Randomization to Endovascular Treatment Alone or Preceded by Systemic Thrombolysis With Tenecteplase in Ischemic Stroke

NCT ID: NCT05199194

Last Updated: 2025-04-04

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 398 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-27
• Study Completion Date: 2027-07-31

Brief Summary

A phase III randomized, multi-center, double-blinded, placebo-controlled clinical trial that will examine two strategies for the treatment of acute ischemic stroke associated with a large vessel anterior occlusion within 4.5 hours from symptoms onset: direct endovascular treatment vs. endovascular treatment preceded by intravenous tenecteplase.

Detailed Description

Randomized, prospective, multicenter, double-blinded, placebo-controlled clinical trial with adaptive desing. Randomization will be 1:1 according to reperfusion treatment modalities: (A) (with placebo TNK) direct mechanical thrombectomy vs. (B) Intravenous thrombolysis with TNK (0.25 mg/kg) plus mechanical thrombectomy. Randomization will be done by a minimization process using age, National Institute of Health Stroke Scale (NIHSS) score, and site of the occluded artery. For the primary outcome, the subjects will be followed up within 90 days after randomization. The primary outcome will be the ordinal distribution from the modified Rankin scale score (mRS).

Subjects presenting acute ischemic stroke within 4.5 hours of the onset of symptoms attributable to an occlusion of intracranial internal carotid or of the proximal middle cerebral artery (MCA, M1- or M2-segment) with or without tandem occlusion of cervical internal carotid confirmed by vascular neuroimaging. Subjects should be eligible for IV thrombolysis. In the sample size calculation, a difference in treatment effect between the groups (achievement of mRS 0 to 2 at 90 days) of 10.6% was considered, with 33.8% in the intervention group (TNK + thrombectomy) and 23.2% in the control group (placebo + thrombectomy), using a unilateral alpha of 0.025, with a power of 80%, resulting in a sample size of 358 participants. Considering a loss ratio of 10%, a sample size of 398 participants is estimated (199 in each treatment arm). An interim analysis is planned to be executed with 50% and 75% of the total sample. It allows the trial to be terminated in the case of efficacy or futility, in addition to enabling adaptive designed based on conditional probability of a positive result.

Conditions

Stroke, Ischemic; Stroke, Acute

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Mechanical Thrombectomy preceded by TNK

Subjects assigned to this arm will receive an intravenous bolus of tenecteplase (0.25mg/kg) before the mechanical thrombectomy.

Group Type: EXPERIMENTAL

Tenecteplase

Intervention Type: DRUG

Intravenous thrombolysis with tenecteplase 0.25mg/kg

Mechanical Thrombectomy preceded by Placebo

Subjects assigned to this arm will receive an intravenous bolus of matching placebo (with the same volume of infusion as of 0.25mg/kg of tenecteplase) before the mechanical thrombectomy.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Intravenous administration of placebo, matching the volume of tenecteplase 0.25mg/kg

Interventions

Tenecteplase

Intravenous thrombolysis with tenecteplase 0.25mg/kg

Intervention Type: DRUG

Placebo

Intravenous administration of placebo, matching the volume of tenecteplase 0.25mg/kg

Intervention Type: DRUG

Other Intervention Names

TNK

Eligibility Criteria

Inclusion Criteria

• Acute ischemic stroke where a patient is eligible for IV thrombolytic treatment within 4.5 hours of stroke onset.
• No significant pre-stroke functional disability (mRS ≤ 1)
• Baseline NIHSS scores obtained before randomization must be equal to or higher than 6 points
• Age equal ≥ 18 and =< 85 years
• Occlusion (TICI 0-1) of the ICA or proximal MCA segments (M1 or M2) suitable for endovascular treatment, as evidenced by CTA, MRA, or angiogram, with or without concomitant cervical carotid stenosis or occlusion.
• Patient randomized within 4.5 hours of symptom onset. Symptoms onset is defined as the point in time the patient was last seen well (at baseline). Treatment start is defined as groin puncture, max 90 minutes after randomization.

• Patients who have woken up with the symptoms and who have a mismatch FLAIR-DWI according to the WAKE-UP Trial will be considered as having a time window of <4.5h.
• Informed consent obtained from the patient or acceptable patient surrogate.

Exclusion Criteria

• Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > 1.7 or direct oral anticoagulants such as thrombin antagonists (ex: dabigatran) or X factor (ex: rivaroxaban, apixaban, edoxaban) at the least 48 hours.
• Baseline platelet count < 100.000/μL
• Baseline blood glucose of < 50mg/dL or > 400mg/dl
• Severe, sustained hypertension (SBP > 185 mm Hg or DBP > 110 mm Hg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using AHA guidelines recommended medication (including iv antihypertensive drips), the patient can be enrolled.
• Patients in coma (NIHSS item of consciousness >1) (Intubated patients for transfer could be randomized only in case an NIHSS is obtained by a neurologist prior transportation).
• Seizures at stroke onset which would preclude obtaining a baseline NIHSS
• Serious, advanced, or terminal illness with anticipated life expectancy of less than one year.
• History of life-threatening allergy (more than rash) to contrast medium.
• Subjects who has received IV t-PA treatment before the randomization.
• Renal failure with serum creatinine ≥ 3 mg/dl
• Woman of childbearing potential who is known to be pregnant or who has a positive pregnancy test on admission.
• Subject participating in a study involving an investigational drug or device that would impact this study.
• Cerebral vasculitis, endocarditis or subarachnoid hemorrhage.
• Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations.
• Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor from overseas).
• Hypodensity on CT more than one third of MCA territory or hypersignal in more than one third of MCA territory on MR-DWI.
• ASPECTS score < 6 (no contrast at least 5 mm cut imaging on CT) or on MR-DWI sequence.
• CT or MR evidence of hemorrhage (the presence of < 5 GRE, SWI, SWAN microbleeds is allowed).
• Significant mass effect with midline shift.
• Evidence of ipsilateral carotid occlusion, high grade stenosis or arterial dissection in the extracranial or petrous segment of the internal carotid artery that cannot be treated or will prevent access to the intracranial clot or excessive tortuosity of cervical vessels precluding device delivery/deployment.
• Subjects with occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation).
• Evidence of intracranial tumor (except small meningioma).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Health, Brazil

OTHER_GOV

Sponsor Role: collaborator

Boehringer Ingelheim

INDUSTRY

Sponsor Role: collaborator

Medtronic

INDUSTRY

Sponsor Role: collaborator

Hospital Moinhos de Vento

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Octavio M Pontes-Neto, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Clínicas da Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo

Sheila CO Martins, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital Moinhos de Vento

Raul G Nogueira, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh Medical College

Locations

Hospital Moinhos de Vento

Porto Alegre, Rio Grande do Sul, Brazil

Site Status: RECRUITING

Hospital das Clínicas Botucatu

Botucatu, , Brazil

Site Status: RECRUITING

Hospital de Base do Distrito Federal

Brasília, , Brazil

Site Status: RECRUITING

Hospital das Clínicas da UFPR

Curitiba, , Brazil

Site Status: RECRUITING

Hospital Geral de Fortaleza

Fortaleza, , Brazil

Site Status: RECRUITING

Hospital de Clinicas de Porto Alegre

Porto Alegre, , Brazil

Site Status: RECRUITING

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto

Ribeirão Preto, , Brazil

Site Status: RECRUITING

Hospital de Base de Rio Preto

São José do Rio Preto, , Brazil

Site Status: RECRUITING

Hospital das Clínicas de São Paulo

São Paulo, , Brazil

Site Status: RECRUITING

Hospital Sao Paulo

São Paulo, , Brazil

Site Status: RECRUITING

Santa Casa de Misericordia de Sao Paulo

São Paulo, , Brazil

Site Status: RECRUITING

Hospital Universitário de Uberlândia

Uberlândia, , Brazil

Site Status: RECRUITING

Hospital Estadual Central

Vitória, , Brazil

Site Status: RECRUITING

Countries

Brazil

Central Contacts

Octavio M Pontes-Neto, MD, PhD

Role: CONTACT

opontesneto@fmrp.usp.br

+551636053779

Leonardo A Carbonera, MD, MSc

Role: CONTACT

leonardo.carbonera@hmv.org.br

+555135378195

Facility Contacts

Sheila Martins

Role: primary

Rodrigo Bazan, MD

Role: primary

Leticia Rebello

Role: primary

Viviane Zetola

Role: primary

Francisco Mont'Alverne, MD

Role: primary

Rosane Brondani

Role: primary

Otavio Pontes Neto, MD

Role: primary

Raquel Hidalgo

Role: primary

Guilherme Diogo

Role: primary

Gisele Sampaio

Role: primary

Rubens Gagliardi

Role: primary

Jullyanna Shinosaki

Role: primary

José Fiorot JR, MD

Role: primary

Other Identifiers

RESILIENT DIRECT-TNK

Identifier Type: -

Identifier Source: org_study_id