A multicenter, prospective, randomized, open-label, blinded endpoint trial of intravenous thrombolysis with tenecteplase for acute non-large vessel occlusion in extended time window (OPTION): Rationale and design

Trial design

OPTION is a phaseⅢ, multicenter, prospective, randomized, open-label, blinded endpoint (PROBE), controlled clinical trial, aiming to investigate the superiority of intravenous tenecteplase, compared with standard medical treatment, to increase 90-day excellent outcome in patients with acute non-LVO stroke and evidence of salvageable brain tissue on baseline computed tomography perfusion (CTP) imaging who are treatable between 4.5-24 h of symptom onset (Figure 1). The OPTION trial is being conducted in compliance with the Declaration of Helsinki principles and is registered at ClinicalTrials. gov (NCT05752916). The protocol has received approval from Institutional Review Boards (IRB) at all participating sites before enrollment (IRB with Xuanwu Hospital, Capital Medical University with number [2022]205). Written informed consent was obtained from all subjects or from their legally authorized representatives before the study. The trial is being performed in approximately 50 centers in China.

Figure 1

Study Flow Chart. mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; CT, computed tomography; CTA, computed tomography angiography; CTP, computed tomography perfusion imaging; rhTNK- tPA, recombinant human tenecteplase tissue-type plasminogen activator; EQ-5D-5L, EuroQoL 5-Dimensions 5-Level questionnaire; BI, Barthel Index.

Patient population

Patients with AIS due to non-LVO presenting between 4.5-24 h from last-seen-well (including wake-up stroke and unwitnessed stroke), baseline the National Institutes of Health Stroke Scale (NIHSS) from 6 to 25 (or 4 to 5 with disabling deficit) and target mismatch profile on CTP (defined as ischemic core volume <50 mL, a mismatch ratio ≥1.2, and a mismatch volume ≥10 mL) are enrolled into this trial. Based on these imaging criteria, the study population primarily includes patients with acute intracranial non-large vascular occlusions, including the M2 (vertical MCA branches) or more distal segments of MCA, anterior cerebral artery (ACA), posterior cerebral artery (PCA), anterior inferior cerebellar artery (AICA), posterior inferior cerebellar artery (PICA), superior cerebellar artery (SCA), as well as those with large- to medium-vessel stenosis, or a combination of both. The detailed inclusion and exclusion criteria are presented in Table 1.

Randomization and blinding

Patients are randomized, in a 1 : 1 ratio, using a minimization process to receive either intravenous tenecteplase or standard medical treatment, stratified by vessel occlusion location (anterior or posterior circulation), age (<65 or ≥65 years), baseline NIHSS (<16 or ≥16) and center. The randomization will be done by a computerized central interactive web response system. All endpoints will be evaluated by an independent investigator who is unaware of the treatment group.

Intervention

Patients allocated in the interventional arm will receive intravenous tenecteplase at 0.25 mg/kg, not exceeding a maximum dose of 25 mg. Each vial of tenecteplase is reconstituted with 3 mL of sterile water for injection and injected based on body weight in a single bolus over 5-10 seconds.

Patients allocated in the control arm will receive antiplatelet therapy (aspirin or clopidogrel alone) at the discretion of local investigators.

All enrolled patients are treated according to the 2023 Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke and 2022 Chinese Guideline for the Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack.^[24,25] Patients who are planned or anticipated to be treated with endovascular thrombectomy (EVT) are excluded from the trial. No antiplatelet therapy (e.g. aspirin, clopidogrel, ticagrelor, or glycoprotein IIb/IIIa inhibitors) should be administered within 24 h after tenecteplase. Oral or parenteral anticoagulants (e.g. warfarin, dabigatran, heparin, low molecular weight heparin, argatroban) are prohibited for the first 24 h in both arms. Close attention should be paid to patient’s changes of symptoms and signs in order to detect bleeding events in time. The management of bleeding events should follow the clinical routine and be taken immediately.

Clinical and imaging evaluation

Study visits are performed at the screening period, 0 h, 24 (-2/+12) hours, 48 (±6) hours, 7 (±2) days/discharge (whichever is earlier), and 90 (±7) days. During the screening period, all participants undergo CT, computed tomography angiography (CTA), and CTP after clinical evaluation. Clinical examination and radiological follow-up with CT, CTA, and CTP are performed at 24 (-2/+12) hours. If symptom deterioration with suspected intracranial hemorrhage occurs during hospitalization, an immediate CT scan should be performed. A non-contrast CT is recommended to be done, if possible, at 7 (±2) days or at discharge. At baseline and follow-up visits, clinical evaluation includes vital signs, concomitant medications, NIHSS and modified Rankin Scale (mRS) score. At 90 (±7) days, mRS, EuroQoL 5-Dimensions 5-Level questionnaire (EQ-5D-5L) and Barthel Index (BI) are assessed via a standardized telephone interview. All trial procedures are summarized in Table 2.

If a suspected or confirmed serious adverse event (SAE) occurs, necessary assessments should be performed according to the protocol. The SAEs will be reviewed by the Clinical Events Committee (CEC).

Primary outcome

The primary outcome is the proportion of excellent functional outcome defined as an mRS of 0-1 at 90 (±7) days.

Secondary outcomes

There are seven secondary outcomes, (1): Disability level (ordinal mRS score) at 90 (±7) days; (2): Proportion of functional independence (mRS of 0-2) at 90 (±7) days; (3): Proportion of reperfusion at 24 (-2/+12) h, defined as >90% reduction in Tmax >6 s lesion volume by CTP; (4): Infarct volume at 24 (-2/+12) h, measured by CT scan at 24 (-2/+12) h; (5): Proportion of early clinical response at 24 (-2/+12) h, defined as a NIHSS score of 0 or 1 or NIHSS drop of ≥8 from baseline; (6): NIHSS change from baseline at 7 (±2) days/discharge (whichever is earlier); (7): Health status and quality of life (EQ-5D-5L) at 90 (±7) days.

Safety outcomes

The safety outcomes are (1): Proportion of patients with sICH within 36 h, as defined by Heidelberg bleeding classification;^[26] (2): Proportion of systemic bleeding within 90 (±7) days, as defined by The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO): moderate and severe bleeding; (3): Mortality within 90 (±7) days.

Sample size estimation

The sample size is based on the primary outcome. Based on the reported pooled data of the stroke thrombolysis trials in the extended time window,^[27] we expect a 12% absolute difference in the proportion of patients reaching the primary outcome between patients treated with tenecteplase and standard medical treatment (expected rate of excellent functional outcome 50% in patients treated with tenecteplase and 38% in patients treated with standard medical treatment). Considering the potential impact of one interim efficacy analysis on the probability of type I error, we adjusted the alpha error to a two-sided alpha of 0.049. The total sample size of 568 (n = 284 per treatment group) will have 80% power to detect the specified difference at the two-sided 0.049 significance level, with a 5% dropout rate.

One efficacy interim analysis is planned when 50% of the target sample size has completed 90-day follow-up. A Lan-DeMets alpha spending function will be used to control the overall alpha level, using O’Brien and Fleming boundaries (corresponding to an alpha level of 0.003 and 0.049 at the interim and final analysis, respectively).

Statistical analysis

The analysis population for the efficacy analyses will be performed on the intention-to-treat (ITT) population. For the primary outcome, the proportions of mRS 0-1 at 90 (±7) days will be compared between two treatment groups using a modified Poisson regression. The risk ratio (RR) and its 95% confidence interval (CI) will be reported. We will also perform adjusted analysis of the primary outcome with adjustment for pre-specified covariates.

The distribution of mRS score at 90 (±7) days will be analyzed using ordinal logistic regression, with treatment effect reported as a common odds ratio and its corresponding 95% CI. If the proportional odds hypothesis is rejected, the generalized odds ratio (GenOR) with 95% CI will be calculated. For binary secondary efficacy endpoints, modified Poisson regression model will be employed to determine RR and its 95% CI. For continuous secondary efficacy endpoints, linear regression models will be employed to estimate mean difference as a measurement of treatment effect. In case the normality assumption for the residuals is violated, win ratio will be calculated. Safety analyses will be performed on the safety population who received one of the study interventions according to the treatment they actually received. Safety endpoints will be compared using the modified Poisson regression. Subgroup analyses include age (<65 years and ≥ 65 years), time from symptom onset (last-seen-well) to randomization (>4.5-9 h and >9-24 h and stroke on awakening), baseline NIHSS score (<10 and ≥10), vessel occlusion location (anterior circulation and posterior circulation), occlusion site (M2 segment of MCA, M3-M4 segment of MCA, ACA, PCA and stenosis), baseline serum glucose (<100 mg/dL and ≥100 mg/dL) and baseline systolic blood pressure (≤140 mmHg and >140 mmHg).

Three safety interim analyses were planned when the first 100, 200, 300 patients have completed the 90-day follow-up. One efficacy interim analysis was planned to be conducted when 50% of the total patients have completed the 90-day follow-up. All statistical analyses will be performed following a statistical analysis plan (SAP) which will be finalised before the database lock and unblinding of the trial. SAS software version 9.4 (SAS Institute) and R version 4.4.1 will be used for the statistical analyses.

Data safety and monitoring board

An independent data safety and monitoring board (DSMB) will regularly monitor the safety of the trial and guarantee the safety of all patients. The DSMB will perform safety reviews when the first 100, 200 and 300 patients are enrolled and complete 90-day follow-up. If there are concerns about safety, the DSMB will make a recommendation to the trial steering committee about continuing, stopping or modifying the trial. One prespecified efficacy interim analysis will be performed when 284 patients have completed 90-day follow-up. Results of the interim analysis will only be presented to the DSMB.

Due to the fast speed of enrollment, after review with the DSMB in June 2025, the original interim analysis plan was considered no longer to serve its purpose. On the recommendation of the DSMB, the steering committee rescinded the planned efficacy interim analysis and the third safety analysis. Since no formal assessment of efficacy is done and no alpha is spent, we will not adjust the alpha level or p values for the final analysis.

Study organization and funding

OPTION is an investigator initiated clinical trial. It is sponsored by Yangfan 3.0 Diagnosis and Treatment Capability Enhancement Project (ZLRK202514) and CSPC Recomgen Pharmaceutical (Guangzhou) Co., LTD (Guangzhou, China). The funders have no role in the design, conduct, statistical analysis or reporting of the results. A steering committee provides scientific and strategic guidance for the trial. An executive committee manages the day-to-day activities of the trial. Endpoint events, safety endpoints and SAEs are reviewed by a CEC and all clinical imaging data are independently reviewed by an imaging core laboratory.