Effects of Butylphthalide Enhanced With Tenecteplase on Neurological Function in Mild Disabling Acute Ischemic Stroke

Phase 3Not Yet RecruitingNCT07369999

Xiangya Hospital of Central South University1,062 enrolled

Overview

Abstract Background Intravenous thrombolysis is the cornerstone of early treatment for acute ischemic stroke (AIS), but some still have a poor prognosis, especially in patients with mild disabling stroke. Tenecteplase (TNK), a novel thrombolytic agent with favorable pharmacokinetic profiles, and butylphthalide (NBP), a multi-targeted neuroprotective drug, have shown promising efficacy in separate clinical applications. However, evidence for their combined use in mild disabling AIS is lacking. Aim To determine whether TNK combined with NBP can improve functional outcomes compared with TNK monotherapy in patients with mild disabling AIS who receive thrombolysis within 4.5 hours of onset. Design BENEFIT-2 is a prospective, multicenter, randomized, double-blind, active-controlled trial. Eligible patients are randomized 1:1 to receive either TNK plus NBP (combination group) or TNK plus placebo (control group) via stratified block randomization. The combination group receives sequential NBP sodium chloride injection (25mg/100ml, twice daily for 7 days) and oral NBP soft capsules (0.2g, three times daily) until day 14; the control group receives matching placebos. Eligibility criteria include age 18-80 years, onset time ≤4.5 hours, NIHSS score 2-5 with disabling manifestations (hemianopia, aphasia, or limb weakness), and pre-stroke modified Rankin Scale (mRS) score ≤1. Study outcomes The primary outcome is the proportion of patients with mRS score 0-1 at 90±7 days. Secondary outcomes include changes in NIHSS score, recurrence of ischemic stroke, composite vascular events, quality of life (assessed by EQ-5D scale), and ischemic penumbra salvage rate. Safety outcomes include symptomatic intracranial hemorrhage (sICH), vascular death, all-cause death, and adverse events within 90 days. Discussion BENEFIT-2 is the first large-scale randomized trial to evaluate the synergistic effect of "vascular recanalization + neuroprotection" in mild disabling AIS. By combining TNK and NBP, this study aims to fill the evidence gap and provide a new therapeutic option to improve functional recovery in this specific population.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

Combination GroupDRUG

Combination Group: TNK 0.25 mg/kg (maximum 25 mg) administered as a single intravenous infusion. Immediately after that, NBP 100 ml (25 mg) is initiated as an intravenous infusion, twice daily (bid), for 7 consecutive days. If the hospitalization duration is less than 7 days, oral NBP soft capsules (0.2 g, three times daily \[tid\]) will be started on the day of discharge, and continued until Day 14.

Control GroupDRUG

Control Group: TNK 0.25 mg/kg (maximum 25 mg) administered as a single intravenous infusion. Immediately after that, a 100 ml intravenous infusion of NBP placebo (visually identical to NBP) is initiated twice daily (bid) for 7 consecutive days. If the hospitalization duration is less than 7 days, oral NBP placebo soft capsules (visually identical, 0.2 g, three times daily \[tid\]) will be started on the day of discharge and continued until Day 14.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 1\. Age 18-80 years, regardless of gender. * 2\. Clinically diagnosed with acute ischemic stroke and meets the criteria for tenecteplase intravenous thrombolysis. * 3\. Onset of the current stroke within 4.5 hours. * 4\. Clinical diagnosis of minor ischemic stroke with a NIHSS score of 2-5, accompanied by persistent unilateral limb weakness or speech symptoms, defined as a score ≥1 on either the language item or any one limb item of the NIHSS * 5\. Pre-stroke mRS score ≤1. * 6\. The subject or their legal representative is able and willing to sign the informed consent form. Exclusion Criteria: * 1\. History of intracranial hemorrhage. * 2\. Patients who have received or plan to undergo mechanical thrombectomy. * 3\. History of major head trauma or stroke within the past 3 months. * 4\. Known severe liver/kidney dysfunction or patients receiving dialysis (severe liver dysfunction: ALT/AST \>3 times the upper limit of normal; severe kidney dysfunction: serum creatinine \>3.0 mg/dl \[265.2 μmol/L\] or GFR \<30 ml/min/1.73 m²). * 5\. Systolic blood pressure \<90 mmHg or \>220 mmHg. * 6\. Patients with bradycardia (heart rate \<60 beats/min) or sick sinus syndrome. * 7\. History of drug/food allergy or known allergy to the components of the study drugs. * 8\. Patients treated with drugs containing butylphthalide after stroke onset. * 9\. History of congenital/acquired hemorrhagic diseases, coagulation factor deficiency, or thrombocytopenic diseases. * 10\. Pregnant or lactating subjects or subjects planning to become pregnant within 90 days. * 11\. Subjects with severe mental disorders or dementia who cannot cooperate with informed consent and follow-up. * 12\. Subjects with concurrent malignant tumors or severe systemic diseases, with an expected survival of \<90 days. * 13\. Patients who have participated in other clinical interventional studies within 30 days prior to randomization, or who are currently participating in other clinical interventional studies; * 14\. Patients who are unable to complete follow-up visits as scheduled; * 15\. Any other reasons that, in the investigator's opinion, render the patient unsuitable for participation in the study.

Outcomes

Primary Outcomes

Proportion of patients with Modified Rankin Scale score 0-1 (scores 0 = fully asymptomatic to 6 = death)

Time frame: From enrollment to the end of treatment at 90 days

Secondary Outcomes

proportion of patients with Modified Rankin Scale score 0-2 (scores 0 = fully asymptomatic to 6 = death)

Time frame: From enrollment to the end of treatment at 90 days

Proportion of patients with National Institutes of Health Stroke Scale score improvement ≥2 points at 90±7 days compared with baseline. (0-42, higher scores indicate more severe neurological impairment)

Time frame: at 90±7 days compared with baseline.

Changes in National Institutes of Health Stroke Scale score from baseline to 6±1 days and 90±7 days. (0-42 points,higher scores indicate more severe neurological impairment)

Time frame: From enrollment to 6±1 days and 90±7 days

Incidence of early neurological deterioration (NIHSS score increase ≥4 points) at 24±2 hours and 6±1 days.

Time frame: From enrollment to 24±2 hours and 6±1 days.

Recurrence rate of ischemic stroke

Time frame: From enrollment to 90±7 days.

Proportion of composite vascular events (stroke recurrence, myocardial infarction, vascular death)

Time frame: From enrollment to90±7 days.

Ischemic penumbra salvage rate (change in DWI/PWI mismatch volume from baseline to 6±1 days).

Time frame: from baseline to 6±1 days

Quality of life assessed by the EQ-5D scale (utility score and visual analog scale)