Abstract
IMPORTANCE: Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited. OBJECTIVE: To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset. DESIGN, SETTING, AND PARTICIPANTS: The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement. INTERVENTIONS: Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg). MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality. RESULTS: Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23]). CONCLUSIONS AND RELEVANCE: In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04915729.