A Study of XY03-EA Tablets in the Treatment of Acute Ischemic Stroke

A Multicenter, Randomized, Double-blind, Placebo-parallel Controlled, Dose-exploration Phase Ⅱ Clinical Study to Evaluate the Efficacy and Safety of XY03-EA Tablets in the Treatment of Acute Ischemic Stroke

Overall Design: a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-exploration study.

Main outcome: 1.To evaluate the efficacy and safety of XY03-EA tablets in the treatment of acute ischemic stroke.

The population is patient who with acute ischemic stroke within 48 hours of onset (including RT-PA intravenous thrombolytic therapy) . The patients were randomized based on being received rt-PA Intravenous thrombolysis or not. Patients who met the inclusion criteria for the protocol were stratified randomly and assigned in a 1:1:1 ratio to three groups: the XY03-EA 300mg, 600mg two-dose group, and the placebo group. The study was divided into 3 stages: screening stage, treatment stage and follow-up stage. The sample size was 420 patients.

Main outcome: 1.To evaluate the efficacy and safety of XY03-EA tablets in the treatment of acute ischemic stroke.

Secondary outcome:

1. Explore the dose-response relationship of XY03-EA tablets in the treatment of acute ischemic stroke, and provide data support for later clinical study;
2. Explore PK characteristics of XY03-EA and its metabolites in patients with acute ischemic stroke based on population PK analysis method.

Inclusion Criteria:

1. Age 18-80 years old (including 18 and 80 years old) ；
2. The patients who diagnosed as acute ischemic stroke according to the Chinese guidelines for the diagnosis and treatment of acute ischemic stroke 2018, total or partial anterior circulation infarction according to the Oxfordshire community stroke classification (OCSP) ;
3. For the patients who received standard intravenous thrombolytic therapy, only the patients who received rt-PA standard intravenous thrombolytic therapy within 4.5 hours of onset were enrolled；
4. Before randomization, 6 points ≤ NIHSS score ≤20 points;
5. From"The last time it seemed normal" to ≤48 hours after the beginning of the study , for the patients who had stroke after waking up or because of aphasia, disturbance of consciousness and other reasons can not accurately time the appearance of symptoms, the time of onset should take the last time the patient showed normally as standard;
6. The patients who first attacked, or the patients who relapsed had a good prognosis after the last attacked , their mRS score was ≤1 before the onset of the disease.
7. Understand and follow the procedure of the study, the patient or guardian agrees to participate, and sign the informed consent form.

Exclusion Criteria:

1. Imaging confirmed intracranial hemorrhagic diseases: hemorrhagic stroke, transformation of symptomatic hemorrhage, epidural hematoma, intracranial hematoma, subarachnoid hemorrhage, intraventricular hemorrhage, traumatic intracerebral hemorrhage, etc.
2. The patients who received urokinase thrombolysis after the onset of the disease were prepared to undergo or had undergone intravascular interventional therapy;
3. Severe disturbance of consciousness:People with consciousness disorder can be defined as "NIHSS score Ia ≥2 points"；
4. Neuroprotective drugs, including Edaravone, Edaravone dexborneol , Butylphthalide, Piracetam and Citicoline, were used after the onset of the disease；
5. Renal insufficiency: serum creatinine > 1.2 times the upper limit of normal, or other known severe renal insufficiency;
6. Liver function damage: AST or ALT > 1.5 times the upper limit of normal value, or other known liver diseases such as acute and chronic hepatitis, cirrhosis, etc.
7. Patients with poor blood pressure control after active treatment: systolic blood pressure ≥220mmHg and/or diastolic blood pressure ≥120mmHg; hypotension: systolic blood pressure ≤80mmHg and/or diastolic blood pressure ≤40mmhg;
8. Severe hyperglycaemia/hypoglycaemia: blood glucose ≥400 mg/dl (22.2 mmol/l) or ≤50 mg/dl (2.8 mmol/L) ;
9. Heart rate less than 50 beats/min and/or heart rate greater than 120 beats/min; Second to third degree atrioventricular block; Patients with previous heart failure (NYHA Class III or IV) , unstable angina, acute myocardial infarction, and severe arrhythmia within 6 months;
10. Patients with dementia, severe Parkinson's disease, mental disorders, claudication, osteoarthropathy, and other disorders that may affect the outcome of treatment；
11. Patients with malignancy, hematologic, digestive, or other serious diseases of the system, or the diseases with bleeding tendency (hemophilia, for example) ；
12. Expected survival time ≤3 months;
13. Patients with a history of severe food or drug allergies, or known allergies to butylphthalide, or celery;
14. Pregnant and lactating or planning pregnancy;
15. Those who had met the criteria for heavy drinking within 3 months before the screening period, that is, daily drinking ≥5 standard drinking quantity (1 standard drinking quantity is equal to 120 ml (2.5 units) of wine, 360 ml (1 can) of beer or 45 ml (1 unit) of liquor) ；
16. Patients with substance abuse or addiction in the past year(narcotic or drugs , for example) ；
17. Those who had taken any clinical trial drug or participated in any drug or device clinical trial or participated in other medical research activities in 3 months before screening and were judged not fit to participate in this study by the investigator;
18. Any other circumstances considered by the investigator might affect the informed consent of the subject or adherence to the study protocol, otherwise the participation of the subject in the study might affect the outcome or his or her own safety.