NOR-TEST 2 (Part A): Tenecteplase 0.4 mg/kg vs Alteplase in Moderate-Severe Stroke
In patients with moderate-to-severe acute ischemic stroke (NIHSS ≥6) within 4.5 hours, is IV tenecteplase 0.4 mg/kg non-inferior to IV alteplase 0.9 mg/kg for excellent functional outcome (mRS 0-1) at 3 months? (Stopped by DSMB for harm.)
Kvistad CE, et al. (Lancet Neurol 2022) · 204 patients
Population
Included
- Acute ischemic stroke within 4.5 hours of onset
- NIHSS ≥6 (moderate-severe stroke only)
- Standard thrombolysis criteria met
- Age 18 or older
- Clinically suspected acute ischaemic stroke
- Aged 18 years or older
- Living independently before the stroke
- Admitted within 4.5 h of stroke onset
- NIHSS score of 6 or more (moderate to severe stroke)
- Eligible for thrombolytic treatment according to Norwegian guidelines, which are similar to the European guidelines
- Patients undergoing thrombectomy were included if they received thrombolysis as a bridging therapy
Excluded
- Mild stroke (NIHSS <6). Enrolled in NOR-TEST, not NOR-TEST 2
- Contraindication to IV thrombolysis
- Hemorrhagic transformation or large established infarct on baseline imaging
- NIHSS score below 6 (mild stroke)
- Standard contraindications to intravenous thrombolysis per Norwegian and European guideline recommendations
- Conditions identified on per-protocol review as disorders other than stroke (stroke mimics), pre-stroke modified Rankin Scale score of 3 or more, or an established large infarct or haemorrhagic transformation on baseline imaging
Source: Kvistad CE, et al., Lancet Neurol 2022· Retrieved 2026-06-09
Primary Outcome
STOPPED FOR HARM: The DSMB terminated NOR-TEST 2 Part A early after tenecteplase 0.4 mg/kg showed 6× higher sICH (6% vs 1%) and 3× higher mortality (16% vs 5%) versus alteplase. This harm is specific to the 0.4 mg/kg dose and does not apply to tenecteplase 0.25 mg/kg.
Negligible absolute difference
mRS 0-1 at 3 Months
Study Arms
- Agent
- Tenecteplase
- Dose
- 0.4 mg/kg (max 40 mg)
- Route
- IV
- Frequency
- Single bolus
- Duration
- One-time
This 0.4 mg/kg dose in moderate-to-severe stroke was the dose stopped early for harm. Part B continued with a lower dose (0.25 mg/kg). The harm does not apply to the 0.25 mg/kg dose.
- Agent
- Alteplase
- Dose
- 0.9 mg/kg (max 90 mg)
- Route
- IV
- Frequency
- 10% as initial bolus, then remainder over a 1-h infusion
- Duration
- 60 minutes
Safety
Symptomatic intracranial hemorrhage
6%
1%
sICH was 6× higher with tenecteplase 0.4 mg/kg (6% vs 1%), the primary safety signal that prompted DSMB-mandated trial termination.
Mortality at 3 months
16%
5%
Mortality was 3× higher with tenecteplase 0.4 mg/kg (16% vs 5%). This finding was the key harm signal alongside the sICH excess.
Trial Design
Type
- Phase 3, randomized, open-label, blinded-endpoint noninferiority trial
- Moderate to severe acute ischemic stroke only
- Stopped early for safety at tenecteplase 0.4 mg/kg
Timeline
Norway; October 2019 to September 2021
N
204
Enrollment
204 of 432 planned patients. Stopped by DSMB for safety. October 2019 to September 2021. Published Lancet Neurol 2022.
ClinicalTrials.gov
NCT03854500Bedside Pearl
NOR-TEST 2 Part A is a clear harm signal: tenecteplase 0.4 mg/kg in moderate-severe stroke caused 6× more sICH and 3× more deaths than alteplase. The 0.4 mg/kg dose is not used in practice. Current guidelines endorse tenecteplase 0.25 mg/kg as a safe alternative based on entirely separate trials (AcT, TRACE-2). Do not conflate the doses.