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

Stroke, Acute Clinical Trial

— DIRECT-TNK  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05199194
• Other study ID #: RESILIENT DIRECT-TNK
• Status: Recruiting
• Phase: Phase 3
• Start date: May 27, 2022
• Est. completion date: July 2027

Study information

• Verified date: January 2024
• Source: Hospital Moinhos de Vento
• Contact: Octavio M Pontes-Neto, MD, PhD
• Phone: +551636053779
• Email: opontesneto[@]fmrp.usp.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Randomized, prospective, multicenter, double-blinded, placebo-controlled clinical trial. 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 390
• Est. completion date: July 2027
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.
• 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).

Related Conditions & MeSH terms

• Ischemia
• Ischemic Stroke
• Stroke
• Stroke, Acute
• Stroke, Ischemic

Intervention

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

Locations

Country	Name	City	State
Brazil	Hospital das Clínicas Botucatu	Botucatu
Brazil	Hospital de Base do Distrito Federal	Brasília
Brazil	Hospital das Clínicas da UFPR	Curitiba
Brazil	Hospital Geral de Fortaleza	Fortaleza
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre
Brazil	Hospital Moinhos de Vento	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto	Ribeirão Preto
Brazil	Hospital de Base de Rio Preto	São José Do Rio Preto
Brazil	Hospital das Clínicas de São Paulo	São Paulo
Brazil	Hospital Sao Paulo	São Paulo
Brazil	Santa Casa de Misericordia de Sao Paulo	São Paulo
Brazil	Hospital Universitário de Uberlândia	Uberlândia
Brazil	Hospital Estadual Central	Vitória

Sponsors (4)

Lead Sponsor	Collaborator
Hospital Moinhos de Vento	Boehringer Ingelheim, Medtronic, Ministry of Health, Brazil

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mortality at 90 days	Mortality at 90 days	90 days
Other	Mortality related to stroke and complications at 90 days	Mortality related to stroke and complications at 90 days	90 days
Other	Clinically significant ICH rates at 24 (-2/+12) hours.	All intracerebral hemorrhages will be classified by a central core-lab using the ECASS criteria. Symptomatic ICH will be defined as per the SITS-MOST definition: deterioration in NIHSS score of =4 points within 24 hours from treatment and evidence of intraparenchymal hemorrhage type 2 in the 22 to 36 hours follow-up imaging scans. The incidence of any asymptomatic hemorrhage measured at 24 (-2/+12) hours will also be compared.	24 hours
Other	Procedural related complications	arterial perforation, arterial dissection, and embolization in a previously uninvolved vascular territory	7 days
Primary	Distribution of the modified Rankin Scale scores at 90 days	Distribution of the modified Rankin Scale scores (shift analysis).	90 days
Secondary	Functional independence defined as modified Rankin Score = 2	Functional independence defined as modified Rankin Score = 2	90 days
Secondary	Infarct volume evaluated on CT at 24 hours (-2/+12 hours).	Infarct volume evaluated on CT at 24 hours (-2/+12 hours).	24 hours
Secondary	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.	Dramatic early favorable response as determined by a National Institute of Health Stroke Scale of 0-2 or NIHSS improvement = 10 points at 24 (-2/+12 hours) hours.	24 hours
Secondary	Cost-effectiveness analysis of endovascular therapy alone vs. endovascular therapy associated with tenecteplase	Cost-effectiveness analysis of endovascular therapy alone vs. endovascular therapy associated with tenecteplase	12 months
Secondary	Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year among the groups	Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year among the groups	3 months, 6 months and 12 months
Secondary	Score distribution of mRS at 90 days (shift analysis) in patients presenting M2-CMA occlusion	Score distribution of mRS at 90 days (shift analysis) in patients presenting M2-CMA occlusion	90 days
Secondary	Vessel recanalization evaluated by CT angiography or MRA at 24 hours in both treatment groups	Vessel recanalization evaluated by CT angiography or MRA at 24 hours in both treatment groups	24 hours
Secondary	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.	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.	Immediately Post-procedure