E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To test the hypothesis that ischemic stroke patients selected with significant penumbral mismatch at 4.5-9 hours post onset of stroke or wake up with stroke symptoms will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
Collection of explorative data of functional outcome, including depression and cognitive impairment and the effect of thrombolysis. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients presenting with acute ischemic Middle Cerebral Artery (MCA) stroke
- Patient, or legally acceptable representative has given written informed consent. An independent witness may sign the consent form if the patient is able to give verbal consent, but unable to sign
- Patient’s age is ≥18 years
- Treatment onset within ≥ 4.5 – 9 hours after stroke onset*
*Patients with 'wake up' strokes may be included. 'Wake up’ strokes are defined as having no stroke symptoms at sleep onset, but on waking. The time of stroke onset is to be taken as the mid-point between sleep onset (or last known to be normal) and time of waking.
- NIHSS score of 4 to 26 with clinical signs of hemispheric infarction
- Penumbral mismatch imaging via local assessment using a computer based analysis system (e.g. RAPID) if available, using a perfusion volume (PWI) to infarct core (DWI) ratio of ≥ 1.2, and a minimum perfusion lesion volume of 20 ml. |
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E.4 | Principal exclusion criteria |
- Intracranial hemorrhage (ICH) identified by CT or MRI
- Rapidly improving symptoms, particularly if, in the opinion of the investigator, the improvement is likely to result in the patient having an NIHSS score of <4 at randomization
- Pre-stroke mRS score of >1 (indicating previous disability)
- Contra indication to imaging with MRI
- Infarct core >1/3 MCA territory qualitatively or >100 ml quantitatively (determined by DWI lesion on MRI)
- Any MRI findings indicative of a high risk of ICH related to potential iv-rtPA treatment in the judgment of the investigator
- Participation in any investigational study in the previous 30 days
- A life expectancy of <3 months
- Any condition that, in the opinion of the investigator, 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).
- Pregnant (clinically evident) or breastfeeding women
- Previous stroke within the three months prior to randomization
- Recent history (in the opinion of the investigator) or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm.
- Use of oral anticoagulants within 48 hours prior to randomization (including, but not limited to Rivaroxaban, Apixaban, or Edoxaban) and a prolonged prothrombin time (INR > 1.6) or any activated partial thromboplastin (aPTT) time exceeding 1.5 times the normal range or prolonged Thrombin-Time (TT), indicating the potential use of Dabigatran-Etexilate.
- Use of heparin, except for low dose subcutaneous heparin, within 48 hours prior to randomization
- Use of glycoprotein IIb-IIIa inhibitors within 72 hours prior to randomization.
- Platelet count <100.000/μl (<100G/l)
- Blood glucose <50mg/dl (2.8 mmol/l) or >400mg/dl (22.2mmol/l)
- Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or >110 mmHg diastolic on at least 2 separate occasions at least 10 minutes 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 investigator.
- Hereditary or acquired hemorrhagic diathesis
- Gastrointestinal or urinary bleeding within 21 days prior to randomization
- 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 72 hours prior to randomization
- Hypersensitivity to alteplase or any of the excipients |
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E.5 End points |
E.5.1 | Primary end point(s) |
Categorical shift in the modified Rankin Scale (mRS) at Day 90 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
90 days after administration of IMP |
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E.5.2 | Secondary end point(s) |
- Disability at Day 90, dichotomized as a favorable outcome
(mRS) 0–1 vs. 2 - 6*
*This is the key secondary endpoint to ensure the combined analysis with the EXTEND trial
- Change in ≥ 11 National Institute of Health Stroke Scale (NIHSS) points or reaching ≤ 1 on this scale at day 1 and day 90
- Reperfusion at 12-24 hours after treatment
- Recanalization at 12-24 hours after treatment
- Infarct growth on diffusion weighted imaging (DWI) within 12-24 hours after treatment
- NIHSS at day 7
- Barthel Index (BI) at day 90
- Montreal Cognitive Assessment (MoCA) score at day 90
Tertiary endpoints (in some centers)
- Montgomery-Asberg Depression Rating Scale (MADRS) score at day 90
Safety endpoints
- Death due to any cause
- Neurological death
- Symptomatic intracranial hemorrhage (ICH) as defined by ECASS-3 definition |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
90 days after administration of IMP |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study will be defined as the last visit of the last patient remaining in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |