TIMELESS Trial: Tenecteplase 4.5-24 Hours with Perfusion-Imaging Selection
In patients with LVO and perfusion-imaging evidence of salvageable tissue presenting 4.5 to 24 hours after stroke onset, does tenecteplase 0.25 mg/kg improve 90-day functional outcome compared with placebo?
Albers GW, et al. (NEJM 2024) · doi:10.1056/NEJMoa2310392 · 458 patients
Population
Included
- ICA or MCA (M1 or proximal M2) occlusion on CTA
- Perfusion imaging mismatch confirming salvageable tissue
- 4.5 to 24 hours from stroke onset
- Age 18 or older
- At least 18 years of age
- Independent function before the stroke (baseline pre-stroke modified Rankin scale score 0 to 2)
- Ischaemic stroke able to receive tenecteplase or placebo 4.5 to 24 hours after the time the patient was last known to be well
- National Institutes of Health Stroke Scale (NIHSS) score of at least 5
- Occlusion of the internal carotid artery (cervical or intracranial) or the M1 or M2 segment of the middle cerebral artery, or both, on CT angiography or magnetic resonance angiography
- Evidence of salvageable brain tissue on CT perfusion or perfusion-diffusion MRI: an ischaemic core volume of less than 70 mL, a ratio of the volume of ischaemic tissue to the initial infarct volume of at least 1.8, and an absolute volume of potentially reversible ischaemia (penumbra) of at least 15 mL
- Administration of tenecteplase or placebo required within 90 minutes after the qualifying imaging of the head
Excluded
- ASPECTS below 6 on CT or DWI-ASPECTS below 6 on MRI
- Contraindication to thrombolysis
- No large vessel occlusion on imaging
- No evidence of salvageable tissue on perfusion imaging by the prespecified RAPID software criteria
- No qualifying large-vessel occlusion of the internal carotid artery or M1 or M2 segment
- Pre-stroke disability (modified Rankin scale score greater than 2)
- Standard contraindication to thrombolytic therapy
Source: Albers GW et al. (TIMELESS), NEJM 2024;390:701-711· Retrieved 2026-06-09
Primary Outcome — mRS Distribution at 90 Days
All randomized patients (458 patients, 77% underwent EVT)
Study Arms
- Agent
- Tenecteplase
- Dose
- 0.25 mg/kg (maximum 25 mg)
- Route
- IV
- Frequency
- Single bolus over a period of 5 seconds
- Duration
- One-time, given 4.5 to 24 hours after last known well
- Co-interventions
- Tenecteplase was given as soon as possible, ideally before the arterial puncture for a planned endovascular thrombectomy. 77.3% of enrolled patients subsequently underwent thrombectomy. All patients received medical care per institutional protocols and AHA-ASA guidelines.
Late-window thrombolysis selected by CT or MRI perfusion mismatch (ICA or MCA occlusion with salvageable tissue). The trial was neutral: tenecteplase did not improve the 90-day ordinal mRS distribution (adjusted common OR 1.13, 95% CI 0.82-1.57, P=0.45). Because most patients underwent thrombectomy, the result applies to the bridging context, not to thrombolysis alone in the late window.
- Agent
- Matching placebo
- Route
- IV
- Frequency
- Single bolus over a period of 5 seconds
- Duration
- One-time
- Co-interventions
- Placebo was given as soon as possible, ideally before the arterial puncture for a planned endovascular thrombectomy. Endovascular thrombectomy and medical care followed institutional protocols and AHA-ASA guidelines.
Trial Design
Type
- Multicenter, double-blind, placebo-controlled trial
- ICA/MCA occlusion with salvageable tissue 4.5-24 hours
- Most patients subsequently underwent EVT
Timeline
NEJM 2024
N
458
Enrollment
Multicenter, double-blind, placebo-controlled trial. ICA or MCA occlusion with CTP-confirmed salvageable tissue. 4.5-24 hours from onset. Published NEJM 2024. 77% of patients proceeded to EVT.
ClinicalTrials.gov
NCT03785678Bedside Pearl
TIMELESS is not evidence against late-window IVT in all settings. It is specifically negative for bridging tenecteplase before thrombectomy in the 4.5-24 hour window (77% of patients underwent EVT). The contrast is TRACE-III: in perfusion-selected LVO patients without EVT access, late-window tenecteplase improved mRS 0-1 from 24.2% to 33.0% (NNT 11). The rule is: late-window IVT may help when EVT is unavailable; it adds nothing as a bridge when EVT is being performed.
See also