Randomization	Via IVRS	X
Treatment administration			X
Vital signs	Temperature, BP & heart rate	X	X	X
Neurological examination	NIHSS	X		X	X	X	X
Clinical examination	ECG	X
	Physical examination	X					X
	mRS	Pre-stroke				X	X
	Barthel Index						X
	Symptomatic ICH			X	X
	Quality of life (stroke impact scale)				X		X
	MADRS				X		X
	MoCA						X
Safety	AEs			X	X
Routine laboratory assessments^a	Hematology – Full blood examination	X		X	X
	Clinical Chemistry – Urea & electrolytes, glucose, lipid profile	X		X	X
	Coagulation profile – PT, INR	X		X	X

MRI: magnetic resonance imaging; DWI: diffusion weighted image; MRA: magnetic resonance angiography; PWI: perfusion weighted imaging; FLAIR: fluid attenuated inversion recovery; IVRS: interactive voice randomisation system; NIHSS: National Institutes of Health Stroke Score; ECG: electrocardiogram; mRS: modified Rankin scale; ICH: intracranial hemorrhage; MADRS: Montgomery-Asberg Depression Rating Scale; MoCA: Montreal Cognitive Assessment; AEs: adverse events; PT: prothrombin time.

Standard care clinical safety tests, local laboratory.

Sample size

The power of the study has been explored through simulation of 10,000 samples with the SAS system. The simulated model consists of one parameter: the proportion of patients scoring each of the mRS categories, based on data from the ECASS III trial. Due to an improved patient selection it is assumed that outcome in the verum-group is slightly better, whereas the placebo group should demonstrate identical outcomes. Using this assumption a sample size of 250 patients would be required to achieve a nearly 80% power. To compensate for drop outs 5% additional patients will be included. Thus the overall sample size will be 264 patients.

Statistical analyses

The primary outcome analysis of the categorical shift in mRS will be undertaken on the full range (0–6) of the mRS using Cochran-Mantel-Haenszel shift test and proportional odds logistic regression subject to the validity of shift analysis model assumptions. Adjustment for prognostic baseline variables (such as age and baseline NIHSS score, using its medians) will be made prior to this if significant imbalances are observed. For the secondary analysis, the proportions of mRS 0–1 outcomes will be compared between treatment and placebo arms using a logistic regression with time between stroke onset and treatment (<6 vs. 6–9 h), initial stroke severity (NIHSS) and age as covariates. Other secondary outcome analyses will be carried out according to standard statistical principles for comparison of parametric or non-parametric distributions as appropriate.

Data and results will be also pooled with the START-ExTEND trial.

Summary and conclusions

ECASS-4: ExTEND is a randomized, multi-center, double-blinded, placebo-controlled phase 3 trial investigating the efficacy and safety of MRI-based intravenous thrombolytic therapy in a 4.5–9-h time window after stroke onset in an enriched population of acute stroke patients. Furthermore, this study assesses the impact of thrombolytic therapy on post stroke depression. The advantages of extension of the therapeutic time window for thrombolysis would be of significant benefit to the global stroke community, given an estimated increase of 22% of patients, who could be considered for this therapy.

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The sponsor of the trial (ECASS-4: ExTEND) is the University hospital Heidelberg. Monitoring will be done by Trial Form Support International, Spain.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: ECASS-4: ExTEND is an investigator driven trial supported with an unrestricted grant from Boehringer Ingelheim (Germany).

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