Intravenous Thrombolysis With Tenecteplase Plus Thrombectomy Versus Thrombectomy Alone In Patients With A Large Ischemic Stroke: A Multicenter Randomized Controlled Trial (IVT-ALL-IN) (IVT-ALL-IN)
Stroke is a frequent and severe disease worldwide, representing the second leading cause of death and the leading cause of acquired disability. Over the last thirty years, reperfusion therapies have transformed the prognosis of ischemic stroke. For patients with acute ischemic stroke due to large-vessel occlusion (LVOS) and a small- to moderate-sized irreversibly injured tissue (core), the recommended treatment consists of intravenous thrombolysis (IVT) followed by mechanical thrombectomy (MT). However, for the fifth of LVOS patients with large core, MT has demonstrated its effectiveness, but the benefits of prior IVT remain unclear. In fact, no randomized trial has compared IVT+MT and MT alone in this population.
Tenecteplase is increasingly replacing alteplase for LVOS due to two key advantages. First, it is administered as a single intravenous bolus, which speeds up treatment and transfers. Second, it improves reperfusion and functional outcomes in LVOS patients without large core. Emerging real-world evidence with tenecteplase reports lower rates of symptomatic intracranial hemorrhage than alteplase, suggesting superior overall efficacy. To date, no randomized trial has explored the benefit of tenecteplase in LVOS patients with large core.
The IVT ALL IN trial is a French multicenter open randomized controlled trial with two parallel groups (IVT with tenecteplase followed by MT [IVT+MT] vs MT alone) and blinded endpoint assessment following a PROBE design. Its main objective is to assess which treatment strategy between IVT+MT and MT alone has a superior efficacy in terms of 3-month good functional outcome, defined as a modified Rankin scale (mRS) score ≤ 3 at 3 months, for LVOS patients with large core of the anterior circulation. Our trial will provide high-level evidence on the optimal reperfusion treatment strategy for LVOS patients with large ischemic core, who currently still have a low likelihood of achieving a favorable neurological outcome.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
The IVT ALL IN trial is a French multicenter open-label randomized controlled trial with two parallel groups and blinded endpoint assessment following a PROBE design. Patients will be randomized between two treatment groups: the IVT with tenecteplase followed by MT group (IVT+MT; experimental group) or the MT alone group (control group). Randomization will be minimized on center, core size (very large [ASPECTS 2-3] versus large [ASPECT 4-5] infarcts) and treatment time window (within 4.5 hours vs others).
We plan to include 486 adult patients with a pre-stroke mRS ≤ 1 presenting an anterior circulation LVOS eligible to MT within 24 hours of onset, or unknown onset with a DWI-FLAIR mismatch, with a large core defined as:
- ASPECTS 2-5 or a core volume between 70 and 130 ml on MRI or perfusion CT for patients with process times compatible with IVT administration within 4.5 hours of onset or unknown onset with process times compatible with IVT administration within 4.5 hours of last seen well or unknown onset with a DWI-FLAIR mismatch
- ASPECTS 2- 5 with a core volume ≤ 70 ml and core/perfusion mismatch > 1.2 for patients with process times compatible with IVT administration within 4.5 and 9 hours of onset, defined as the mid-point between last known to be normal and symptoms constatation in case of unknown onset
The primary endpoint is the rate of good functional outcome (independent ambulation) at 3 months defined as a modified Rankin scale (mRS) score of 0-3.
In the six recently published trials comparing MT to best medical management for LVOS patients with large ischemic cores, rates of 3-month independent ambulation (mRS ≤ 3) range from 30% to 47% with a weighted average around 38%. In the first 5 RCTs that focused on the benefit of MT in LVOS, the minimal difference observed with MT was 13%. With these assumptions and for a global alpha risk of 0.05, a power of 0.8 and a bilateral test, the total number of patients to randomize would be 486 patients (243 in each arm) to increase the rate of good functional outcomes from 38% in the control group to 51% in the experimental group accounting for 5% of lost to follow-up and considering one interim analysis and the final analysis using a Lan and Demets method with an O'Brien & Fleming type alpha risk expenditure function We plan a sequential analysis of the primary outcome with 2 analyses: one interim analysis after the evaluation of the primary outcome for one third of the planned number of participants randomized, and a final analysis at the end of the study (end of follow-up of the last randomized participant). This sequential analysis is planned to be able to stop the trial in case of a large difference between the 2 groups or for futility if the conditional power is too low. It is planned according to the Lan & DeMets approach with a control of alpha risk according to the method of O'Brien & Flemming.
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 3
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Anne Bissery
- Número de teléfono: +33 1 42 16 24 32
- Correo electrónico: anne.bissery@aphp.fr
Copia de seguridad de contactos de estudio
- Nombre: Gaspard GERSCHENFELD, MD, PhD
- Número de teléfono: +33 1 84 82 82 85
- Correo electrónico: gaspard.gerschenfeld@aphp.fr
Ubicaciones de estudio
-
-
-
Aix-en-Provence, Francia, 13100
- CH Pays d'Aix - Site d'Aix-en-Provence
-
Investigador principal:
- Silvia DI EGGE
-
Besançon, Francia, 25030
- CHU Besançon
-
Investigador principal:
- Guillaume CHARBONNIER
-
Bordeaux, Francia, 33076
- CHU Bordeaux - Groupe Hospitalier Pellegrin
-
Investigador principal:
- Igor Sibon
-
Brest, Francia, 29609
- CHU Brest - Hôpital de La Cavale Blanche
-
Investigador principal:
- Serge TIMSIT
-
Bron, Francia, 69500
- HCL - Hôpital Pierre Wertheimer
-
Investigador principal:
- Tae-Hee Cho
-
Caen, Francia, 14000
- CHU Caen Normandie
-
Investigador principal:
- Marion BOULANGER
-
Corbeil-Essonnes, Francia, 91106
- Ch Sud Francilien
-
Investigador principal:
- Nicolas CHAUSSON
-
Créteil, Francia, 94000
- AP-HP - Hôpital Henri Mondor-Albert Chenevier
-
Investigador principal:
- Aymeric WITTWER
-
Dijon, Francia, 21079
- CHU Dijon Bourgogne
-
Investigador principal:
- Yannick BEJOT
-
Gonesse, Francia, 95500
- CH Gonesse
-
Investigador principal:
- Eric MANCHON
-
Grenoble, Francia, 38043
- CHU Grenoble Alpes - Site Nord
-
Investigador principal:
- Olivier DETANTE
-
Le Chesnay, Francia, 78000
- CH Versailles - Hôpital André Mignot
-
Investigador principal:
- Fernando PICO
-
Le Kremlin-Bicêtre, Francia, 94275
- AP-HP - Hôpital Bicêtre
-
Investigador principal:
- Laura VENDITTI
-
Lille, Francia, 59000
- CHU Lille - Hôpital Roger Salengro
-
Investigador principal:
- Lucie DELLA SCHIAVA
-
Limoges, Francia, 87042
- CHU Limoges - Hôpital Dupuytren
-
Investigador principal:
- Francisco MACIAN-MONTORO
-
Marseille, Francia, 13005
- AP-HM - Hopital de la Timone
-
Investigador principal:
- Laurent SUISSA
-
Montpellier, Francia, 34295
- CHU MONTPELLIER - Hôpital Saint-Eloi
-
Investigador principal:
- Caroline ARQUIZAN
-
Nancy, Francia, 54035
- CHRU Nancy - Hôpital central
-
Investigador principal:
- Sébastien Richard
-
Nantes, Francia, 44093
- CHU Nantes - Hopital Nord Laënnec
-
Investigador principal:
- Benoit GUILLON
-
Nice, Francia, 6000
- CHU Nice - Hôpital Pasteur
-
Investigador principal:
- Barbara CASOLLA
-
Paris, Francia, 75019
- Fondation Adolphe de Rothschild
-
Investigador principal:
- Michael OBADIA
-
Paris, Francia, 75013
- Hôpital Pitié-Salpêtrière
-
Investigador principal:
- Gaspard GERSCHENFELD
-
Paris, Francia, 75018
- AP-HP - Hôpital Bichat
-
Investigador principal:
- Philippa LAVALLEE
-
Paris, Francia, 75010
- AP-HP - Hôpital Lariboisiere-Fernand Widal
-
Investigador principal:
- Elodie BERTHET
-
Paris, Francia, 75014
- GH Paris Saint-Joseph - Hôpital Paris Saint-Joseph
-
Investigador principal:
- Benjamin MAYER
-
Paris, Francia, 75014
- GHU Paris Psychiatrie et Neurosciences - Hôpital Sainte-Anne
-
Investigador principal:
- Guillaume TURC
-
Perpignan, Francia, 66046
- CH Perpignan
-
Investigador principal:
- Denis Sablot
-
Poitiers, Francia, 86000
- CHU Poitiers - Hôpital de La Milétrie
-
Reims, Francia, 51100
- CHU Reims - Hôpital Maison Blanche
-
Investigador principal:
- Solène MOULIN
-
Rennes, Francia, 35033
- CHU Rennes - Hôpital Pontchaillou
-
Investigador principal:
- Stéphane VANNIER
-
Rouen, Francia, 76031
- CHU Rouen - Hôpital Charles-Nicolle
-
Investigador principal:
- Florian BASILLE
-
Saint-Denis, Francia, 93200
- CH Saint-Denis - Hôpital Delafontaine
-
Investigador principal:
- Carole HENRY
-
Saint-Etienne, Francia, 42055
- CHU Saint-Etienne - Hôpital Nord
-
Investigador principal:
- Pierre GARNIER
-
Strasbourg, Francia, 67098
- Hôpitaux Universitaires de Strasbourg - Hôpital de Hautepierre
-
Investigador principal:
- Valérie Wolff
-
Suresnes, Francia, 92150
- Hôpital Foch
-
Investigador principal:
- Bertrand Lapergue
-
Tours, Francia, 37000
- CHRU Tours - Hôpital Bretonneau
-
Investigador principal:
- Marco PASI
-
-
Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
- Adulto
- Adulto Mayor
Acepta Voluntarios Saludables
Descripción
Inclusion criteria :
- Age ≥ 18 years
- mRS ≤ 1 before stroke
- Anterior circulation large vessel occlusion stroke eligible to mechanical thrombectomy (MT) within 24 hours of onset or unknown onset with a DWI-FLAIR mismatch
Large core defined either as:
- ASPECTS 2-5 or a core volume between 70 and 130 ml on MRI or perfusion CT for patients with process times compatible with IVT administration within 4.5 hours of onset or unknown onset with process times compatible with IVT administration within 4.5 hours of last seen well or unknown onset with a DWI-FLAIR mismatch
- ASPECTS 2- 5 with a core volume ≤ 70 ml and core/perfusion mismatch > 1.2 for patients with process times compatible with IVT administration within 4.5 and 9 hours of onset, defined as the mid-point between last known to be normal and symptoms constatation in case of unknown onset
- Written informed consent signed by the patient or the trustworthy person / family member / close relative, or inclusion in case of emergency (to note, written informed consent will be signed by the patient (if needed, by trustworthy person, family member or close relative) as soon as possible (article 35 of the European regulation N°536/2014))
Exclusion criteria :
Anterior circulation stroke with a distal occlusion not eligible to MT
- Posterior circulation stroke
- Pregnancy or breastfeeding woman
Any contraindication to IVT, based on the Metalyse SmPC and the latest AHA/ASA guidelines on IVT (Prabhakaran et al. Stroke. 2026), other than those related to the NIHSS score upper limit, infarct size and symptoms-to-onset time, such as (but not limited to):
- Persistent incapacity to lower blood pressure under 185/110 mmHg
- Respiratory or hemodynamic failure
- Externalized bleeding
- Hypersensitivity to the active substance or to any of its excipients
- Hypersensitivity to gentamicin (a trace residue from the manufacturing process
- Known haemorrhagic diathesis
- Bacterial endocarditis, pericarditis
- Acute pancreatitis
- Significant impairment of hepatic function, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and progressive hepatitis
- Active ulcerative gastrointestinal disease
- Neoplasia associated with an increased risk of haemorrhage
- Known bleeding disorders, such as thrombocytopenia (platelet count < 100 G/L) or severe coagulopathy (INR > 1.7, activated partial thromboplastin time > 40s or prothrombin time > 15s) either currently or within the last 3 weeks
- Treatment with effective doses of oral anticoagulants (e.g. vitamin K antagonists with an INR > 1.7)
- Any history of intracerebral neoplasm
- History of intracranial / spinal surgery or acute spinal cord injury within 3 months
- Recent ST-segment elevation myocardial infarction within 3 months
- Major non-central nervous system surgery, biopsy of a parenchymal organ or significant trauma within the last 10 days
- Recent moderate to severe traumatic brain injury
- Known arterial or venous malformation, except unruptured intracranial aneurysm
- History of intracerebral haemorrhage within 3 months
- Known cerebral amyloid angiopathy
- History of acute ischaemic stroke within 3 months
Any contra-indication to MT:
- Contra-indication to femoral, radial or humeral arterial puncture
- Allergy to iodinated contrast media
Known Renal insufficiency at inclusion time (confirmed biologically by a creatinine clearance < 30 ml/min calculated with the Cockcroft-Gault formula)
- Anticipated life expectancy of less than 3 months
- Participation in another interventional clinical trial evaluating a health product or any randomized clinical trial
- Absence of affiliation to National French social security system
- Under legal protection measure (tutorship or curatorship) and patient deprived of freedom
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
|
Experimental: IVT with Tenecteplase followed by MT
Intravenous administration of Tenecteplase (0.25 mg/kg, maximum 25 mg) followed by mechanical thrombectomy
|
Intravenous administration of Tenecteplase (0.25 mg/kg, maximum 25 mg) followed by mechanical thrombectomy (MT)
|
|
Comparador activo: Active Comparator: MT alone
Mechanical thrombectomy alone
|
Mechanical thrombectomy alone
|
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Rate of good functional outcome (independent ambulation) at 3 months
Periodo de tiempo: 3 months
|
defined as a modified Rankin scale (mRS) score of 0-3. mRS scores will be determined by certified raters unaware of the treatment arm or baseline characteristics of the individual patient by in person interview or, if not possible, by telephone. The Modified Rankin Scale (mRS) measures degree of disability/dependence after a stroke. Scores range from 0 to 6 (death) |
3 months
|
Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
|
Early neurological improvement.
Periodo de tiempo: D1
|
Defined as a ≥ 8-points decrease of the NIHSS score or a NIHSS score ≤ 1 at day 1. National Institutes of Health Stroke Scale (NIHSS) is a questionnaire to evaluate neurologic outcome and degree of recovery for patients with stroke. Scores range from 0 to 42 (worse) |
D1
|
|
3-month functional independence rate
Periodo de tiempo: 3 months
|
Defined as a 3-month mRS score of 0-2
|
3 months
|
|
Distribution of 3-month mRS scores
Periodo de tiempo: 3 months
|
Ordinal analysis 3-month functional outcome
|
3 months
|
|
One-year independent ambulation rate
Periodo de tiempo: 1 year
|
Defined as a 1-year mRS score of 0-3.
|
1 year
|
|
One-year functional independence
Periodo de tiempo: 1 year
|
Defined as a 1-year mRS score of 0-2.
|
1 year
|
|
Mean change in infarct volume from baseline at day 1
Periodo de tiempo: Day 1
|
Defined as (day 1 volume) - (baseline volume).
|
Day 1
|
|
Early neurological worsening.
Periodo de tiempo: Day 1
|
Defined as a ≥ 4-point increase on the NIHSS score within 24 hours due to the stroke itself.
|
Day 1
|
|
Intracerebral hemorrhage.
Periodo de tiempo: Day 2
|
Intracerebral hemorrhage defined according to the Heidelberg Bleeding Classification.
|
Day 2
|
|
Symptomatic intracerebral hemorrhage.
Periodo de tiempo: Day 2
|
Symptomatic intracerebral hemorrhage defined according to the Heidelberg Bleeding Classification.
|
Day 2
|
|
3-month mortality rate.
Periodo de tiempo: 3 months
|
All-cause mortality.
|
3 months
|
|
1-year mortality rate.
Periodo de tiempo: 1 year
|
All-cause mortality.
|
1 year
|
|
Medico-economic study.
Periodo de tiempo: 1 year
|
Incremental cost utility ratio analysis.
|
1 year
|
|
Successful recanalisation rates
Periodo de tiempo: Day 1
|
Defined as a modified Treatment In Cerebral Ischemia (mTICI) scores of 2b50/2b67/2c/3 on the first angiographic run, after the first pass and at the end of the procedure
|
Day 1
|
|
Excellent recanalisation rates
Periodo de tiempo: Day 1
|
Defined as a modified Treatment In Cerebral Ischemia (mTICI) scores of 2c/3 respectively on the first angiographic run, after the first pass and at the end of the procedure
|
Day 1
|
|
Complete recanalisation rates
Periodo de tiempo: Day 1
|
Defined as a modified Treatment In Cerebral Ischemia (mTICI) scores of 3 respectively on the first angiographic run, after the first pass and at the end of the procedure
|
Day 1
|
|
Adverse events
Periodo de tiempo: 3 months
|
Type, frequency and severity of adverse events
|
3 months
|
|
Serious adverse events
Periodo de tiempo: 3 months
|
Type, frequency and severity of serious adverse events
|
3 months
|
Colaboradores e Investigadores
Patrocinador
Investigadores
- Director de estudio: Gaspard GERSCHENFELD, MD, PhD, APHP
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades Cerebrales
- Enfermedades del Sistema Nervioso Central
- Enfermedades del Sistema Nervioso
- Enfermedades cardiovasculares
- Procesos Patológicos
- Infarto
- Necrosis
- Isquemia
- Condiciones Patológicas, Signos y Síntomas
- Accidente cerebrovascular isquémico
- Carrera
- Infarto cerebral
- Enfermedades Vasculares
- Trastornos cerebrovasculares
- Isquemia cerebral
- Infarto cerebral
- Terapéutica
- Rutas de administración de drogas
- Terapia con drogas
- Administración, intravenosa
Otros números de identificación del estudio
- APHP240911
- 2024-520414-21-00 (Ctis)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Descripción del plan IPD
The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.
Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.
Marco de tiempo para compartir IPD
Criterios de acceso compartido de IPD
Tipo de información de apoyo para compartir IPD
- PROTOCOLO DE ESTUDIO
- SAVIA
- CIF
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .