T-FLAVOR
Standard-Dose Tenecteplase vs Low-Dose Alteplase for Acute Ischemic Stroke From Large-Vessel Occlusion: A Randomized Clinical Trial
Bottom Line
Standard-dose tenecteplase (0.25 mg/kg) prior to thrombectomy produced ~3-fold higher early substantial reperfusion than low-dose alteplase (0.6 mg/kg) with comparable functional and safety outcomes, supporting tenecteplase as a thrombolytic option in Asian regions where low-dose alteplase is standard of care.
Major Points
- First RCT to directly compare tenecteplase 0.25 mg/kg with low-dose alteplase 0.6 mg/kg — the Asian standard of care.
- Substantial reperfusion on initial angiogram was 10.3% (tenecteplase) vs 3.6% (alteplase), a 6.5-percentage-point absolute difference (90% CI 0.89–12.1) that met the prespecified success threshold.
- 90-day functional outcome shift favored tenecteplase (common OR 1.47, 95% CI 0.92–2.35) but did not reach statistical significance in this modestly powered trial.
- Symptomatic ICH (2.8% vs 1.8%) and 90-day mortality (6.5% vs 9.9%) were similar between groups.
- Effect appeared larger at more distal (M2) and posterior (basilar) occlusions, where reperfusion rates favored tenecteplase by >10 percentage points.
- Median thrombolysis-to-angiogram interval was only 24 minutes — may have limited absolute reperfusion rates by not allowing full lytic effect.
Design
Study Type: Randomized Controlled Trial
Phase: Phase 2
Randomization: 1
Blinding: Open-label with blinded endpoint assessment (PROBE); central blinded imaging adjudication
Enrollment Period: August 19, 2022 - March 13, 2025
Follow-up Duration: 90 days
Centers: 18
Countries: Japan
Sample Size: 218
Analysis: Full analysis set (primary); per-protocol as sensitivity; safety analysis set for AEs. Mantel-Haenszel method for group differences stratified by occlusion site; ordinal logistic regression for mRS.
Inclusion Criteria
- Age ≥20 years
- Acute ischemic stroke eligible for IV thrombolysis within 4.5 hours of symptom onset per Japanese guidelines
- Confirmed occlusion on CTA or MRA of internal carotid artery, M1 or M2 segment of MCA, or basilar artery
- Scheduled for mechanical thrombectomy
- No upper age limit or NIHSS restriction
- Written informed consent from patient or legally authorized representative
Exclusion Criteria
- Ineligible for intravenous thrombolysis under Japanese guidelines
- Delay beyond 4.5-hour window for treatment initiation
- Coexisting subarachnoid hemorrhage
- Concomitant abdominal aneurysm or other contraindication to thrombolysis
- Major protocol deviations (detailed exclusions in eMethods, Supplement 1)
Arms
| Field | Tenecteplase | Control |
|---|---|---|
| Intervention | Intravenous tenecteplase 0.25 mg/kg (single bolus, max 25 mg) prior to mechanical thrombectomy | Intravenous alteplase 0.6 mg/kg (max 60 mg; 0.06 mg/kg bolus then remainder infused over 60 min) prior to mechanical thrombectomy |
| Duration | Single dose | 60 min infusion |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Substantial reperfusion on initial angiogram (mTICI grade 2b, 2c, or 3, or no retrievable thrombus) | Primary | 0.06 | |||
| 90-day mRS shift (favorable direction) | Secondary | 0.11 | |||
| Independent outcome (mRS 0–2 or no change at 90 d) | Secondary | 48.6% (54) | 56.1% (60) | 0.27 | |
| Excellent outcome (mRS 0–1 or no change at 90 d) | Secondary | 40.5% (45) | 43.0% (46) | 0.71 | |
| Early neurological improvement at 72 h (≥8-point NIHSS drop or NIHSS 0–1) | Secondary | 55.9% (62) | 67.3% (72) | 0.08 | |
| Clot migration on initial angiogram | Secondary | 14.4% (16) | 20.6% (22) | 0.23 | |
| Reperfusion at 24–36 h | Secondary | 69.4% (77) | 72.9% (78) | 0.57 | |
| ASPECTS at 24–36 h (mean) | Secondary | 6.2 (95% CI 5.7–6.8) | 6.0 (95% CI 5.5–6.5) | 0.53 | |
| Symptomatic Intracranial Hemorrhage (24–36 h) | Adverse | 2.8% (3/107) tenecteplase vs 1.8% (2/111) alteplase; difference 1.0 pp (95% CI −2.99 to 4.99), P=.62 | |||
| Any Intracranial Hemorrhage (24–36 h) | Adverse | 40.2% (43) tenecteplase vs 42.3% (47) alteplase; difference −2.2 pp (95% CI −15.22 to 10.91), P=.75 | |||
| Death at 90 days | Adverse | 6.5% (7/107) tenecteplase vs 9.9% (11/111) alteplase; difference −3.4 pp (95% CI −10.6 to 3.90), P=.36 | |||
| Serious Adverse Events and Procedure-Related Complications | Adverse | Similar between groups (details in eTables 5–6, Supplement 1) | |||
Subgroup Analysis
No significant heterogeneity of treatment effect on primary outcome across prespecified subgroups (age, sex, baseline NIHSS, atrial fibrillation, prior stroke/TIA, prestroke antithrombotic therapy, time from thrombolysis to angiogram, baseline ASPECTS). Effect favored tenecteplase most at M2 occlusions (17.2% vs 7.1%) and basilar artery occlusions (16.9% vs 0%). Tenecteplase associated with higher mRS 0–1 at 90 d in the shorter thrombolysis-to-angiogram subgroup (P for interaction = .04).
Criticisms
- Modest sample size (218) with sample size calculation using 90% CI and P<.10 rather than standard 95% CI and P<.05; the traditional 95% CI for primary outcome was −0.19% to 13.2%, crossing 0.
- Open-label design at both thrombolytic administration and thrombectomy procedure, though endpoint assessment was blinded.
- Absolute reperfusion rate after tenecteplase (10.3%) was lower than reported in EXTEND-IA TNK (22%), likely due to short median thrombolysis-to-angiogram time (24 min) limiting full lytic effect.
- Conducted exclusively in Japanese patients — generalizability outside East Asia is limited given the low-dose alteplase comparator regimen is not standard elsewhere.
- Enrollment slowed by COVID-19 and by logistical constraints in procuring investigational tenecteplase from a US supplier.
- Mechanical thrombectomy procedures were not standardized across centers.
Funding
Japan Agency for Medical Research and Development (AMED; JP20lk0201109, JP24lk0221186), Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center, and Crowd Funding. Investigator-initiated; funders had no role in design, conduct, analysis, or publication.
Based on: T-FLAVOR (JAMA Neurology, 2026)
Authors: Inoue M, Hirano T, Fukuda-Doi M, ..., et al. for the T-FLAVOR trial Investigators
Citation: JAMA Neurol. 2026;83(8):769-777. doi:10.1001/jamaneurol.2026.1590
Content summarized and formatted by NeuroTrials.ai.