A Phase Ⅱb Study of XY03-EA Tablets in Acute Ischemic Stroke

Study Background and Rationale Acute ischemic stroke (AIS) is a leading cause of death and long-term disability worldwide. Despite advances in reperfusion therapies, including intravenous thrombolysis and endovascular thrombectomy, a substantial proportion of patients still experience poor functional outcomes, highlighting an unmet need for effective neuroprotective strategies that can salvage ischemic brain tissue and improve neurological recovery.

XY03-EA is a novel oral neuroprotective agent developed for the treatment of AIS. Preclinical pharmacodynamic and pharmacological studies have demonstrated that XY03-EA exerts neuroprotective effects by promoting reactive oxygen species (ROS) clearance and modulating autophagy-related proteins and signaling pathways in neural cells. These mechanisms significantly improve neurological function impaired by cerebral ischemia, with low toxicity and high activity observed in non-clinical studies.

Study Design This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase Ⅱb/Ⅲ clinical study conducted to evaluate the efficacy and safety of XY03-EA tablets in the treatment of acute ischemic stroke and to explore the dose-response relationship. The study was designed as a seamless Phase Ⅱb/Ⅲ trial; the Phase Ⅱb stage served as a dose-exploration phase to provide data support for the subsequent Phase Ⅲ stage.

Eligible patients were aged 18 to 80 years, diagnosed with acute ischemic stroke according to the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke (2023), classified as total or partial anterior circulation infarction by the Oxfordshire Community Stroke Project (OCSP) classification, with a National Institutes of Health Stroke Scale (NIHSS) score of 6 to 20, and enrolled within 48 hours from the time they were last seen normal.

In the Phase Ⅱb stage, 360 eligible subjects were enrolled and randomly assigned in a 1:1:1:1:1 ratio to four XY03-EA dose groups or one placebo group. Study treatment was administered for up to 90 days, with follow-up assessments conducted at scheduled time points.

Endpoints The primary efficacy endpoint was the proportion of patients with a modified Rankin Scale (mRS) score ≤ 1 at Day 90 after the start of study treatment. Secondary efficacy endpoints included the proportion of patients with mRS ≤ 2 at Day 14 (discharge), Day 30, and Day 90; the proportion of patients with mRS ≤ 1 at Day 30; the change from baseline in NIHSS score at Day 14 (discharge), Day 30, and Day 90; the proportion of patients with NIHSS ≤ 1 or a decrease of ≥ 4 points from baseline at Day 30 and Day 90; the proportion of patients with a Barthel Index (BI) ≥ 95 at Day 90; the change from baseline in Mini-Mental State Examination (MMSE) score at Day 90; and the proportion of patients with new vascular events (ischemic stroke, hemorrhagic stroke, transient ischemic attack, myocardial infarction, or vascular death) within 90 days after treatment. Safety was assessed throughout the study by monitoring adverse events, laboratory tests, vital signs, and physical examinations.

**Inclusion Criteria:**

• Age 18 to 80 years, inclusive (including both 18 and 80 years);
• Patients diagnosed with acute ischemic stroke according to the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke (2023), classified as total or partial anterior circulation infarction by the Oxfordshire Community Stroke Project (OCSP) classification;
• National Institutes of Health Stroke Scale (NIHSS) score of 6 to 20 at randomization;
• Time from "last seen normal" to initiation of study drug treatment ≤ 48 hours. For wake-up stroke, or when the time of symptom onset cannot be accurately determined due to aphasia, impaired consciousness, or other reasons, the time at which the patient was last seen to be normal shall be used;
• Patients with a first onset, or a recurrent onset with good recovery from the previous episode (modified Rankin Scale [mRS] score ≤ 1 before the current episode);
• The patient must understand and comply with the study procedures, voluntarily consent to participate, or have consent provided by a legal guardian, and sign the informed consent form.

**Exclusion Criteria:**

Subjects who meet any of the following criteria will be excluded:

• Hemorrhagic cerebrovascular disease confirmed by imaging: cerebral hemorrhage, subarachnoid hemorrhage, subdural and epidural hemorrhage, symptomatic hemorrhagic transformation, etc.;
• Patients who have received or intend to receive vascular recanalization therapy (intravenous thrombolysis or endovascular intervention);
• Severe disturbance of consciousness: NIHSS item 1a (level of consciousness) score ≥ 2;
• Use of neuroprotective agents after the onset of the current episode, including edaravone, edaravone dexborneol, butylphthalide, piracetam, citicoline, urinary kallidinogenase, etc.;
• Renal insufficiency: serum creatinine > 1.5 times the upper limit of normal, or other known severe renal insufficiency diseases;
• Abnormal liver function: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times the upper limit of normal, or other known liver diseases such as acute or chronic hepatitis, cirrhosis, etc.;
• Poor blood pressure control despite active treatment: systolic blood pressure ≥ 220 mmHg and/or diastolic blood pressure ≥ 120 mmHg; hypotension: systolic blood pressure ≤ 80 mmHg and/or diastolic blood pressure ≤ 40 mmHg;
• Severe hyperglycemia or hypoglycemia: blood glucose ≥ 400 mg/dL (22.2 mmol/L) or ≤ 50 mg/dL (2.8 mmol/L);
• Heart rate < 50 beats/min or > 120 beats/min; second- or third-degree atrioventricular block; heart failure (New York Heart Association [NYHA] Class III or IV), unstable angina, acute myocardial infarction, or severe arrhythmia within the previous 6 months;
• Dementia, severe Parkinson's disease, mental disorders, limb dysfunction caused by claudication, osteoarthropathy, or other diseases, and other diseases that may affect the assessment of efficacy;
• Patients with malignant tumors, severe diseases of the hematologic, digestive, or other systems, or diseases with a bleeding tendency (e.g., hemophilia);
• Expected survival ≤ 3 months;
• Patients with a history of severe food or drug allergy, or known allergy to butylphthalide or celery;
• Patients who are pregnant, lactating, or planning pregnancy;
• Those who met the criteria for heavy drinking within 3 months before screening, i.e., daily drinking ≥ 5 standard drinks (1 standard drink equals 120 mL [approximately 2.5 liang] of wine, 360 mL [1 can] of beer, or 45 mL [approximately 1 liang] of liquor);
• Patients with drug abuse or addiction (e.g., narcotics or illicit drugs) within the past year;
• Those who have taken any investigational drug, or participated in any drug or device clinical trial or other medical research activities within 3 months before screening, and who were judged by the investigator to be unsuitable for participation in this study;
• Any other circumstances that, in the investigator's judgment, may affect the subject's ability to provide informed consent or compliance with the study protocol, or that may affect the study outcomes or the subject's safety.