Stroke
Conditions
Keywords
Ischemic stroke, Thrombolysis, Cerebral Infarction, Cerebrovascular Disorders, Thrombectomy, Vascular Diseases, Plasminogen Activators, Brain Infarction, Brain Ischemia, large core infarct
Brief summary
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.
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.
Interventions
Intravenous administration of Tenecteplase (0.25 mg/kg, maximum 25 mg) followed by mechanical thrombectomy (MT)
PROCEDUREMT alone
Mechanical thrombectomy alone
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Multicenter, controlled, randomized, open trial with blinded evaluation of the primary endpoint (Prospective Open Blinding Endpoint PROBE study).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of good functional outcome (independent ambulation) at 3 months | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early neurological improvement. | 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) |
| 3-month functional independence rate | 3 months | Defined as a 3-month mRS score of 0-2 |
| Distribution of 3-month mRS scores | 3 months | Ordinal analysis 3-month functional outcome |
| One-year independent ambulation rate | 1 year | Defined as a 1-year mRS score of 0-3. |
| One-year functional independence | 1 year | Defined as a 1-year mRS score of 0-2. |
| Mean change in infarct volume from baseline at day 1 | Day 1 | Defined as (day 1 volume) - (baseline volume). |
| Early neurological worsening. | Day 1 | Defined as a ≥ 4-point increase on the NIHSS score within 24 hours due to the stroke itself. |
| Intracerebral hemorrhage. | Day 2 | Intracerebral hemorrhage defined according to the Heidelberg Bleeding Classification. |
| Symptomatic intracerebral hemorrhage. | Day 2 | Symptomatic intracerebral hemorrhage defined according to the Heidelberg Bleeding Classification. |
| 3-month mortality rate. | 3 months | All-cause mortality. |
| 1-year mortality rate. | 1 year | All-cause mortality. |
| Medico-economic study. | 1 year | Incremental cost utility ratio analysis. |
| Successful recanalisation rates | 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 |
| Excellent recanalisation rates | 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 |
| Complete recanalisation rates | 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 |
| Adverse events | 3 months | Type, frequency and severity of adverse events |
| Serious adverse events | 3 months | Type, frequency and severity of serious adverse events |
Countries
France
Contacts
CONTACTGaspard GERSCHENFELD, MD, PhD
CONTACTAnne BISSERY
STUDY_DIRECTORGaspard GERSCHENFELD, MD, PhD
APHP
Outcome results
None listed