Study on Tenecteplase vs Alteplase

In a dose of 0.4 mg/kg, tenecteplase yielded worse safety and functional outcomes compared with alteplase in a prematurely terminated study. The study failed to establish non-inferiority of tenecteplase to alteplase in moderate and severe ischaemic stroke, according to a recent study published in The Lancet Neurology.

Tenecteplase is a modified tissue plasminogen activator with pharmacological and practical advantages over alteplase—which is currently the only approved thrombolytic drug for ischaemic stroke. The NOR-TEST trial showed that 0.4 mg/kg of tenecteplase had an efficacy and safety profile similar to that of a standard dose (0.9 mg/kg) of alteplase, albeit in a patient population with a high prevalence of minor stroke. The aim of NOR-TEST 2 was to establish the non-inferiority of tenecteplase 0.4 mg/kg to alteplase 0.9 mg/kg for patients with moderate or severe ischaemic stroke.

This phase 3, randomised, open-label, blinded endpoint, non-inferiority trial was performed at 11 hospitals with stroke units in Norway. Patients with suspected acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or more who were eligible for thrombolysis and admitted within 4.5 hours of symptom onset were consecutively included. Random assignment, done by a computer with a block size of 4 and with allocations placed into opaque envelopes to be opened consecutively, was 1:1 between intravenous tenecteplase (0.4 mg/kg) or standard-dose alteplase (0.9 mg/kg). Doctors and nurses providing acute care were not masked to treatment, but primary outcome assessment at 3 months was masked.

The primary outcome was a favourable functional outcome defined as a modified Rankin Scale score of 0–1 at 3 months, assessed in the modified intention-to-treat analysis (excluding patients who did not qualify for thrombolysis after randomisation or who withdrew informed consent). The non-inferiority margin was 3%. This trial (NOR-TEST 2) is registered with EudraCT (number 2018–003090–95) and ClinicalTrials.gov (NCT03854500). The trial was stopped early for safety reasons and is designated part A for analysis. Part B is ongoing with a lower dose of tenecteplase (0.25 mg/kg).

Findings of the Study

• Between Oct 28, 2019, and Sept 26, 2021, 216 patients were enrolled.
• Patient enrolment was stopped after a per-protocol safety review showed an imbalance in the rates of symptomatic intracranial haemorrhage between the treatment groups, which surpassed the prespecified criteria for stopping the trial.
• Of 204 patients entering the modified intention-to-treat analysis, 100 were randomly allocated tenecteplase, and 104 were allocated alteplase.
• All patients were followed up within 14 days of the end of the 3-month follow-up period. A favourable functional outcome was reported less frequently in tenecteplase patients than in alteplase.
• Any intracranial haemorrhage was significantly more frequent with tenecteplase than with alteplase.
• Mortality at 3 months was also significantly higher with tenecteplase (15 [16%] of 96 patients) than with alteplase.
• Numerically more cases of symptomatic intracranial haemorrhage were reported with tenecteplase.

Thus, in this prematurely terminated study (terminated to fulfil the prespecified safety criteria), tenecteplase at a dose of 0.4 mg/kg yielded worse safety and functional outcomes than alteplase. Their study consequently could not show that 0.4 mg/kg tenecteplase is non-inferior to alteplase in moderate and severe ischaemic stroke. Future stroke trials should assess a lower dose of tenecteplase versus alteplase in moderate or severe stroke patients.

Reference

Tenecteplase versus alteplase for managing acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial by Christopher Elnan Kvistad, et al. published in The Lancet Neurology.

DOI: https://doi.org/10.1016/S1474-4422(22)00124-7