PDF: TIMELESS
(2024)Objective
To evaluate whether intravenous tenecteplase administered 4.5 to 24 hours after stroke onset in patients with large vessel occlusion and salvageable tissue improves 90-day outcomes compared to placebo.
Study Summary
Intervention
Tenecteplase 0.25 mg/kg (max 25 mg) IV bolus vs. placebo, administered 4.5–24 hours after last known well, in patients with LVO and salvageable tissue on perfusion imaging. Endovascular thrombectomy allowed.
Inclusion Criteria
Adults with NIHSS ≥5, ICA/M1/M2 occlusion, perfusion imaging showing core <70 mL, mismatch ratio ≥1.8, penumbra ≥15 mL. Time last known well to randomization: 4.5–24 hrs.
Study Design
Arms: Tenecteplase vs. Placebo (both with standard medical care ± thrombectomy)
Patients per Arm: Tenecteplase: 228, Placebo: 230
Outcome
Bottom Line
In patients with ischemic stroke due to large vessel occlusion and favorable perfusion imaging profiles, tenecteplase administered 4.5 to 24 hours after last known well did not improve functional outcomes compared to placebo. Rates of symptomatic intracranial hemorrhage and mortality were similar between groups.
Major Points
- 458 patients were randomized (228 tenecteplase, 230 placebo); 77.3% underwent thrombectomy.
- Median time from last known well to randomization was ~12.3 hours (tenecteplase) and ~12.7 hours (placebo).
- No significant difference in mRS distribution at 90 days (adjusted common OR 1.13; 95% CI, 0.82–1.57; P=0.45).
- Functional independence (mRS 0–2) occurred in 46.0% (tenecteplase) vs. 42.4% (placebo).
- Complete recanalization at 24 hours was more common in the tenecteplase group (76.7% vs 63.9%; OR 1.89; 95% CI, 1.21–2.95).
- Rates of angiographic reperfusion (TICI 2b–3) were similar: 89.1% (tenecteplase) vs 85.4% (placebo).
- Symptomatic intracranial hemorrhage occurred in 3.2% (tenecteplase) vs 2.3% (placebo).
- Trial was not powered for subgroup analysis; adjusted OR for M1 occlusions favored tenecteplase (1.59; 95% CI, 1.00–2.52).
Study Design
- Study Type
- Multicenter, double-blind, randomized, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind (patients, investigators, and assessors)
- Sample Size
- 458
- Follow-up
- 90 days
- Centers
- 112
- Countries
- United States, Canada
Primary Outcome
Definition: Distribution of mRS score at 90 days (ordinal analysis)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Median 3 (IQR 1–4) | Median 3 (IQR 1–5) | 1.13 (0.82 to 1.57) | 0.45 |
Limitations & Criticisms
- Primary endpoint showed no statistically significant benefit for tenecteplase over placebo.
- Trial population was predominantly at thrombectomy-capable centers, limiting generalizability to other settings.
- Short interval from drug to arterial puncture (median 15 min) may have limited effect size of thrombolysis.
- Subgroup analyses not adjusted for multiplicity and underpowered for definitive conclusions.
Citation
N Engl J Med 2024;390:701-11. DOI: 10.1056/NEJMoa2310392