E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Anterior Circulation Ischaemic Stroke |
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E.1.1.1 | Medical condition in easily understood language |
Acute Anterior Circulation Ischaemic Stroke |
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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 trial 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 ischaemic 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 |
The secondary objectives are to study mortality, degree of disability or dependency as assessed by modified Rankin Scale (mRS), 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 functional independence (mRS ≤ 2) at 90 days. The mRS is the standard tool to assess neurological outcome in trials with acute severe brain disease. This outcome measure has been established in several large randomised trials. The time point of 90 days is chosen due to the known capability of improvement in the first months after AIS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
90 ± 15 days after randomisation |
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E.5.2 | Secondary end point(s) |
- All-cause mortality at 90 days post randomisation: Mortality will be assessed by the (Modified Ranking Scale)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 randomisation: NIHSS will be assessed at day 0, at 24 ± 6 hours post-randomisation, at day 7-10 or discharge and at 90 ± 15 days after randomisation 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: 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 randomisation 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 randomisation |
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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 thrombectomy alone 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 | 13 |
E.8.5 | The trial involves multiple Member States | No |
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 |
Austria |
Canada |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 31 |