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TNK-PLUS

Intravenous Tenecteplase Prior to Endovascular Treatment for Ischemic Stroke at 4.5 to 24 Hours: The TNK-PLUS Randomized Clinical Trial

Year of Publication: 2026

Authors: Yunyun Xiong, Fengyuan Che, Hao Wang, ..., Yongjun Wang; for the TNK-PLUS Investigators

Journal: JAMA

Citation: Xiong Y, Che F, Wang H, et al. Intravenous Tenecteplase Prior to Endovascular Treatment for Ischemic Stroke at 4.5 to 24 Hours: The TNK-PLUS Randomized Clinical Trial. JAMA. 2026. doi:10.1001/jama.2026.4292

Link: https://doi.org/10.1001/jama.2026.4292

Clinical Question

In patients with proximal MCA occlusion presenting 4.5–24 hours after stroke onset who have direct access to EVT, does bridging intravenous tenecteplase improve functional outcomes compared to EVT alone?

Bottom Line

Intravenous tenecteplase before endovascular treatment does not improve functional independence at 90 days in patients with proximal MCA occlusion presenting in the 4.5–24-hour window; EVT alone remains the standard of care, and adding tenecteplase may increase bleeding risk.

        Major Points
        Tenecteplase 0.25 mg/kg before EVT did not improve functional independence (mRS 0–2) at 90 days: 44.2% vs 43.2%, adjusted RR 1.01 (95% CI, 0.83–1.24), P = 0.89
Risk difference for functional independence was 0.99% (95% CI, −8.84% to 10.83%), confirming no clinically meaningful or statistically significant benefit
Symptomatic ICH within 36 hours was numerically higher in the tenecteplase group: 5.1% (10/197) vs 2.6% (5/190)
90-day mortality was numerically lower in the tenecteplase group but not significantly different: 12.7% (25/197) vs 14.2% (27/190)
An interim adaptive sample size reestimation showed conditional power of only 0.03 (below the promising zone of 0.33–0.80), confirming futility without requiring sample size expansion
Results align with TIMELESS and together indicate that in patients with direct EVT access, adding bridging tenecteplase in the late window provides no additional benefit beyond EVT alone
Unlike TRACE-III where thrombolysis benefited patients without EVT access, the availability of EVT appears to negate any incremental benefit of tenecteplase in the late time window

      

Design

Study Type: Multicenter, prospective, open-label, blinded endpoint (PROBE), phase 3, randomized controlled superiority trial

Randomization: 1

Blinding: Open-label with blinded endpoint assessment; all clinical efficacy and adverse event endpoints evaluated by physicians unaware of treatment allocation; neuroimaging independently adjudicated by central imaging core laboratory

Allocation: 1:1 ratio via centralized web-based system, stratified by LVO site (M1 or M2), block size 4

Enrollment Period: January 25, 2024 – July 21, 2025

Follow-up Duration: 90 days (final follow-up October 14, 2025)

Centers: 40

Countries: China

Sample Size: 391

Analyzed: 391

Analysis: Full analysis set (ITT, all randomly assigned participants) as primary; per-protocol set as secondary (tenecteplase+EVT n=189; EVT alone n=178)

Power Calculation: Estimated conservative effect size of 10% based on TIMELESS and TRACE-III data; minimum sample size 390 (powered for 14% effect), maximum 754 (powered for 10% effect); 2-sided alpha 0.05, power 0.80, anticipated attrition 5%; prespecified interim adaptive sample size reestimation at 273 participants showed conditional power 0.03, outside promising zone (0.33–0.80), so no sample size increase was required

Registration: NCT06221371

Inclusion Criteria

Age ≥18 years
Acute ischemic stroke with last known well 4.5–24 hours before randomization, including wake-up stroke and unwitnessed onset
Pre-stroke mRS score 0–2
NIHSS score 6–25
Confirmed MCA-M1 or proximal M2 occlusion on CT angiography or MR angiography
Ischemic core volume <70 mL (CBF <30% of normal on CT-perfusion or ADC <620×10−6 mm2/s on DWI-MRI)
Mismatch ratio (hypoperfused tissue / ischemic core volume) ≥1.8
Mismatch volume ≥15 mL (hypoperfused tissue defined as Tmax >6 seconds on CT or MR perfusion)
Salvageable brain tissue confirmed on CT-perfusion or MR perfusion-diffusion imaging

Exclusion Criteria

No MCA-M1 or proximal M2 occlusion
Did not meet target mismatch profile on CTP or MRI with MR perfusion
Large infarct on noncontrast CT or MRI (>1/3 MCA territory)
Time from onset to randomization <4.5 hours or >24 hours
Multiple arterial occlusions
Already received thrombolytic therapy at external hospital
NIHSS score <6 or >25
Chronic occlusion
Unable to perform CTP or perfusion-weighted imaging
Known coagulation impairment
Brain surgery or brain tumor within the last 3 months
Active internal bleeding
Pre-stroke mRS score >2
Declined EVT or intravenous thrombolytic at time of randomization
Unlikely to adhere to trial protocol or follow-up

Arms

Field	Tenecteplase + EVT	Control
N	199	192
Intervention	Intravenous tenecteplase 0.25 mg/kg (maximum dose 25 mg) administered as a single IV bolus over 5–10 seconds immediately after randomization, followed by EVT as soon as possible (stent retriever, aspiration, balloon angioplasty, stent placement, or combination)	Endovascular treatment alone without preceding thrombolysis (stent retriever, aspiration, balloon angioplasty, stent placement, or combination)
Duration	Single dose pre-EVT; 90-day follow-up	90-day follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Functional independence defined as modified Rankin Scale score 0–2 at 90 days	Primary	43.2% (83/192)	44.2% (88/199)	1.01	0.89
No disability (mRS ≤1) at 90 days — results not available in source text					Secondary
mRS score ≤3 at 90 days — results not available in source text					Secondary
Ordinal mRS distribution at 90 days — results not available in source text					Secondary
Severe disability or death (mRS 5–6) at 90 days — results not available in source text					Secondary
Early neurologic improvement at 72 hours (NIHSS decrease ≥8 points from baseline or NIHSS 0–1) — results not available in source text					Secondary
Change in NIHSS score from baseline to day 7 — results not available in source text					Secondary
Reperfusion prior to EVT (>50% reperfusion; eTICI 2b50–3) — results not available in source text					Secondary
Complete recanalization at 24 hours on CTA or MRA — results not available in source text					Secondary
Symptomatic ICH within 36 hours: 5.1% (10/197) tenecteplase+EVT vs 2.6% (5/190) EVT alone					Safety
Death within 90 days: 12.7% (25/197) tenecteplase+EVT vs 14.2% (27/190) EVT alone					Safety
5.1% (10/197)					Adverse
2.6% (5/190)					Adverse
12.7% (25/197)					Adverse
14.2% (27/190)					Adverse

Subgroup Analysis

Context from TIMELESS noted in background: patients with M1 occlusion appeared to benefit from tenecteplase, while M2 patients did not in TIMELESS; TNK-PLUS-specific subgroup results by occlusion site (M1 vs proximal M2) are not reported in the available source text.

Criticisms

Open-label design may introduce performance bias despite blinded endpoint assessment
Conducted exclusively in China at high-volume EVT centers, which may limit generalizability to lower-resource settings or health systems with longer door-to-groin times
Interim analysis revealed very low conditional power (0.03), indicating early futility signal; trial continued to minimum prespecified sample size
Numerically higher sICH rate in tenecteplase group (5.1% vs 2.6%) raises safety concern not resolvable given the trial was not powered for this endpoint
Internal carotid artery and anterior cerebral artery occlusions were excluded, limiting scope; TIMELESS ICA subgroup data suggest ICA occlusion does not benefit anyway
Full secondary outcome results not available in the published abstract/early release text

Funding

Unrestricted grant from China Shijiazhuang Pharmaceutical Company Pharmaceutical (Guangzhou), which also manufactured the tenecteplase used in the trial

Based on: TNK-PLUS (JAMA, 2026)

Authors: Yunyun Xiong, Fengyuan Che, Hao Wang, ..., Yongjun Wang; for the TNK-PLUS Investigators

Content summarized and formatted by NeuroTrials.ai.

TNK-PLUS

(2026)

Objective

To investigate the efficacy and safety of intravenous tenecteplase administered prior to endovascular treatment (EVT) in patients with acute ischemic stroke due to proximal MCA (M1 or proximal M2) occlusion presenting 4.5 to 24 hours after last known well.

Study Summary

• Functional independence (mRS 0–2) at 90 days: 44.2% (tenecteplase+EVT) vs 43.2% (EVT alone); adjusted RR 1.01 (95% CI, 0.83–1.24); P = 0.89
• Risk difference: 0.99% (95% CI, −8.84% to 10.83%) — no clinically meaningful benefit
• Symptomatic ICH within 36 hours: 5.1% (tenecteplase) vs 2.6% (EVT alone)
• 90-day mortality: 12.7% (tenecteplase) vs 14.2% (EVT alone)
• Intravenous tenecteplase before EVT did not improve clinical outcomes vs EVT alone in the 4.5–24-hour time window

Intervention

Intravenous tenecteplase 0.25 mg/kg (maximum 25 mg) as a single bolus immediately before EVT vs EVT alone

Inclusion Criteria

Adults ≥18 years with acute ischemic stroke 4.5–24 hours after last known well; MCA-M1 or proximal M2 occlusion on CTA or MRA; ischemic core <70 mL; mismatch ratio ≥1.8; mismatch volume ≥15 mL; NIHSS 6–25; pre-stroke mRS 0–2

Study Design

Arms: Tenecteplase 0.25 mg/kg IV before EVT (n=199) vs EVT alone (n=192)

Patients per Arm: 199 vs 192

Outcome

• Primary — mRS 0–2 at 90 days: 44.2% vs 43.2%; adjusted RR 1.01 (95% CI, 0.83–1.24); P = 0.89 — no significant difference
• Symptomatic ICH within 36 hours: 5.1% (10/197) vs 2.6% (5/190)
• 90-day mortality: 12.7% (25/197) vs 14.2% (27/190)

Bottom Line

Major Points

Tenecteplase 0.25 mg/kg before EVT did not improve functional independence (mRS 0–2) at 90 days: 44.2% vs 43.2%, adjusted RR 1.01 (95% CI, 0.83–1.24), P = 0.89
Risk difference for functional independence was 0.99% (95% CI, −8.84% to 10.83%), confirming no clinically meaningful or statistically significant benefit
Symptomatic ICH within 36 hours was numerically higher in the tenecteplase group: 5.1% (10/197) vs 2.6% (5/190)
90-day mortality was numerically lower in the tenecteplase group but not significantly different: 12.7% (25/197) vs 14.2% (27/190)
An interim adaptive sample size reestimation showed conditional power of only 0.03 (below the promising zone of 0.33–0.80), confirming futility without requiring sample size expansion
Results align with TIMELESS and together indicate that in patients with direct EVT access, adding bridging tenecteplase in the late window provides no additional benefit beyond EVT alone
Unlike TRACE-III where thrombolysis benefited patients without EVT access, the availability of EVT appears to negate any incremental benefit of tenecteplase in the late time window

Study Design

Study Type: Multicenter, prospective, open-label, blinded endpoint (PROBE), phase 3, randomized controlled superiority trial
Randomization: Yes
Blinding: Open-label with blinded endpoint assessment; all clinical efficacy and adverse event endpoints evaluated by physicians unaware of treatment allocation; neuroimaging independently adjudicated by central imaging core laboratory
Sample Size: 391
Follow-up: 90 days (final follow-up October 14, 2025)
Centers: 40
Countries: China

Primary Outcome

Definition: Functional independence defined as modified Rankin Scale score 0–2 at 90 days

Control	Intervention	HR/OR	P-value
43.2% (83/192)	44.2% (88/199)	- (0.83–1.24)	0.89

Limitations & Criticisms

Open-label design may introduce performance bias despite blinded endpoint assessment
Conducted exclusively in China at high-volume EVT centers, which may limit generalizability to lower-resource settings or health systems with longer door-to-groin times
Interim analysis revealed very low conditional power (0.03), indicating early futility signal; trial continued to minimum prespecified sample size
Numerically higher sICH rate in tenecteplase group (5.1% vs 2.6%) raises safety concern not resolvable given the trial was not powered for this endpoint
Internal carotid artery and anterior cerebral artery occlusions were excluded, limiting scope; TIMELESS ICA subgroup data suggest ICA occlusion does not benefit anyway
Full secondary outcome results not available in the published abstract/early release text

Citation

Xiong Y, Che F, Wang H, et al. Intravenous Tenecteplase Prior to Endovascular Treatment for Ischemic Stroke at 4.5 to 24 Hours: The TNK-PLUS Randomized Clinical Trial. JAMA. 2026. doi:10.1001/jama.2026.4292

View Original Publication →

TNK-PLUS

Intravenous Tenecteplase Prior to Endovascular Treatment for Ischemic Stroke at 4.5 to 24 Hours: The TNK-PLUS Randomized Clinical Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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