TIMELESS
Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection
Year of Publication: 2024
Authors: G.W. Albers, M. Jumaa, B. Purdon, ..., and B.C.V. Campbell
Journal: The New England Journal of Medicine
Citation: N Engl J Med 2024;390:701-11. DOI: 10.1056/NEJMoa2310392
PDF: Clinical Question
Does tenecteplase administered 4.5 to 24 hours after last known well time, with perfusion-imaging selection, improve clinical outcomes in ischemic stroke patients, most of whom also undergo endovascular thrombectomy, compared to placebo?
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).
Design
Study Type: Multicenter, double-blind, randomized, placebo-controlled trial
Randomization: 1
Blinding: Double-blind (patients, investigators, and assessors)
Enrollment Period: March 2019 through December 2022
Follow-up Duration: 90 days
Centers: 112
Countries: United States, Canada
Sample Size: 458
Analysis: Intention-to-treat; primary outcome analyzed via proportional-odds model adjusted for baseline age, NIHSS, occlusion site, center type, protocol version, and thrombectomy intention. Sensitivity analyses and multiple imputation used.
Inclusion Criteria
- Age ≥18 years
- Prestroke mRS 0–2
- NIHSS ≥5
- LVO in internal carotid artery or M1/M2 MCA on CTA/MRA
- Can receive drug 4.5–24 hours after last known well
- Perfusion imaging showing ischemic core <70 ml, penumbra/core ratio ≥1.8, and penumbra ≥15 ml
- Drug administration within 90 minutes of qualifying imaging
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Median age (IQR) - yr | 73 (63–82) | 72 (62–79) |
| Female sex no. (%) | 123 (53.5%) | 122 (53.5%) |
| Race or ethnic group - White | 170 (73.9%) | 169 (74.1%) |
| Race or ethnic group - Black | 32 (13.9%) | 31 (13.6%) |
| Median NIHSS score (IQR) | 12 (8–18) | 12 (8–17) |
| Occlusion site - Internal carotid artery | 17 (7.4%) | 20 (8.8%) |
| Occlusion site - M1 | 117 (50.9%) | 110 (48.2%) |
| Occlusion site - M2 | 84 (36.5%) | 89 (39.0%) |
| Median time last known well to randomization (hr) | 12.7 (8.7–16.5) | 12.3 (9.2–15.6) |
| Thrombectomy performed | 178 (77.4%) | 176 (77.2%) |
Arms
| Field | Tenecteplase | Control |
|---|---|---|
| Intervention | Tenecteplase 0.25 mg/kg (max 25 mg) as single IV bolus over 5 seconds. Most patients anticipated to undergo thrombectomy. | Matching IV placebo bolus over 5 seconds. Most patients anticipated to undergo thrombectomy. |
| Duration | Single administration with 90-day follow-up | Single administration with 90-day follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Distribution of mRS score at 90 days (ordinal analysis) | Primary | Median 3 (IQR 1–4) | Median 3 (IQR 1–5) | 1.13 | 0.45 |
| Functional independence (mRS 0–2) at 90 days | Secondary | 97/229 (42.4%) | 104/226 (46.0%) | 1.18 | |
| Complete recanalization at 24 hours | Secondary | 124/194 (63.9%) | 148/193 (76.7%) | 1.89 | |
| ≥90% penumbra reduction at 24 hr | Secondary | 105/182 (57.7%) | 99/174 (56.9%) | 1.04 | |
| TICI 2b–3 at thrombectomy completion | Secondary | 152/178 (85.4%) | 156/175 (89.1%) | 1.42 | |
| Death within 30 days | Adverse | 32/214 (15.0%) | 32/218 (14.7%) | ||
| Death within 90 days | Adverse | 39/214 (18.2%) | 43/218 (19.7%) | ||
| Symptomatic intracranial hemorrhage | Adverse | 5/214 (2.3%) | 7/218 (3.2%) | ||
| Parenchymal hematoma Type 1 | Adverse | 1/214 (0.5%) | 2/218 (0.9%) | ||
| Parenchymal hematoma Type 2 | Adverse | 6/214 (2.8%) | 8/218 (3.7%) |
Subgroup Analysis
Prespecified subgroups showed no significant heterogeneity. Among patients with M1 occlusion, adjusted OR favored tenecteplase (1.59; 95% CI, 1.00–2.52). Trial not powered for subgroup conclusions and analyses were not multiplicity-adjusted.
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.
Funding
Genentech (subsidiary of F. Hoffmann–La Roche)
Based on: TIMELESS (The New England Journal of Medicine, 2024)
Authors: G.W. Albers, M. Jumaa, B. Purdon, ..., and B.C.V. Campbell
Citation: N Engl J Med 2024;390:701-11. DOI: 10.1056/NEJMoa2310392
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