The Clinical Trial of Chinese Herbal Medicine SaiLuoTong Capsule

Phase 2 Clinical Trial of SaiLuoTong Capsule for Vascular Dementia：A 26-week, Multicentre, Randomized, Double -Blind, Placebo-controlled Trial With a 26-week Open-label Extension

As a traditional Chinese medicine compound, SaiLuoTong capsule is proven to have beneficial effects on learning and memory ability in animal models of vascular dementia (VaD). The study hypothesis is that SaiLuoTong capsule will be effective in the treatment of patients with VaD and will be well tolerated. The purpose of the study is to determine the efficacy and safety of SaiLuoTong capsule on patients with mild to moderate VaD. The outcome measures include general cognitive function, executive function, daily living skills, and mental behavior changes of symptoms in VaD patients.

Vascular dementia (VaD) is a clinical syndrome of acquired intellectual and functional impairment that results from cerebrovascular diseases. SaiLuoTong capsule is a traditional Chinese medicine compound; it is composed of ginseng extract (the main composition: ginseng total saponins), ginkgo biloba extract (the main composition: YinXingTong ester) and safflower extract (the main composition: the west safflower total glycosides). The function of SaiLuoTong capsule is Yiqi Huoxue and Huayu Tongluo in Chinese traditional medicine theory. Pharmacodynamics studies showed that SaiLuoTong capsule can significantly improve neurological symptoms caused by focal cerebral ischemia in animals, and learning and memory ability in animal models of VaD. Based on these previous evidences, we conduct this study to assess the efficacy and safety of SaiLuoTong capsule in patients with mild to moderate VaD. This study is a phase 2 clinical trial of SaiLuoTong capsule for treatment of vascular dementia. The initial study is a 26-week, multicentre, randomized, double -blind, placebo-controlled study. Patients who complete the initial 26-week trial will be eligible to continue in a 26-week open-label extension study.

The primary and secondary objectives of this study are as following:

Primary Objectives:

1. To assess the efficacy of SaiLuoTong capsule on cognitive and global functioning in patients with mild-to-moderate VaD;
2. To assess the safety and tolerability of SaiLuoTong capsule in patients with mild-to-moderate VaD.

Secondary Objectives:

1. To assess the efficacy of SaiLuoTong capsule in improving the ability to do activities of daily living, executive function, and neuropsychiatric symptoms in patients with mild-to-moderate VaD;
2. To assess the efficacy of different dosage regimens of SaiLuoTong in patients with mild-to-moderate VaD;
3. To assess the efficacy of SaiLuoTong treatment of different duration in patients with mild-to-moderate VaD;
4. To assess the efficacy of SaiLuoTong capsule on different etiological subtypes of VaD, including large-vessel VaD, small-vessel VaD, and VaD of mixed large-vessel and small-vessel origin;
5. To assess the efficacy of SaiLuoTong capsule in mild VaD patients and moderate VaD patients separately;
6. To assess to effect of apolipoprotein E (ApoE) ε4 allele on trial outcomes.

The study will assess the changes in cognitive function, daily living skills, executive functions, behavioral and psychological symptoms. The primary measures of effectiveness include the change from baseline in the vascular dementia assessment scale cognitive subscale (V-ADAS-cog) and Alzheimer's disease cooperative study-clinical global impression of change (ADCS-CGIC). Secondary measures of effectiveness include the change from baseline in the Alzheimer's disease cooperative study-activities of daily living inventory (ADCS-ADL), mini-mental state examination (MMSE), clinical dementia rating scale (CDR), sum of boxes of CDR(CDR-sb), clock drawing task (CLOX), Chinese version of executive interview 25 (C-EXIT25) and neuropsychiatric inventory (NPI). Safety measures include physical examinations, vital signs, electrocardiography, laboratory tests, and adverse events records.

Inclusion Criteria:

• 40 years old or above, gender is not limited;
• Education≥primary-school;
• Dementia diagnosed according to Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV) criteria;
• Probable VaD diagnosed by the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences(NINDS-AIREN) criteria;
• Modified Hachinski ischemic scale(MHIS) total score≥4;
• Evidence of ischemic cerebrovascular disease on magnetic resonance imaging (MRI)and /or CT (corresponding with the imaging criteria of NINDS-AIREN)
• Mild-to-moderate dementia defined by MMSE score between 10 and 26, CDR score between 1 and 2, both inclusive
• Modified Hachinski ischemic scale(MHIS) total score≥4;
• Hamilton depression scale (HAMD) total score≤17;
• The patients agree to participate in the study and able to understand informed consent as well as signing it. In cases where patients are unable to do so, carer's consent will be obtained as proxy;
• There are carers accompanying patients at least 4 days a week and can accompany patients to participate in each visit.

Exclusion Criteria:

• Dementia caused by other brain diseases except VaD (e.g. Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Parkinson's disease, demyelinated disease of the central nervous system, tumour, hydrocephalus, head injury, central nervous system infection including syphilis, acquired immune deficiency syndrome, etc.);
• The patient who can not complete examination because of severe brain or nerve function loss, such as convenient hand hemiplegia, all sorts of aphasia and audio-visual obstacles, etc;
• The presence of abnormal laboratory parameters: Hemoglobin (Hb) and platelet (Plt)less than the lower limit; activated partial thromboplastin time (APTT) beyond the normal value more than 10 seconds, prothrombin time (PT) beyond the normal value more than 3 seconds; creatinine (Cr) more than 1.5 times the upper limit value; alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphates (ALP), γ-glutamyl transferase (γ-GT) more than 2 times the upper limit of normal, total bilirubin (TBiL) more than 1.5 times the upper limit of normal;
• Nutrition metabolic diseases and endocrine system lesions such as thyroid disease, parathyroid diseases,and deficiency of vitamins or other elements;
• Severe circulatory, respiratory, urinary, digestive, hematopoietic system diseases (such as unstable angina, incontrollable asthma, active bleeding, etc.) and cancer;
• Severe mental illness (such as depression, schizophrenia) and epilepsy;
• Gastrointestinal disorders that affect drug absorption, distribution, and metabolism;
• Alcohol and drug abuse;
• Patients who are using and cannot stop the following drugs including Chinese herba preparation containing ginseng, ginkgo leaf or any component of the saffron; medications that may affect cognitive functioning, such as donepezil, rivastigmine, huperzine A, memantine, nimodipine; etc.;
• Known to be allergic to the composition of SaiLuoTong;
• Pregnancy or breast-feeding women;
• New strokes within 3 months before baseline
• Had participated in other clinical trials before this study 3 months prior to this study.