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

Official title

Randomization to EndoVascular Treatment Alone or Preceded by Systemic Thrombolysis With Tenecteplase in Acute Ischemic Stroke Due to Large Intracranial VEssel OcclusioN Trial - DIRECT Thrombectomy vs. Intravenous TNK Plus Thrombectomy

Overview

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.

Interventions

• Drug Tenecteplase
  Intravenous thrombolysis with tenecteplase 0.25mg/kg
• Drug Placebo
  Intravenous administration of placebo, matching the volume of tenecteplase 0.25mg/kg

Primary outcome measures

• Distribution of the modified Rankin Scale scores at 90 days [Time frame: 90 days]

Secondary outcome measures (8)

• Functional independence defined as modified Rankin Score ≤ 2 [Time frame: 90 days]
• Infarct volume evaluated on CT at 24 hours (-2/+12 hours). [Time frame: 24 hours]
• Dramatic early favorable response as determined by a National Institute of Health Stroke Scale (NIHSS) of 0-2 or NIHSS improvement ≥ 10 points at 24 (-2/+12 hours) hours. [Time frame: 24 hours]
• Cost-effectiveness analysis of endovascular therapy alone vs. endovascular therapy associated with tenecteplase [Time frame: 12 months]
• Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year among the groups [Time frame: 3 months, 6 months and 12 months]
• Score distribution of mRS at 90 days (shift analysis) in patients presenting M2-CMA occlusion [Time frame: 90 days]
• Vessel recanalization evaluated by CT angiography or MRA at 24 hours in both treatment groups [Time frame: 24 hours]
• Vessel recanalization post procedure in the endovascular arm assessed by TIMI grades and adjudicated by a central core-lab. Successful recanalization is defined as TICI (Thrombolysis in Cerebral Infarction) 2b or 3 on the post-procedure angiogram. [Time frame: Immediately Post-procedure]

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Brazil · 13 centers

• Hospital Moinhos de Vento — Porto Alegre
• Hospital das Clínicas Botucatu — Botucatu
• Hospital de Base do Distrito Federal — Brasília
• Hospital das Clínicas da UFPR — Curitiba
• Hospital Geral de Fortaleza — Fortaleza
• Hospital de Clinicas de Porto Alegre — Porto Alegre
• Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto — Ribeirão Preto
• Hospital de Base de Rio Preto — São José do Rio Preto
• … and 5 more centers

Identifiers

NCT: NCT05199194 · RESILIENT DIRECT-TNK

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗