The Norwegian Tenecteplase Stroke Trial (NOR-TEST)

By Dr. Klearchos Psychogios

Even in the era of mechanical thrombectomy which was inaugurated with the major trials of 2015, the quest for new thrombolytics is ongoing. Tenecteplase (TNK) is a three-point mutated variant of alteplase that has been used for many years as the thrombolytic agent of choice for myocardial infarction. It has several significant pharmacological advantages, including higher fibrin specificity, increased resistance to plasminogen activator inhibitor-1, and a longer half-life that allows TNK to be administered as a single bolus injection. Until 2017, only one small randomized phase 2b trial (1) showed that TNK was superior to alteplase in patients with penumbra and large vessel occlusion who were selected by imaging.

At ESOC 2017, held in Prague, Prof. Logallo from the University Hospital of Bergen from Norway presented the NOR-TEST trial. NOR-TEST trial was the first pragmatic multicenter phase 3 superiority trial, which enrolled patients eligible for standard alteplase treatment. For this study which was conducted in 13 stroke units in Norway, 1107 patients with ischemic stroke were randomly assigned within 4.5 hours of symptom onset to tenecteplase, at the dose of 0.4 mg/kg bolus, or alteplase, 0.9 mg/kg infusion. Patients with an increased bleeding risk and those with a pre-stroke modified Rankin Scale (mRS) score of 3 or more were excluded.

Results showed that the primary endpoint, an excellent outcome (mRS score of 0 – 1) at 3 months, did not significantly differ between the two groups as it was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group. The secondary outcome of neurologic improvement (NIHSS in 24 hours) and the frequency of serious adverse events were also similar between groups.

Despite the fact that NOR-TEST was a “negative” trial because it lacked the statistical power to show a large treatment effect, it assisted in paving the way for further trials (2) and metanalyses (3) that demonstrated TNK’s efficacy and safety, and ultimately resulted in the drug’s recent approval for the treatment of acute ischemic stroke by the European Medicines Agency (EMA) (4).

References
1. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099-1107. doi:10.1056/NEJMoa1109842
2. Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400(10347):161-169. doi:10.1016/S0140-6736(22)01054-6
3. Palaiodimou L, Katsanos AH, Turc G, et al. Tenecteplase for the treatment of acute ischemic stroke in the extended time window: a systematic review and meta-analysis. Ther Adv Neurol Disord. 2024;17:17562864231221324. Published 2024 Jan 6. doi:10.1177/17562864231221324
4. Metalyse – opinion on variation to marketing authorisation. European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/variation/metalyse