E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with acute ischemic stroke proven by MRI and unknown time from symptom onset which otherwise fulfil the approval criteria for intravenous thrombolysis in acute stroke |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with acute ischemic stroke |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061256 |
E.1.2 | Term | Ischaemic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
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 |
The objective is to test efficacy and safety of MRI-based intravenous thrombolysis with Alteplase in patients waking up with stroke symptoms or patients with unknown symptom onset. |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Clinical Inclusion Criteria - Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g., stroke symptoms recognized on awakening) - Last known well (without neurological symptoms) >4.5 hours of treatment initiation - Measurable disabling neurological deficit (defined as an impairment of one or more of the following: language, motor function, cognition, gaze, vision, neglect) - Age 18-80 years -Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening) - Written informed consent by patient or proxy
Imaging Inclusion Criteria: - Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed and showing a pattern of “DWI-FLAIR-mismatch”, i.e. acute ischemic lesion visibly on DWI (“positive DWI”) but no marked parenchymal hyperintensity visible on FLAIR (“negative FLAIR”) indicative of an acute ischemic lesion ≤4.5 hours of age
|
|
E.4 | Principal exclusion criteria |
Clinical Exclusion Criteria - Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra-arterial thrombolysis, mechanical recanalization techniques) - Pre-stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability corresponding to an MRS score >1) - Participation in any investigational study in the previous 30 days - Severe stroke by clinical assessment (e.g. NIHSS >25) - Hypersensitivity to Alteplase or any of the excipients - Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed in women up to 55 years of age) - Significant bleeding disorder at present or within past 6 months - Known haemorrhagic diathesis - Manifest or recent severe or dangerous bleeding - Known history of or suspected intracranial haemorrhage - Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from aneurysm - History of CNS damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery) - Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel -Current effective use of anticoagulants (e.g. Phenprocoumon, Warfarin, or new direct oral anticoagulants such as Apixaban, Dabigatran or Rivaroxaban) or current use of heparin and elevated thromboplastin time (low-dose subcutaneous heparin is allowed); inclusion may be considered in patients using vitamin K-antagonists (Phenprocoumon or Warfarin) when appropriate tests of anticoagulant activity (INR) show no clinically relevant activity - Platelet count <100.000/mm3 (<100G/l) - Blood glucose <50 or >400 mg/dl (<2.8 or 22.2 mmol/l) - Severe uncontrolled hypertension, i.e. systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits) - Manifest or recent bacterial endocarditis, pericarditis - Manifest or recent acute pancreatitis - Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations - Neoplasm with increased bleeding risk - Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis - Major surgery or significant trauma in past 3 months - Stroke within 30 days - Life expectancy 6 months or less by judgement of the investigator - Any condition associated with a significantly increased risk of severe bleeding not mentioned above - Any contraindication to MRI (e.g. cardiac pacemaker)
Imaging Exclusion Criteria: - Poor MRI quality precluding interpretation according to the study protocol - Any sign of intracranial haemorrhage on baseline MRI - FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion inidicative of an acute ischemic lesion with a high likelihood of being > 4.5 hours old - Large DWI lesion volume > 1/3 of the MCA or >50% of the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory (visual inspection) or >100 ml - Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV-tPA treatment in the judgement of the investigator
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint • “Favourable outcome” defined by a score of 0-1 on the modified Rankin Scale (MRS) 90 (±10) days after stroke Primary Safety Endpoints • Mortality 90( ±)10 days after stroke • Death or dependency 90 (±10) days after stroke (MRS 4-6)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy Endpoint • 90 ±10 days after stroke Primary Safety Endpoints • 90 ±10 days after stroke • 90 ±10 days after stroke |
|
E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints - Global Outcome Score (combination of MRS 0-1, NIHSS 0-1, Barthel Index [BI] 95-100, Glasgow Outcome Scale [GOS] 1) 90 (±10) days after stroke - Categorical shift in MRS 90 (±10) days after stroke - Responder analysis relating MRS 90 (±10) days after stroke to baseline NIHSS score: “response” defined by NIHSS <7 = MRS 0; NIHSS 8-14 = MRS 0-1; NIHSS >14 = MRS 0-2 - Infarct volume after 22-36 hours - Depressive symptoms 90 (±10) days after stroke (Beck Depression Inventory [BDI]) - Functional health status and quality of life 90 (±10) days after stroke (EQ-5D) - Use of health care system resources - 90 +/- 10 days after stroke
Secondary Safety Endpoints - Symptomatic intracranial haemorrhage (SICH) as defined in SITS-MOST - SICH as defined ECASS II - SICH as defined in NINDS - Parenchymal haemorrhage type 2 (PH-2) - 22-36 hours after treatment
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
90 (±10) days after stroke |
|
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |