Effects of Butylphthalide Enhanced With Tenecteplase on Neurological Function in Mild Disabling Acute Ischemic Stroke (BENEFIT-2)

Central South University

Status and phase

Not yet enrolling

Phase 3

Conditions

Mild Disabling Acute Ischemic Stroke

Treatments

Drug: Combination Group

Drug: Control Group

Study type

Interventional

Funder types

Other

Identifiers

NCT07369999

202512130

Details and patient eligibility

About

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.

Enrollment

1,062 estimated patients

Sex

All

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

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. Mild disabling stroke defined as NIHSS score 2-5, with at least one of the following disabling manifestations:
(a) complete hemianopia (NIHSS item 3 score ≥2);
(b) severe aphasia (NIHSS item 9 score ≥2);
(c) limb weakness (NIHSS item 6 or 7 score ≥2, unable to resist gravity).
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. Patients with posterior circulation stroke.
5. Inability to complete MRI follow-up.
6. 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).
7. Systolic blood pressure <90 mmHg or >220 mmHg.
8. Patients with bradycardia (heart rate <60 beats/min) or sick sinus syndrome.
9. History of drug/food allergy or known allergy to the components of the study drugs.
10. Patients treated with drugs containing butylphthalide after stroke onset.
11. History of congenital/acquired hemorrhagic diseases, coagulation factor deficiency, or thrombocytopenic diseases.
12. Pregnant or lactating subjects or subjects planning to become pregnant within 90 days.
13. Subjects with severe mental disorders or dementia who cannot cooperate with informed consent and follow-up.
14. Subjects with concurrent malignant tumors or severe systemic diseases, with an expected survival of <90 days.