DATE
(2025)Objective
To evaluate the dose-dependent safety and signals of efficacy of adjunctive intra-arterial tenecteplase after successful reperfusion by endovascular thrombectomy in patients with anterior circulation large vessel occlusion stroke.
Study Summary
• Phase 1b dose-escalation: sICH rates were acceptable at 0.0313 mg/kg (7.1%) and 0.0625 mg/kg (9.1%), but exceeded the safety threshold at 0.1250 mg/kg (25.0%, P=.04).
• Phase 2a: 90-day no-disability outcome (mRS 0–1) occurred in 33.8% (control), 37.0% (0.0313 mg/kg), and 43.5% (0.0625 mg/kg) — no statistically significant differences.
• Both low doses showed adequate safety to advance to a larger phase 2b/3 trial; 0.1250 mg/kg was deemed not tolerated.
• Phase 2a: 90-day no-disability outcome (mRS 0–1) occurred in 33.8% (control), 37.0% (0.0313 mg/kg), and 43.5% (0.0625 mg/kg) — no statistically significant differences.
• Both low doses showed adequate safety to advance to a larger phase 2b/3 trial; 0.1250 mg/kg was deemed not tolerated.
Intervention
Intra-arterial tenecteplase (0.0313 or 0.0625 mg/kg) administered via distal access catheter or microcatheter within 10 minutes after successful EVT (eTICI 2b–3) vs control (no intra-arterial thrombolysis)
Inclusion Criteria
Age ≥18 years; anterior circulation LVO (intracranial ICA, M1, or M2); presenting within 24 hours of last known well; baseline NIHSS 6–24; baseline ASPECTS ≥6 on NCCT; eTICI score 2b–3 after EVT; no prior IV thrombolysis
Study Design
Arms: Tenecteplase 0.0313 mg/kg vs Tenecteplase 0.0625 mg/kg vs Control (no intra-arterial thrombolysis)
Patients per Arm: Phase 2a: 0.0625 mg/kg n=46; 0.0313 mg/kg n=46; Control n=65
Outcome
• Primary (Phase 2a — mRS 0–1 at 90 days): Control 33.8%, 0.0313 mg/kg 37.0% (adjusted RR 0.85, 95% CI 0.54–1.35, P=.50), 0.0625 mg/kg 43.5% (adjusted RR 1.15, 95% CI 0.73–1.80, P=.55)
• mRS 0–2 at 90 days: Control 50.8%, 0.0313 mg/kg 50.0% (adjusted RR 0.91, 95% CI 0.64–1.32), 0.0625 mg/kg 56.5% (adjusted RR 1.12, 95% CI 0.80–1.56)
• sICH within 24h: Control 3.1%, 0.0313 mg/kg 4.3%, 0.0625 mg/kg 6.5% — no significant difference
• 90-day mortality: Control 21.5%, 0.0313 mg/kg 15.2% (adjusted RR 0.77, 95% CI 0.34–1.79), 0.0625 mg/kg 19.6% (adjusted RR 0.78, 95% CI 0.36–1.66)
• mRS 0–2 at 90 days: Control 50.8%, 0.0313 mg/kg 50.0% (adjusted RR 0.91, 95% CI 0.64–1.32), 0.0625 mg/kg 56.5% (adjusted RR 1.12, 95% CI 0.80–1.56)
• sICH within 24h: Control 3.1%, 0.0313 mg/kg 4.3%, 0.0625 mg/kg 6.5% — no significant difference
• 90-day mortality: Control 21.5%, 0.0313 mg/kg 15.2% (adjusted RR 0.77, 95% CI 0.34–1.79), 0.0625 mg/kg 19.6% (adjusted RR 0.78, 95% CI 0.36–1.66)
Bottom Line
Intra-arterial tenecteplase at 0.0313 mg/kg or 0.0625 mg/kg after successful EVT showed acceptable safety (sICH rates 4.3% and 6.5%, no significant difference from control 3.1%), whereas the 0.1250 mg/kg dose exceeded the prespecified safety threshold with 25% sICH. Neither low dose demonstrated a statistically significant improvement in 90-day no-disability outcome (mRS 0–1: 37.0% and 43.5% vs 33.8% control), but the trial was not powered for efficacy; both doses advance to larger phase 2b/3 testing.
Major Points
- First systematic dose-escalation study of intra-arterial tenecteplase after successful EVT. Phase 1b used a 14+8 design across 4 dose tiers (0.0313, 0.0625, 0.1250, 0.1875 mg/kg); phase 2a was a randomized 3-arm trial at 30 sites in China enrolling 157 patients (February–August 2024).
- Dose-escalation phase (phase 1b, n=48): sICH within 24h was 1/14 (7.1%) at 0.0313 mg/kg, 2/22 (9.1%) at 0.0625 mg/kg, and 3/12 (25.0%) at 0.1250 mg/kg — the latter exceeded the prespecified safety threshold (P=.04), halting escalation. The 0.1875 mg/kg tier was never tested.
- Phase 2a primary outcome (mRS 0–1 at 90 days): Control 33.8% (22/65), 0.0313 mg/kg 37.0% (17/46; adjusted RR 0.85, 95% CI 0.54–1.35, P=.50), 0.0625 mg/kg 43.5% (20/46; adjusted RR 1.15, 95% CI 0.73–1.80, P=.55). No statistically significant differences, but trial was exploratory and not powered for efficacy.
- Secondary functional outcome (mRS 0–2 at 90 days): Control 50.8%, 0.0313 mg/kg 50.0% (adjusted RR 0.91), 0.0625 mg/kg 56.5% (adjusted RR 1.12). Ordinal mRS distribution (GenOR): 0.0625 mg/kg 1.18 (95% CI 0.70–1.99, P=.53), 0.0313 mg/kg 0.95 (95% CI 0.55–1.62, P=.84) vs control.
- Phase 2a safety outcomes: sICH within 24h occurred in 3.1% (control), 4.3% (0.0313 mg/kg; RR 1.41, 95% CI 0.21–9.67, P=.72), and 6.5% (0.0625 mg/kg; RR 2.12, 95% CI 0.37–12.18, P=.40) — numerically higher but not statistically significant. Any radiologic ICH: ~28% across all three arms.
- 90-day mortality: 21.5% (control), 15.2% (0.0313 mg/kg; adjusted RR 0.77, 95% CI 0.34–1.79, P=.55), 19.6% (0.0625 mg/kg; adjusted RR 0.78, 95% CI 0.36–1.66, P=.51). Numerically lower in tenecteplase arms but not statistically significant.
- Angiographic reperfusion improvement (eTICI upgrade after intra-arterial infusion): 6.5% in 0.0625 mg/kg group and 8.7% in 0.0313 mg/kg group. When excluding baseline eTICI 3 patients: 3/26 (11.5%) and 4/30 (13.3%), respectively. Control group not applicable.
- Trial rationale: Even after macrovascular reperfusion (eTICI 2b–3), only 27% of patients achieve disability-free outcomes. No-reflow phenomenon from microvascular thrombosis and distal embolization are key contributors. Smaller thrombi are more susceptible to pharmacologic dissolution than large proximal clots.
- Randomization in phase 2a was stratified by age (<70 vs ≥70 years) and admission NIHSS score (<15 vs ≥15), allocated 1:1:√2 (tenecteplase A : tenecteplase B : control = 0.293 : 0.293 : 0.414). Outcomes assessed centrally by blinded raters; video/audio recordings retained for all 90-day mRS assessments.
- Contextual significance: Other ongoing trials (POST-TNK using 0.0625 mg/kg, ANGEL-TNK using 0.1250 mg/kg, ALLY using 1.5–4.5 mg fixed-dose) selected doses empirically without prior dose-escalation data. DATE provides the first empirical dose-safety data, establishing 0.0313 and 0.0625 mg/kg as the safe range for future pivotal trials.
Study Design
- Study Type
- Prospective, multicenter, open-label, blinded-outcome assessment, adaptive phase 1b (nonrandomized dose-escalation) and phase 2a (randomized dose-expansion) clinical trial
- Randomization
- Yes
- Blinding
- Open-label intervention; blinded central outcome assessment (2 independent certified central raters for mRS at 90 days; blinded core laboratory for imaging)
- Sample Size
- 205
- Follow-up
- 90 days (±14 days)
- Centers
- 30
- Countries
- China
Primary Outcome
Definition: mRS 0-1 at 90 days (phase 2a)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 22/65 (33.8%) | 20/46 (43.5%) [0.0625 mg/kg], 17/46 (37.0%) [0.0313 mg/kg] | - (0.73-1.80 (0.0625 vs control, adjusted)) | 0.55 (0.0625), 0.50 (0.0313) |
Limitations & Criticisms
- Phase 1b was nonrandomized — patients were assigned sequentially by dose tier, introducing potential temporal bias as practice patterns may have evolved between 2023 and 2024.
- Phase 2a was open-label — interventionalists and treating clinicians were aware of treatment assignment, risking performance bias in post-procedure management, though outcome assessors were blinded.
- Trial was not powered to detect a statistically significant efficacy benefit — with only 46 patients per tenecteplase arm, the study was exploratory only; failure to reach significance does not exclude a clinically meaningful effect.
- Significant baseline imbalance in occlusion site: 38.5% of control patients had ICA occlusion vs 10.9–17.4% in tenecteplase arms. ICA occlusion is associated with worse prognosis, potentially confounding the control group outcome. Adjusted analyses were performed but residual confounding remains possible.
- Exclusively Asian (100% Chinese) population — generalizability to other ethnic groups is unknown. Thrombus characteristics, atrial fibrillation prevalence, and pharmacogenomic profiles may differ in non-Asian populations.
- No perfusion imaging (CT perfusion or MRI DWI/PWI) was required — penumbral volume and ischemic core status were not characterized, limiting mechanistic insight into which patients might benefit from adjunctive thrombolysis.
- IV thrombolysis-treated patients were excluded — a substantial proportion of real-world EVT patients receive bridging IV tPA; these results may not apply to them.
- The sICH definition used ECASS III criteria rather than the more conservative SITS-MOST criteria — comparisons with trials using different definitions require caution.
- Small sample sizes in individual dose tiers (especially 0.1250 mg/kg n=12 in phase 1b) limit the precision of sICH rate estimates; the upper confidence bounds are wide.
- Only anterior circulation LVOs were enrolled — posterior circulation strokes (basilar artery occlusion) were excluded; results cannot be extrapolated to basilar thrombectomy.
Citation
Hou X, et al. Intra-Arterial Tenecteplase After Successful Reperfusion in Large Vessel Occlusion Stroke: A Randomized Clinical Trial. JAMA Neurol. 2025. doi:10.1001/jamaneurol.2025.2036. Published online July 5, 2025.