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.

Study Overview

• Status: Not yet recruiting
• Conditions: Stroke
• Intervention / Treatment: Drug: Intravenous administration; Procedure: MT alone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 486
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anne BISSERY; Phone Number: +33 1 42 16 24 32; Email: anne.bissery@aphp.fr
• Study Contact Backup: Name: Gaspard GERSCHENFELD, MD, PhD; Phone Number: +33 1 84 82 82 85; Email: gaspard.gerschenfeld@aphp.fr

Study Locations

• France
  • Aix-en-Provence, France, 13100
    • CH Pays d'Aix - Site d'Aix-en-Provence
    • Principal Investigator: Silvia DI EGGE
  • Besançon, France, 25030
    • CHU Besançon
    • Principal Investigator: Guillaume CHARBONNIER
  • Bordeaux, France, 33076
    • CHU Bordeaux - Groupe Hospitalier Pellegrin
    • Principal Investigator: Igor SIBON
  • Brest, France, 29609
    • CHU Brest - Hôpital de la Cavale Blanche
    • Principal Investigator: Serge TIMSIT
  • Bron, France, 69500
    • HCL - Hôpital Pierre Wertheimer
    • Principal Investigator: Tae-Hee CHO
  • Caen, France, 14000
    • CHU Caen Normandie
    • Principal Investigator: Marion BOULANGER
  • Corbeil-Essonnes, France, 91106
    • Ch Sud Francilien
    • Principal Investigator: Nicolas CHAUSSON
  • Créteil, France, 94000
    • AP-HP - Hôpital Henri Mondor-Albert Chenevier
    • Principal Investigator: Aymeric WITTWER
  • Dijon, France, 21079
    • Chu Dijon Bourgogne
    • Principal Investigator: Yannick BEJOT
  • Gonesse, France, 95500
    • CH Gonesse
    • Principal Investigator: Eric MANCHON
  • Grenoble, France, 38043
    • CHU Grenoble Alpes - Site Nord
    • Principal Investigator: Olivier DETANTE
  • Le Chesnay, France, 78000
    • CH Versailles - Hôpital André Mignot
    • Principal Investigator: Fernando PICO
  • Le Kremlin-Bicêtre, France, 94275
    • AP-HP - Hôpital Bicêtre
    • Principal Investigator: Laura VENDITTI
  • Lille, France, 59000
    • CHU Lille - Hôpital Roger Salengro
    • Principal Investigator: Lucie DELLA SCHIAVA
  • Limoges, France, 87042
    • CHU Limoges - Hopital Dupuytren
    • Principal Investigator: Francisco MACIAN-MONTORO
  • Marseille, France, 13005
    • AP-HM - Hôpital de la Timone
    • Principal Investigator: Laurent SUISSA
  • Montpellier, France, 34295
    • CHU Montpellier - Hôpital Saint-Eloi
    • Principal Investigator: Caroline ARQUIZAN
  • Nancy, France, 54035
    • CHRU Nancy - Hôpital Central
    • Principal Investigator: Sébastien RICHARD
  • Nantes, France, 44093
    • CHU Nantes - Hopital Nord Laënnec
    • Principal Investigator: Benoit GUILLON
  • Nice, France, 6000
    • CHU Nice - Hôpital Pasteur
    • Principal Investigator: Barbara CASOLLA
  • Paris, France, 75019
    • Fondation Adolphe de Rothschild
    • Principal Investigator: Michael OBADIA
  • Paris, France, 75013
    • Hôpital Pitié-Salpétrière
    • Principal Investigator: Gaspard GERSCHENFELD
  • Paris, France, 75018
    • AP-HP - Hôpital Bichat
    • Principal Investigator: Philippa LAVALLEE
  • Paris, France, 75010
    • AP-HP - Hôpital Lariboisiere-Fernand Widal
    • Principal Investigator: Elodie BERTHET
  • Paris, France, 75014
    • GH Paris Saint-Joseph - Hôpital Paris Saint-Joseph
    • Principal Investigator: Benjamin MAYER
  • Paris, France, 75014
    • GHU Paris Psychiatrie et Neurosciences - Hôpital Sainte-Anne
    • Principal Investigator: Guillaume TURC
  • Perpignan, France, 66046
    • CH Perpignan
    • Principal Investigator: Denis SABLOT
  • Poitiers, France, 86000
    • CHU Poitiers - Hôpital de La Milétrie
  • Reims, France, 51100
    • CHU Reims - Hôpital Maison Blanche
    • Principal Investigator: Solène MOULIN
  • Rennes, France, 35033
    • CHU Rennes - Hopital Pontchaillou
    • Principal Investigator: Stéphane VANNIER
  • Rouen, France, 76031
    • CHU Rouen - Hôpital Charles-Nicolle
    • Principal Investigator: Florian BASILLE
  • Saint-Denis, France, 93200
    • CH Saint-Denis - Hôpital Delafontaine
    • Principal Investigator: Carole HENRY
  • Saint-Etienne, France, 42055
    • CHU Saint-Etienne - Hôpital Nord
    • Principal Investigator: Pierre GARNIER
  • Strasbourg, France, 67098
    • Hôpitaux Universitaires de Strasbourg - Hôpital de Hautepierre
    • Principal Investigator: Valérie WOLFF
  • Suresnes, France, 92150
    • Hôpital Foch
    • Principal Investigator: Bertrand LAPERGUE
  • Tours, France, 37000
    • CHRU Tours - Hôpital Bretonneau
    • Principal Investigator: Marco PASI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IVT with Tenecteplase followed by MT; Intravenous administration of Tenecteplase (0.25 mg/kg, maximum 25 mg) followed by mechanical thrombectomy	Drug: Intravenous administration; Intravenous administration of Tenecteplase (0.25 mg/kg, maximum 25 mg) followed by mechanical thrombectomy (MT)
Active Comparator: Active Comparator: MT alone; Mechanical thrombectomy alone	Procedure: MT alone; Mechanical thrombectomy alone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of good functional outcome (independent ambulation) at 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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early neurological improvement.	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	Defined as a 3-month mRS score of 0-2	3 months
Distribution of 3-month mRS scores	Ordinal analysis 3-month functional outcome	3 months
One-year independent ambulation rate	Defined as a 1-year mRS score of 0-3.	1 year
One-year functional independence	Defined as a 1-year mRS score of 0-2.	1 year
Mean change in infarct volume from baseline at day 1	Defined as (day 1 volume) - (baseline volume).	Day 1
Early neurological worsening.	Defined as a ≥ 4-point increase on the NIHSS score within 24 hours due to the stroke itself.	Day 1
Intracerebral hemorrhage.	Intracerebral hemorrhage defined according to the Heidelberg Bleeding Classification.	Day 2
Symptomatic intracerebral hemorrhage.	Symptomatic intracerebral hemorrhage defined according to the Heidelberg Bleeding Classification.	Day 2
3-month mortality rate.	All-cause mortality.	3 months
1-year mortality rate.	All-cause mortality.	1 year
Medico-economic study.	Incremental cost utility ratio analysis.	1 year
Successful recanalisation rates	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	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	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	Type, frequency and severity of adverse events	3 months
Serious adverse events	Type, frequency and severity of serious adverse events	3 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Gaspard GERSCHENFELD, MD, PhD, APHP

Study record dates

Study Major Dates

• Study Start (Estimated): June 15, 2026
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: May 18, 2026
• First Submitted That Met QC Criteria: May 18, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Vascular Diseases; Thrombectomy; Ischemic stroke; Cerebral Infarction; Cerebrovascular Disorders; Brain Infarction; Brain Ischemia; Thrombolysis; Plasminogen Activators; large core infarct
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cardiovascular Diseases; Pathologic Processes; Infarction; Necrosis; Ischemia; Pathological Conditions, Signs and Symptoms; Ischemic Stroke; Stroke; Cerebral Infarction; Vascular Diseases; Cerebrovascular Disorders; Brain Ischemia; Brain Infarction; Therapeutics; Drug Administration Routes; Drug Therapy; Administration, Intravenous
• Other Study ID Numbers: APHP240911; 2024-520414-21-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No