| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Anterior Circulation Stroke |
| ictus agudo de la circulación anterior |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute Anterior Circulation Stroke |
| ictus agudo de la circulación anterior |
|
| 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. |
| El objetivo principal de este ensayo aleatorizado es determinar si los sujetos que experimentan un IIA debido a la oclusión de un vaso intracraneal principal en la circulación anterior que son derivados a un centro para ictus con instalaciones para endovasculares y que son candidatos para t-PA IV tendrán resultados funcionales no inferiores a los 90 días cuando sean tratados con TM directa en comparación con sujetos tratados con TM combinada con t-PA IV. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to study mortality, dependency, time to reperfusion and quality of life. |
| Los objetivos secundarios son estudiar las causas de mortalidad, la dependencia y la calidad de vida. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Informed consent as documented by signature
-Age ≥ 18 to < 86 years
-Clinical signs consistent with an acute ischaemic stroke
-Neurological deficit with a NIHSS of ≥ 8 and < 30
-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 ASPECTS greater than or equal to 6 (≥ 6) based on baseline CT or MRI |
- Consentimiento informado documentado mediante firma
- ≥ 18 y < 86 años de edad
- Ictus isquémico agudo (IIA)
- NIHSS ≥ 8 y < 30
-Paciente apto para t-PA IV
- Paciente apto para tratamiento endovascular (TEV)
- La aleatorización debe realizarse no más tarde de 4 horas 15 minutos después del inicio de los síntomas del ictus y el inicio de la t-PA IV debe
hacerse dentro de las 4 horas 30 minutos siguientes al inicio de lossíntomas del ictus
- Oclusión (mTICI 0-1) de la ACI intracraneal, segmento M1 de la ACM o ambas, confirmada mediante angiografía por tomografía computarizada
(TAC) o resonancia magnética (RM), accesible para TM
-Volumen de infarto nuclear según la puntuación de la TAC temprana del programa de ictus de Alberta (ASPECTS, Core-infarct volume of Alberta
Stroke Program Early CT Score) igual o mayor que 6 (≥ 6) respecto a TAC o RM inicial |
|
| 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 |
-Hemorragia intracraneal aguda
-Cualquier contraindicación para t-PA IV
-Tratamiento previo con t-PA IV
-Ictus intrahospitalario
-Mujeres embarazadas o lactantes . Prueba de embarazo negativa antes de la aleatorización se requiere para todas las mujeres con potencial de maternidad.
-Sensibilidad conocida (grave) a los medios de contraste radiográficos,los metales níquel y titanio o sus aleaciones
- Participación actual en un ensayo clínico
- Insuficiencia renal definida por una creatinina sérica> 2.0 mg / dl (o 176.8 µmol / l) o tasa de filtración glomerular (GFR) <30 mL / min y / o historia conocida de insuficiencia renal o requerimiento de hemodiálisis o diálisis peritoneal
-Esperanza de vida inferior a 90 días en el inicio
-Demencia avanzada conocida o discapacidad previa al ictus relevante (mRS ≥ 2)
- Dificultades previsibles en el seguimiento debido a razones geográficas (por ejemplo, pacientes que viven en el extranjero)
-Enfermedad o afección comórbida que podría confundir las evaluaciones neurológicas y funcionales o comprometer la supervivencia o la capacidad para completar las evaluaciones de seguimiento
-El sujeto actualmente usa o tiene un historial reciente de drogas ilícitas o abusa del alcohol (definido como el consumo regular o diario de más de cuatro bebidas alcohólicas por día).
-Historial conocido de tortuosidad arterial, stent preexistente, otra enfermedad arterial y / o enfermedad conocida en el sitio de acceso femoral que evitaría que el dispositivo alcance el vaso objetivo y / o impida una recuperación segura después de la TM
-Pruebas radiológicas confirmadas de efecto de masa o tumor intracraneal (excepto meningioma pequeño)
-Evidencia radiológica confirmada de vasculitis cerebral.
-Pruebas de CTA o MRA de disección carotídea
-Evidencia de oclusión adicional de vasos intracraneales distales en otro territorio (es decir, segmento A2 de arteria cerebral anterior o segmento M3, segmento M4 de MCA) en NCCT / MRI o CTA / MRA iniciales |
|
| 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). |
| El resultado primario se evalúa a los 90 ± 15 días después de la asignación al azar por una persona certificada ciega al tratamiento durante la visita clínica o por una entrevista estructurada por una persona capacitada en el sitio del ensayo (según la rutina clínica local). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 90 ± 15 days after randomization |
| 90 ± 15 días después de la aleatorización |
|
| 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. |
- Mortalidad por todas las causas a los 90 días: la mRS se evaluará durante la visita clínica (7-10 días o alta o 90 días ± 15 días) o mediante una entrevista telefónica estructurada (90 ± 15 días) según la clínica local. rutina. Si los pacientes / familiares no responden, se contactará al médico general o al médico tratante.
- Grado de discapacidad o dependencia a los 90 días según lo evalúa el mRS (análisis de turnos): la discapacidad y la dependencia se evalúan utilizando el mRS durante la visita clínica (7-10 días o alta y 90 ± 15 días) o durante la entrevista telefónica estructurada (90 ± 15 días) según la rutina clínica local. Si los pacientes / familiares no responden, se contactará al médico general o al médico tratante.
- Cambio en los NIHSS a las 24 ± 6 horas posteriores a la asignación aleatoria: los NIHSS se evaluarán el día 0, a las 24 ± 6 horas posteriores a la asignación aleatoria, a los 7-10 días o al alta y a los 90 ± 15 días después de la asignación al azar durante la visita clínica. Neurólogo entrenado independiente.
Tiempo desde la llegada al servicio de urgencias hasta la reperfusión (mTICI ≥ 2b): los puntos de tiempo se evaluarán en el día 0 desde la llegada al hospital hasta el final de la intervención. Los puntos de tiempo de tratamiento adicionales adicionales se registrarán opcionalmente mediante el uso del reloj de carrera de Berna. mTICI se define como: 37
Grad 0 = Sin perfusión
Grado 1 = Reperfusión anterógrada después de la oclusión inicial, pero limitado llenado de la rama distal con poca o lenta reperfusión distal
Grado 2 = Reperfusión anterógrada de menos de la mitad de la arteria diana ocluida en un territorio previamente isquémico (p. Ej., En 1 división principal del ACM y su territorio)
Grado 3 = Reperfusión anterógrada de más de la mitad del territorio isquémico de la arteria diana previamente ocluido (por ejemplo, en 2 divisiones principales de la ACM y sus territorios
- Calidad de vida según lo evaluado por EuroQol 5D-3L a los 90 días: la calidad de vida se evaluará a los 90 ± 15 días después de la asignación al azar utilizando el validado
Cuestionario EuroQol 5D-3L durante la visita clínica o durante una entrevista telefónica estructurada por personal capacitado y de acuerdo con la rutina clínica local.
- Reperfusión exitosa definida como mTICI ≥ 2b antes del tratamiento endovascular / uso del dispositivo: el neurorradiólogo capacitado deberá evaluar la reperfusión antes del tratamiento endovascular / uso del dispositivo antes de la intervención en el día 0, utilizando la escala mTICI.
- Reperfusión exitosa definida como mTICI ≥ 2b o mTICI = 3 después del uso del dispositivo: el neurorradiólogo capacitado evaluará la repetición después del uso del dispositivo durante la intervención en el día 0 por medio de un neurorradiólogo entrenado que usa la escala mTICI. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 |
| El ensayo está abierto a excepción del evaluador de los puntos finales primarios, que está cegado |
| The trial is open with the exception of the assessor of the primary endpoints, who is blinded |
|
| 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 |
|
| 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 | 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 |
| Austria |
| Canada |
| Finland |
| France |
| Germany |
| Spain |
| Switzerland |
|
| 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 | 2 |
| 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 | 3 |
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