E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Anterior Circulation Stroke |
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E.1.1.1 | Medical condition in easily understood language |
Acute Anterior Circulation Stroke |
akuter ischämischer Hirnschlag |
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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 |
The overall objective of this RCT is to measure the effect of direct mechanical thrombectomy (MT) compared with bridging thrombectomy (combined IV t-PA and MT). The primary objective is to determine whether subjects experiencing an acute ischemic stroke due to large intracranial vessel occlusion in the anterior circulation who are referred to a stroke centre with endovascular facilities and who are candidates for IV t-PA will have non-inferior functional outcome at 90 days when treated with direct MT compared to subjects treated with combined IV t-PA and MT.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to study mortality, dependency, time to reperfusion and quality of life. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Informed consent as documented by signature - Age ≥ 18 years - Clinical signs consistent with an acute ischaemic stroke - Neurological deficit with a NIHSS of ≥ 5 and < 30 (deficits judged to be clearly disabling at presentation) - Patient is eligible for IV t-PA - Patient is eligible for endovascular treatment/therapy - Randomization no later than 4 hours 15 minutes after stroke symptom onset and initiation of IV t-PA must be started within 4 hours 30 minutes of stroke symptoms onset (onset time is measured from the time when the subject was last seen well) - Occlusion (mTICI 0-1) of the intracranial internal carotid artery, the M1 segment of the middle cerebral artery, or both confirmed by CT or MR angiography, accessible for MT - Core-infarct volume of Alberta Stroke Program Early CT Score (ASPECTS) greater than or equal to 4 (≥ 4) based on baseline CT or MR imaging (MRI) (a region has to have diffusion abnormality in 20% or more of its volume to be considered MR-ASPECTS positive) |
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E.4 | Principal exclusion criteria |
• Acute intracranial haemorrhage • Any contraindication for IV t-PA • Pre-treatment with IV t-PA • In-hospital stroke • Pregnancy or lactating women. A negative pregnancy test before randomization is required for all women with child-bearing potential. • Known (serious) sensitivity to radiographic contrast agents, nickel, titanium metals or their alloys • Known current participation in a clinical trial • Renal insufficiency as defined by a serum creatinine > 2.0 mg/dl (or 176.8 µmol/l) or glomerular filtration rate (GFR) < 30 mL/min and /or known history of renal insufficiency or requirement for haemodialysis or peritoneal dialysis • Severe comorbid condition with life expectancy less than 90 days at baseline • Known advanced dementia or significant pre-stroke disability (mRS score of ≥ 2) • Foreseeable difficulties in follow-up due to geographic reasons (e.g. patients living abroad) • Comorbid disease or condition that would confound the neurological and functional evaluations or compromise survival or ability to complete follow-up assessments. • Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol (defined as regular or daily consumption of more than four alcoholic drinks per day). • Known history of arterial tortuosity, pre-existing stent, other arterial disease and/or known disease at the femoral access site that would prevent the device from reaching the target vessel and/or preclude safe recovery after MT • Radiological confirmed evidence of mass effect or intracranial tumour (except small meningioma) • Radiological confirmed evidence of cerebral vasculitis • CTA or MRA evidence of carotid dissection • Evidence of additional distal intracranial vessel occlusion in another territory (i.e. A2 segment of anterior cerebral artery or M3, M4 segment of MCA) on initial NCCT/MRI or CTA/MRA |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is assessed at 90 ± 15 days after randomization by a treatment-blinded certified person during the clinical visit or by a structured telephone interview by a trained person at the trial site (according to local clinical routine). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
90 ± 15 days after randomization |
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E.5.2 | Secondary end point(s) |
- All-cause mortality at 90 days: Mortality will be assessed by the mRS during the clinical visit (7-10 days or discharge or 90 day ± 15 days) or by a structured telephone interview (90 ± 15 days) according to local clinical routine. If patients/relatives do not respond the general practitioner or treating physician will be contacted. - Degree of disability or dependence at 90 days as assessed by the mRS (shift analysis): Disability and dependency are assessed using the mRS during the clinical visit (7-10 days or discharge and 90 ± 15 days) or during the structured telephone interview (90 ± 15 days) according to local clinical routine. If patients/relatives do not respond the general practitioner or treating physician will be contacted. - Change in NIHSS at 24 ± 6 hours post randomization: NIHSS will be assessed at day 0, at 24 ± 6 hours post-randomization, at day 7-10 or discharge and at 90 ± 15 days after randomization during the clinical visit by an independent trained neurologist. Time from arrival at emergency department to reperfusion (mTICI ≥ 2b): Time points will be assessed at day 0 from arrival at hospital until end of intervention. Additional important treatment time points will be recorded optionally by using the Bernese Stroke clock. mTICI is defined as:37 Grad 0 = No perfusion Grade 1 = Antegrade reperfusion past the initial occlusion, but limited distal branch filling with little or slow distal reperfusion Grade 2 = Antegrade reperfusion of less than half of the occluded target artery previously ischemic territory (eg, in 1 major division of the MCA and its territory) Grade 3 = Antegrade reperfusion of more than half of the previously occluded target artery ischemic territory (eg, in 2 major divisions of the MCA and their territories - Quality of life as assessed by the EuroQol 5D-3L at 90 days: Quality of life will be assessed at 90 ± 15 days after randomization using the validated EuroQol 5D-3L questionnaire during the clinical visit or during a structured telephone interview by trained personnel and according to local clinical routine. - Successful reperfusion defined as mTICI ≥ 2b prior to endovascular treatment/device use: Reperfusion prior to endovascular treatment/device use will be assessed before the intervention at day 0 by trained neuroradiologist using the mTICI scale. - Successful reperfusion defined as mTICI ≥ 2b or mTICI = 3 following device use: Reperfusion following device use will be assessed during the intervention at day 0 by trained neuroradiologist using the mTICI scale. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
90 ± 15 days after randomization |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The trial is open with the exception of the assessor of the primary endpoints, who is blinded |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire™ Stent-retriever |
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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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Austria |
Finland |
France |
Germany |
Spain |
Switzerland |
United Kingdom |
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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
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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 | 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 | 5 |