E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Spontaneous supratentorial intracerebral haemorrhage |
: Hemorragia cerebral espontánea supratentorial |
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E.1.1.1 | Medical condition in easily understood language |
Brain haemorrhage |
Hemorragia cerebral |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10062025 |
E.1.2 | Term | Intracerebral haematoma evacuation |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 show whether minimally invasive surgery (MIS) plus recombinant tissue plasminogen activator (rt-PA) for three days improves outcome at six months as compared to standard medical treatment in patients with spontaneous bleeding in the brain (with no underlying cause)(ICH). It will also show whether early use of MIS+rt-PA for three days is safe for the treatment of ICH relative to rates of mortality, rebleeding, and infection in the medically treated subject at 30 days. |
El propósito de este ensayo es determinar la eficacia de utilizar una combinación de cirugía mínimamente invasiva y lisis del coágulo con rt-PA para evacuar el HIC. El procedimiento consiste en utilizar cirugía guiada por imagen (RM o TC) para conseguir acceder con el catéter al HIC para la intervención de aspirado del coágulo seguida de instilación de hasta 9 dosis de rt-PA. Nos proponemos investigar si esta intervención facilita una recuperación más rápida y completa de la función y una menor mortalidad por esta condición comparándola con el tratamiento médico convencional sin craniotomía. El objetivo específico de este ensayo es comprobar la eficacia y seguridad de esta intervención y medir su capacidad para evacuar el coágulo sanguíneo del tejido cerebral. |
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E.2.2 | Secondary objectives of the trial |
To show whether the reduction in the size of the blood clot in the brain acheived by using MIS+rt-PA is related to improved functional outcome, as compared to medically treated subjects. |
Evaluar si la reducción del volumen del coágulo sanguineo intracerebral conseguida mediante cirugía mínimamente invasiva + rTPA está relacionada con una mejoría en el pronóstico funcional comparándolo con pacientes tratados médicamente. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Spontaneous supratentorial ICH ? 30 mL diagnosed using radiographic imaging (CT, CTA, etc.), with a GCS ? 14 or a NIHSS ? 6.
Six-hour clot size equal to the most previous clot size (within 5 mL) as determined by additional CT scans at least 6 hours apart using the ABC/2 method.
2) Symptoms less than 24 hours prior to diagnostic CT (dCT) scan (an unknown time of onset is exclusionary).
3) Intention to initiate surgery between 12 and 72 hours after dCT. First dose can be given within 76 hours after dCT (delays for post surgical stabilization of catheter bleeding or because of unanticipated surgical delay are acceptable with approved waiver from the CCC).
4) SBP < 180 mmHg sustained for six hours recorded closest to the time of randomization.
5) Historical Rankin score of 0 or 1.
6) Age ? 18 and ? 80. |
(1) HIC espontáneo supratentorial > 30 cc en el TC diagnóstico, con GCS < 14 o NIHSS > 6. El tamaño del coágulo a las 6 horas debe ser igual al tamaño del coágulo inmediatamente previo + 5 cc (medido en TC sucesivo realizado al menos a 6 horas del TC de estabilidad inicial (método A*B*C)/2). (2) Síntomas presentes durante menos de 24 horas previas al TC diagnóstico (criterio de exclusion si el tiempo de los síntomas es desconocido). (3) Posibilidad de realizar la cirugía entre 12 y 72 horas tras el TC diagnóstico. Que la primera dosis pueda administrarse en 76 horas desde el TC diagnóstico (retrasos debidos a sangrado debidos a la colocación del catéter o por motivos imponderables pueden ser aceptables con la aprovación del. (4) PAs < 180 mmHg registrada mantenida durante las 6 horas más próximas al momento de aleatorización. (5) Rankin score previo de 0-1. (6) Edad 18-80 |
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E.4 | Principal exclusion criteria |
1) Infratentorial hemorrhage.
Intraventricular hemorrhage requiring treatment with extraventricular drainage (obstruction of third and fourth ventricles).
Thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and non-reactive pupils. Other (supranuclear) gaze abnormalities are not exclusions. Note: Patients with a posterior fossa ICH or cerebellar hematomas are ineligible.
Irreversible impaired brain stem function (bilateral fixed, dilated pupils and extensor motor posturing), GCS ? 4.
Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, Moyamoya disease diagnosed with radiographic imaging.
Patients with unstable mass or evolving intracranial compartment syndrome.
2) Platelet count < 100,000, INR > 1.4, or an elevated prothrombin time (PT) or activated partial thromboplastin time (aPTT).
Any irreversible coagulopathy or known clotting disorder.
Inability to sustain INR ? 1.4 using short- and long-active procoagulants (such as but not limited to NovoSeven, FFP, and/or vitamin K).
Subjects requiring long-term anti-coagulation are excluded. Reversal of anticoagulation is permitted for medically stable patients who can realistically tolerate the short term risk of reversal. Patient must not require Coumadin (anticoagulation) during the first 30 days, and normalized coagulation parameters must be demonstrated, monitored closely and maintained during the period of brain instrumentation.
Use of Dabigatran prior to symptom onset.
3) Internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.
4) Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures, etc.) or site of recent surgical intervention.
5) Positive urine or serum pregnancy test in pre-menopausal female subjects without a documented history of surgical sterilization.
6) Allergy/sensitivity to rt-PA.
Prior enrollment in the study.
Planned or simultaneous participation (between screening and Day-30) in another interventional medical investigation or clinical trial. Patients in observational, natural history, and/or epidemiological studies not involving an intervention are eligible.
7) Subjects who are not expected to survive to the day 365 visit due to co-morbidities and/or are DNR/DNI status prior to randomization are excluded.
Any concurrent serious illness that would interfere with the safety assessments including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, and hematologic disease.
Patients with a mechanical heart valve.
Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, or subacute bacterial endocarditis.
Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated.
8) Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
9) In the investigator?s opinion, the patient is unstable and would benefit from a specific intervention rather than supportive care plus or minus MIS+rt-PA removal of the ICH.
10) Inability or unwillingness of subject or legal guardian/representative to give written informed consent. |
(1) Hemorragia infratentorial. Hemorragia intraventricular que requiera tratamiento con drenaje extraventricular (obstrucción de ventrículos 3º o 4º). Sangrado talámico con extension mesencefálica, parálisis del III par o pupilas dilatadas no reactivas. Otras anomalías de la mirada (supranucleares) no son criterio de exclusión. Nota: Pacientes con una hemorragia de fosa posterior o hematoma cerebeloso no son incluibles. Afectación troncoencefálica irreversible (pupilas fijas, dilatadas bilateralmente y signos de descerebración), GCS ≤ 4. Aneurisma roto, MAV, anomalía vascular, enfermedad de Moyamoya. Pacientes con masa inestable o síndrome compartimental intracranial en progresión; (2) Pacientes con nº plaquetas < 100,000, INR > 1.4, o tiempos TP o TTPA elevados. Coagulopatía irreversible o enfermedad de coagulación conocida debida a problemas médicos o previa a randomización. Imposibilidad de mantener INR ≤ 1.4 con procoagulantes de acción corta y larga (como, pero no limitado a, NovoSeven, FFP, y/o vitamina K). Personas que requieran anticoagulación continuada serán excluidas. La reversion de la anticoagulación se permite en pacientes médicamente estables que puedan tolerar de manera realista la reversion a corto plazo. El paciente no debe precisar anticoagulación (Cumarina) durante los primeros 30 días y se deben demostrar parámetros de coagulación normales, monitorizándolos cuidadosamente y manteniéndolos durante el periodo de manipulación cerebral. El uso de Dabigatran previo al comienzo de los síntomas. (3) Sangrado interno retroperitoneal, gastrointestinal, genitourinario o en vías respiratorias; (4) Sangrado superficial o en sábana que se aprecie en punciones vasculares y acceso de vías (p.e. accesos venosos o punciones arteriales) o en el sitio de la cirugía reciente. (5) Test de embarazo positivo en orina o sangre en mujeres premenopáusicas sin historia documentada de esterilización quirúrgica. (6) Alergia/sensibilidad al rt-PA. Inclusión previa en el estudio. Plan de participar o simultaneidad de participación (entre el día de inclusion y el día 30) en otro estudio de intervención médica o ensayo clínico. Pacientes incluidos en estudios observacionales y epidemiológicos que no requieran intervención, pueden ser incluidos. (7) Se excluyen aquellos sujetos que no se espera que sobrevivan 365 días por comorbilidades o que estén en estado de no RCP previo a la aleatorización. Cualquier enfermedad grave concurrente que pudiera interferir con las medidas de seguridad incluyendo enfermedades hepáticas, renales, gastrointestinales, respiratorias, cardiovasculares, endocrinológicas, inmunológicas y hematológicas. Pacientes con válvulas mecánicas. Riesgo conocido de embolias, incluyendo historia de trombo cardiaco, estenosis mitral con fibrilación auricular, pericarditis aguda y endocarditis bacteriana subaguda. Cualquier otra condición que el investigador presuponga que pone al sujeto en peligro por la terapia investigada. (8) Dependencia o uso activo de drogas o alcohol que hagan dudar al investigador que se consiga una adecuada adhesion a los requisistos del estudio. (9) Que en opinión del investigador el paciente esté inestable y que se beneficiaría de una intervención distinta al cuidado de soporte medico con o sin MIS+rtPA. (10) Incapacidad o negativa del sujeto o su representante legal para firmar el consentimiento Informado. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall better functional outcome at 180 days, as defined by the modified Rankin Scale (mRS) using dichotomized adjudicated mRS 0-3 vs. 4-6 at 180 days post-stroke |
Pronóstico funcional a los 180 días definido por la escala de Rankin modificada usando una dicotomización mRS 0-3 vs 4-6.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
180 days post-stroke |
180 días tras el ictus |
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E.5.2 | Secondary end point(s) |
Dichotomized adjudicated mRS at 365 days post-stroke 0-3 vs. 4-6 and 0-2 vs. 3-6
Ordinal adjudicated mRS (0 ? 6) at 180 days post-stroke
Mortality and Safety Events at 30 days post-randomization including procedurerelated
mortality, symptomatic bleeding rate, and infection rate
Mortality at 180 days post stroke
Functional Status: NIHSS, Barthel, GOS, GOSE, MMSE at 180 days
Type and intensity of ICU management: ICU days, hospital days, patient disposition at 180 days and 365 days
Quality of life: SIS, EQ-5D, PBSI,Personal Health Utility Assessment
Cost |
Pronóstico funcional a los 360 días definido por la escala de Rankin modificada usando una dicotomización mRS 0-3 vs 4-6 y 0-2 vs 3-6. Análisis ordinal no dicotomizado de la mRS (0-6) a los 180 tras el ictus. Mortalidad y morbilidad a los 30 días postrandomización incluyendo la mortalidad relacionada con el procedimiento, la incidencia de sangrados sintomáticos y la mortalidad relacionada con infecciones a los 180 días. Otras escalas de situación funcional aplicadas a los 180 días tras ictus: NIHSS, Barthel, GOS, GOSE MMSE. Intensidad del tratamiento realizado en UCI, días de estancia en UCI, días de hospitalización, situación funcional del pacinete a los 180 y 360 días, calidad de vida (SIS, EQ-5D, PBSI), costes de ayuda sanitaria y asistencial.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
30, 180 and 365 days. |
30, 180 y 365 dias |
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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 | No |
E.6.5 | Efficacy | No |
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 | Yes |
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 | No |
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 |
No surgery (the IMP is given following surgery) |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
Australia |
Canada |
China |
Germany |
Hungary |
Israel |
Spain |
United Kingdom |
United States |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 30 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 30 |