Efficacy and Safety of Calculus Bovis Sativus (CBS) for Ischemic Cerebral Vascular Disease (CBSinICVD)

Exclusion Criteria

• •1. Medical History and Current Health Status 1.1. Any clinically significant cardiac, endocrine, hematologic, hepatic, immune, infectious, metabolic, urologic, pulmonary, neurological, dermatologic, psychiatric, and renal disease or other major medical history that the investigator determines would preclude participation in the clinical trial.
• •1.2. Any untreated teratoma or thymoma at the baseline visit (randomization) 1.3. Other causes of symptoms, including CNS infection, septic encephalopathy, metabolic encephalopathy, epileptic disorders, mitochondrial disease, Klein-Levin syndrome, Creutzfeldt-Jakob disease, rheumatic disease, Reyes syndrome, or inborn errors of metabolism.
• •1.4. History of herpes simplex encephalitis within the previous 24 weeks. 1.5. Any surgical procedure within 4 weeks prior to baseline, except laparoscopic surgery or minor surgery (defined as surgery requiring only local anesthesia or conscious sedation, i.e., surgery that does not require general, neuraxial, or regional anesthesia and can be performed on an outpatient basis; e.g., toenail surgery, mole surgery, wisdom tooth extraction), excluding thymoma or teratoma removal.
• •1.6. Planned surgery during the study (except minor surgery). 1.7. History of severe allergic or anaphylactic reactions, or any allergic reaction that the investigator believes may be exacerbated by any component of study treatment.
• •1.8. Current or history of malignant disease, including solid tumors and hematologic malignancies (except for basal cell carcinoma and squamous cell carcinoma that have been completely resected and considered cured for at least 12 months prior to Day -1). Subjects with cancer remission for more than 5 years prior to baseline (Visit 1) may be included after discussion with the sponsor/sponsor approval.
• •1.9. A history of gastrointestinal surgery (except appendectomy or cholecystectomy performed more than 6 months before screening), irritable bowel syndrome, inflammatory bowel disease (Crohn's disease, ulcerative colitis), or other clinically significant active gastrointestinal diseases in the opinion of the investigator.
• •1.10. A history of clinically significant recurrent or active gastrointestinal symptoms (e.g., nausea, diarrhea, dyspepsia, constipation) within 90 days before screening, including the need to start symptomatic treatment (e.g., start medication for gastroesophageal reflux disease) or a change in symptomatic treatment within 90 days before screening (e.g., dose increase).
• •1.11. A history of diverticulitis or concurrent severe gastrointestinal (GI) abnormalities (e.g., symptomatic diverticular disease) because the investigator believes that this may lead to an increased risk of complications such as GI perforation.
• •1.12. A history of blood donation (1 unit or more), plasma donation, or platelet donation within 90 days before screening.
• •1.13. Active suicidal ideation within 6 months before screening, or a history of suicide attempt within 3 years before screening.
• •1.14. Based on the investigator's judgment, there are serious diseases or abnormalities in the clinical laboratory test results that prevent the patient from completing the study or participating in the study safely.
• •1.15. Pregnant or lactating, or planning to become pregnant during the study or within 3 months after the last dose of the study drug; women of childbearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result before the start of the study.
• •1.16. The subject's mental or physical condition will hinder the evaluation of efficacy and safety.
• •1.17. Systolic blood pressure \>150 mmHg or \<90 mmHg after sitting still for 5 minutes or before dosing at screening. If out of range, it can be measured again at screening and before dosing. If the repeated measurement value is still out of range, the subject shall not receive the drug.
• •1.18. Subjects with second or third degree atrioventricular block or sick sinus syndrome, poorly controlled atrial fibrillation, severe or unstable angina, congestive heart failure, myocardial infarction, or significant ECG abnormalities, including QTc\>450 msec (male) or 470 msec (female), where QTc is determined based on the Fridericia correction method, within 3 months prior to the screening visit.
• •1.19. Planned elective procedures or surgeries at any time after signing the ICF by follow-up visit.
• •1.20. Any condition that affects the absorption of study treatment (e.g., gastrectomy).
• •1.21. History of hypersensitivity to heparin or history of heparin-induced thrombocytopenia.
• •1.22. Subjects with abnormalities in medical history, physical examination, ECG, or diagnostic laboratory tests that the investigator considers to be clinically relevant.
• •2. Risk of infection 2.1. History of human immunodeficiency virus (HIV) or positive test results at screening.
• •2.2. Current infection with hepatitis C (defined as positive HCV antibodies and detectable HCV RNA). Subjects with positive HCV antibodies and HCV RNA below the limit of detection are eligible to participate in the study.
• •2.3. Current infection with hepatitis B (defined as positive HBsAg and/or positive total anti-HBc). Subjects who are immune to hepatitis B after previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
• •2.4. Chronic, recurrent, or severe infection (e.g., pneumonia, sepsis) within 90 days prior to baseline (visit 1).
• •2.5. History of TB diagnosis or positive latent TB test result (defined as positive IGRA test result or 2 consecutive times.
• •2.6. Symptoms of bacterial, fungal, or viral infection (including upper respiratory tract infection) within 28 days prior to baseline (visit 1). Subjects with localized fungal infection (e.g., candidiasis, tinea) are eligible for rescreening after successful treatment of the infection.
• •2.7. Infection requiring hospitalization or IV anti-infective medication within 4 weeks prior to baseline visit.
• •2.8. Any live or live attenuated vaccine within 28 days prior to baseline (visit 1) or planned during the study.
• •2.9. Contraindications to all of the following salvage therapies: rituximab, IVIG, high-dose corticosteroids, or IV cyclophosphamide.
• •2.10. History of or receipt of the following treatments:
• •1. Total lymphoid irradiation, cladribine, T-cell or T Cell recipient vaccination, total body irradiation, or total lymphoid irradiation at any time.
• •2. Stem cell transplantation at any time.
• •3. Laboratory Values 3.1. Abnormal laboratory values determined by the investigator to be clinically significant at Screening or Baseline (Visit 1).
• •3.2. Any of the following blood test abnormalities at Screening:
• •1. WBC \< 3.0 × 103/µL
• •2. ANC \< 2.0 × 103/µL
• •3. Absolute lymphocyte count \< 0.5 × 103/µL
• •4. Platelet count \< × 10 × 104/µL
• •5. ALT, AST, or GGT ≥ 3 x ULN or bilirubin \> 2 x ULN
• •6. eGFR ≤ 60 mL/min/1.73 m2
• •7. Lymphocyte count \< LLN 3.3. Any of the following urine test abnormalities at Screening:
• •<!-- -->
• •1. β-2-microglobulin\>0.3 μg/mL
• •2. Albumin/creatinine ratio\>22.6 mg/mmol
• •4. Others 4.1. Previous participation in this study. 4.2. Blood donation (1 unit or more) within 90 days before screening, plasma donation within 1 week before screening, and platelet donation within 6 weeks before screening.
• •4.3. History of alcohol or drug abuse in the past year (determined by the investigator).
• •4.4. Pregnant or lactating subjects, as well as subjects planning to become pregnant or start breastfeeding at any time during the study and within 30 days after completion of study treatment.
• •4.5. Participating in a clinical trial or having participated in a clinical trial within 90 days before screening.
• •4.6. History of clinically significant suicidal thoughts or behaviors in the past 12 months as assessed by C-SSRS at screening.
• •4.7. Unwilling or unable to comply with protocol requirements. 4.8. The patient has obvious hearing or vision impairment, language barriers, claustrophobia, etc., which makes the patient unable to cooperate with the neuropsychological scale assessment and MRI examination.
• •4.9. The researcher or sponsor believes that there are other unknown reasons that make the subject unsuitable for inclusion.