Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia

A Multi-center, Random, Double Blind and Placebo Control Phase III Clinical Study on the Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia

Butylphthalide soft capsule has been confirmed to have beneficial effects for patients with vascular dementia (VaD) in clinical trial of phase II study. So the investigators hypothesize that Butylphthalide soft capsule may have same beneficial effects for patients with VaD in an extended samples in phase III study. In present study the investigators will recruit patients with mild to moderate VaD in a multi-center, random, double blind and placebo control methods to confirm the efficacy and safety of Butylphthalide soft capsule. The outcome measures include general cognitive function, executive function, daily living skills, and mental behavior changes of symptoms in VaD patients.

Butylphthalide soft capsule is a synthetic chiral compound containing L- and D-isomers of butylphthalide. Studies in the past several decades have demonstrated that it could alleviate the learning and memory deficits induced by cerebral ischemia in rats. The phase II study enrolled 281 patients showed greater effects than placebo on ADAS-cog and CIBIC-plus. Butylphthalide soft capsule were uncommon and primarily consisted of mild gastrointestinal symptoms. In the present phase III study the investigators will re-assess the efficacy and the safety of Butylphthalide soft capsule for the treatment of mild to moderate vascular dementia in 700 subjects.

Inclusion Criteria:

• 1. Age ≥50 and ≤75, male or female.
• 2. The subjects must have completed primary school education or above, and be able to complete the cognitive ability test and other tests required by the program.
• 3. Meet the vascular dementia diagnosis criteria specified in the Diagnostic and Statistical Manual of Mental Disorders - 5th Edition (DSM-V).
• 4. Meet the SIVD diagnosis criteria of Erkinjuntti.
• 5. MRI supports the existence of an ischemic cerebrovascular disease; Meet the National Institute of Neurological Disorders and Stroke (NINDS-AIREN) imaging diagnosis criteria; The lesion located between supra-tentorial and subcortical areas; The maximum diameter of the infarction ≤30mm; The number of infarctions ≥3, and/or Fazekas score=2-3.
• 6. The patients need to be enrolled 3 months after the last stroke, if there is a clear history of stroke; otherwise meet other Criteria.
• 7.The subjects are suffering from mild or moderate vascular dementia, with 11≤ MMSE ≤26, and the Clinical Dementia Rating (CDR) score 1≤ CDR ≤2.
• 8. The Hamilton depression scale (HAMD) total score ≤17.
• 9. The patient agrees to participate in this study and the patient or his or her legal guardian has signed the informed consent before the study.
• 10. The subjects must have a care giver who has completed primary school education or above. The MMSE score of the care giver should be within the following range: education level of primary school > 20 points, education level above primary school > 24 points. And the care giver shall also be able to take care of the patient at least 4 days a week for more than 4 hours a day while he or she can accompany the subjects to attend each visit.

Exclusion Criteria:

• 1. Patients suffering from dementia caused by other cerebral diseases other than VaD (such as Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease, demyelinating diseases of the central nervous system, tumors, hydrocephalus, traumas, syphilis, AIDS, Creutzfeldt-Jakob disease, etc.);
• 2. MRI indicates hippocampus or entorhinal cortex atrophy; and patients for whom VaD in combination with AD has been maximally excluded. But the following two cases can be included: ① Those aged 70 years and above with MTA score of grade 2 can be included; ② Those with grade 3 white matter injury score can be included with MTA score of grade 2.
• 3. Patients with severe neurologic impairments that hinder them from completing the required tests, such as hemiplegia of the convenient hand, various kinds of aphasia, and audio or visual disorders.
• 4. Patients who cannot swallow any orally administered drugs, or who is suffering from any disease that can affect the absorption of orally administered drugs, such as active intestinal diseases, partial or complete intestinal obstruction.
• 5. Patients suffering from severe diseases of the circulation system, the respiration system, the urinary system, the digestive system and the hemopoietic system (such as unstable angina pectoris, uncontrollable asthma and active gastric bleeding) and cancer.
• 6. Patients suffering from nutritional and metabolic diseases and endocrine system disorders, such as thyroid disease, parathyroid disease and deficiency of vitamin or other elements.
• 7. Patients suffering from severe mental diseases (such as depression and schizophrenia) and epilepsy.
• 8. Patients with alcohol or drug abuse.
• 9. Patients with a family history of dementia.
• 10. Patients who have been given any drug that can affect the cognitive function, such as cholinergic drugs, antipsychotic drugs and nootropic agents (including traditional Chinese herbal medicines and pills, such as cholinesterase inhibitors, memantine, Cenma Yizhi Capsules and Jiannaoan), for a long period of time (within 3 month before the start of this study and will continue using such drug).
• 11. Patients who have used Butylphthalide soft capsule or injection within 2 weeks before grouping.
• 12. Patients who are allergic to Butylphthalide/celery.
• 13. Patients with severe bleeding tendency or hepatic dysfunction (with transaminase higher than 3 times of the normal upper limit).
• 14. Pregnant or breast feeding women.
• 15. Patients who have participated in other interference clinical studies within 3 months before grouping.
• 16. Patients for whom MRI cranial imaging cannot be performed.