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ROSE-TNK

Intravenous Tenecteplase for Acute Ischemic Stroke Within 4.5–24 Hours of Onset (ROSE-TNK): A Phase 2, Randomized, Multicenter Study

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Year of Publication: 2023

Authors: Lu Wang, Ying-Jie Dai, Yu Cui, ..., Hui-Sheng Chen

Journal: Journal of Stroke

Citation: J Stroke. 2023;25(3):371-377. doi:10.5853/jos.2023.00668

Link: https://doi.org/10.5853/jos.2023.00668

PDF: https://j-stroke.org/upload/pdf/jos-2023-00668.pdf

Clinical Question

Is intravenous tenecteplase safe and effective for treating acute ischemic stroke 4.5–24 hours from onset in MRI-selected patients with DWI-FLAIR mismatch?

Bottom Line

Intravenous tenecteplase within 4.5–24 hours of onset appeared safe and feasible in MRI-selected acute ischemic stroke patients, and was associated with significantly higher early neurological improvement compared to standard care, though no difference in 90-day functional outcomes was observed.

        Major Points
        80 patients with acute ischemic stroke were randomized to receive either intravenous tenecteplase (0.25 mg/kg) or standard care within 4.5–24 hours of onset based on MRI DWI-FLAIR mismatch.
Tenecteplase significantly improved early neurological improvement (27.5% vs 7.5%, P=0.03).
No significant difference in 90-day mRS 0–1 (52.5% vs 50%) or mRS 0–2 (65% vs 60%) between groups.
No symptomatic intracranial hemorrhage occurred; asymptomatic hemorrhagic transformation occurred in 7.5% of TNK group (2 PH-1, 1 PH-2).
This is the first randomized trial of TNK in extended-window AIS using MRI-based selection.

      

Design

Study Type: Phase 2 randomized, open-label trial with blinded endpoint assessment

Randomization: 1

Blinding: Blinded endpoint assessors

Enrollment Period: March 2021 – July 2022

Follow-up Duration: 90 days

Centers: 14

Countries: China

Sample Size: 80

Analysis: Intention-to-treat; adjusted binary logistic regression for outcomes, including age, sex, SBP, NIHSS, ischemic stroke, and onset-to-randomization time as covariates; ordinal logistic regression and generalized linear models

Inclusion Criteria

Age 18–80 years
Acute ischemic stroke 4.5–24 hours from onset (including wake-up stroke)
NIHSS score 6–25
Pre-stroke mRS 0–1
MRI with DWI-FLAIR mismatch (DWI high signal, visually normal FLAIR)
DWI region ≤1/3 of MCA territory, ≤1/2 of ACA territory, or ≤1/2 of PCA territory
DWI infarct volume <70 mL (measured by automated 3D-Slicer)
No hemorrhage on CT

Exclusion Criteria

Planned endovascular treatment/thrombectomy
Premorbid mRS ≥2
Contraindications to intravenous thrombolysis
DWI lesion >1/3 of MCA territory (or >1/2 of ACA/PCA territory)
Poor quality MRI
Uncontrolled hypertension

Baseline Characteristics

Age - TNK: 62.68 ± 8.87

Age - Control: 62.80 ± 8.56

Sex - Female: 22.5% (TNK), 35.0% (Control)

NIHSS Median: 7.5 (IQR 6.00–10.75) (TNK), 7.0 (IQR 6.00–8.75) (Control)

Hypertension: 60.0% (TNK), 70.0% (Control)

Wake-up stroke: 60.0% (TNK), 57.5% (Control)

Onset to randomization (h): 10.97 ± 4.67 (TNK), 11.01 ± 4.14 (Control)

Large vessel occlusion: 42.5% (TNK), 45.0% (Control)

Baseline infarct volume: 0.32 mL (IQR 0.00–2.28) (TNK), 0.40 mL (IQR 0.09–1.48) (Control)

Arms

Field	IV Tenecteplase	Control
Intervention	Single IV bolus of tenecteplase 0.25 mg/kg (max 25 mg) within 4.5–24 hours of onset	Standard care per acute ischemic stroke guidelines (antiplatelets, statins, BP/glucose control, supportive care)
Duration	Single dose, 90-day follow-up	90-day follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Proportion of patients with mRS 0–1 at 90 days	Primary	50.0% (20/40)	52.5% (21/40)	1.1	0.85
mRS 0–2 at 90 days	Secondary	60.0% (24/40)	65.0% (26/40)	1.44	0.50
Early Neurological Improvement (>4 point decrease in NIHSS within 24 hours)	Secondary	7.5% (3/40)	27.5% (11/40)	5	0.03
90-day mRS distribution (ordinal shift)	Secondary	NA	NA	0.89	0.77
Change in NIHSS from baseline to 24 hours (absolute difference)	Secondary	0.00 (IQR -2.00 to 0.00)	-2.00 (IQR -4.00 to 0.00)		0.11
Change in NIHSS from baseline to 7 days (absolute difference)	Secondary	-2.00 (IQR -4.00 to -1.00)	-3.00 (IQR -6.00 to 0.00)		0.78
Symptomatic Intracranial Hemorrhage (48h)	Adverse	0%	0%		>0.99
Asymptomatic Intracranial Hemorrhage / HT within 7 days	Adverse	0% (0/40)	7.5% (3/40)		>0.99
PH-1 (parenchymal hemorrhage type 1)	Adverse	0% (0/40)	5.0% (2/40)		>0.99
PH-2 (parenchymal hemorrhage type 2)	Adverse	0% (0/40)	2.5% (1/40)		>0.99
Death at 14 days	Adverse	0%	0%		>0.99
Any Adverse Events	Adverse	10.0% (4/40)	27.5% (11/40)	0.30 (95% CI 0.08–1.18) adjusted	0.09
Severe Adverse Events	Adverse	5.0% (2/40)	17.5% (7/40)	0.26 (95% CI 0.05–1.37) adjusted	0.11

Subgroup Analysis

No prespecified subgroup analysis was reported; trial was not powered for subgroup efficacy.

Criticisms

Small sample size (n=80) limits statistical power to detect differences in functional outcomes
Open-label design may introduce bias despite blinded endpoint assessment
DWI-FLAIR mismatch alone may not capture all eligible late-window patients
Exclusion of patients planned for thrombectomy limits generalizability
Predominance of wake-up strokes (~59%) may bias applicability to late-presenting known-onset strokes

Funding

Liaoning Province Science and Technology Project (2019JH2/10300027)

Based on: ROSE-TNK (Journal of Stroke, 2023)