CerebrAlcare Pills on CereBral Small VesseL DiseasE（CABLE）

Study Overview
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Brief Summary
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This is a randomized, double-blinded, placebo-controlled, multicenter trial. Cerebral small vessel disease (CSVD) patients will be diagnosed by Magnetic Resonance Imaging (MRI) and randomized into treatment or control groups. The purpose of this trial is to assess the efficacy of cerebralcare pills on cerebral small vessel disease.

Detailed Description
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Cerebral small vessel disease (CSVD) is prevalent in the aging population with insidious onset, almost affecting all levels of the brain vasculature, and challenges the social and healthcare system worldwide. CSVD is the major cause of 25% of strokes and more than doubles the odds of recurrent stroke; furthermore, it contributes to 45% of dementia cases and to global functional decline. However, an incomplete understanding of the pathogenesis of CSVD limits prevention and treatment efforts. Cerebralcare Granule (CG) or Yangxue Qingnao granule, is a polyherbal medicine that was approved in 1997 by the China State Food and Drug Administration for the treatment of headaches and dizziness associated with cerebrovascular diseases. Cerebralcare pill is composed of 11 herbs. These herbs contain small molecules with various pharmacological actions. Cerebralcare pills have the same component as CG. Previous studies have demonstrated that CG significantly attenuated ischemia-reperfusion induced dysfunction, structural abnormalities in the microcirculation, and inflammatory injury. There are also studies confirming that CG also improved cognition function, improved cerebral microcirculation disorders, and hemodynamics. Patients enrolled will be randomly assigned to either the treatment or control group to receive Brain Pill/Brain Pill placebo (from randomization to 6 months at a dose of 2 packs per day). Face-to-face interviews will be conducted at baseline, day 90, day 180, and 1 year after randomization. The primary endpoint is the progression in cognition function which is assessed by Montreal Cognitive Assessment (MoCA) score. The secondary endpoints include changes in clinical characters, imaging markers (number and volume of white matter, number of lacunes, microbleeds, enlarged perivascular space ), hemodynamic parameters, Chinese medical symptoms, blood-brain barrier (BBB) permeability, proteomics, and inflammatory markers. The safety endpoints include severe hemorrhage events, symptomatic and asymptomatic intracranial hemorrhage, moderate hemorrhage, overall mortality, and serious adverse events.

Official Title
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CerebrAlcare Pills on CereBral Small VesseL DiseasE（CABLE）：A Randomized, Double-blinded, Placebo-controlled, Multi-center Trial

Conditions
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Cerebral Small Vessel Diseases

Intervention / Treatment
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* Drug: Cerebralcare pills
* Drug: Cerebralcare pills placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 45-75 years old; No gender limitation; Cerebral small vessel disease is observed on brain MRI. White matter hyperintensity, Fazekas score ≥ 1 and combined more than 2 vascular risk factors (hypertension, hyperlipidemia, diabetes, obesity, smoking, and other vascular events except stroke) or combined with lacunar focus or Imaging findings suggest new subcortical lacunar infarction (within 7 days). Mild or moderate vascular cognitive impairment(16 ≤ MoCA ≤ 24 score, for patients with primary school degree or below,15 ≤ MoCA ≤ 23 score). Daily life independence (mRS ≤ 2). Sign informed consent. Note: The imaging definition of small vessel disease refers to the strong guideline The total score of Fazekas was 6, which was the sum of Fazekas scores of subcortical and periventricular white matter lesions. New subcortical lacunar infarction: head MRI examination, subcortical, basal ganglia or brain stem DWI showed high signal (ADC diffusion limited) lesions with diameter < 20 mm, with or without corresponding clinical symptoms; There were new clinical symptoms. FLAIR sequence of head MRI showed flair hyperintense lesions (diameter < 20 mm) in subcortical, basal ganglia or pons. Exclusion Criteria: Cerebral hemorrhage and subarachnoid hemorrhage occurred within 30 days. Symptomatic middle cerebral artery and/or internal carotid artery stenosis, stenosis rate ≥ 50%; asymptomatic middle cerebral artery and/or internal carotid artery stenosis, stenosis rate ≥ 70%. Coronary CTA or coronary angiography showed severe three vessel lesions or frequent angina pectoris within 30 days. Chronic kidney disease stage 4 or 5. Resistant hypertension which could not be controlled by medicine (SBP > 180mmHg or DBP > 110mmHg). Resistant hyperglycemia which could not be controlled by medicine（fasting blood glucose > 10mmol/L or HB1AC > 7%). In acute cerebral infarction, the lesions showed high signal intensity on DWI, and the diameter was more than 20 mm or history of assive cerebral infarction within 30 days. Neurodegenerative diseases, such as AD and PD, have been diagnosed. There are clear non angiogenic white matter lesions, such as multiple sclerosis, adult white matter dysplasia, metabolic encephalopathy diseases, etc. Untreated cerebrovascular malformations or intracranial aneurysms (d > 3mm). Active gastrointestinal bleeding. Coagulation dysfunction or history of systemic bleeding. Hemorrhagic tendency (including but not limited to)：PLT<100×109/L; heparin treatment within 48h; APTT ≥ 35s; current use of warfarin, INR > 1.7; current use of novel oral anticoagulants; current use of direct thrombin or factor Xa inhibitor. Severe hepatic or renal or heat insufficiency before randomization (severe hepatic insufficiency refers to ALT or AST > 2 times the upper limit of normal; severe renal insufficiency refers to serum creatinine> 1.5 times the upper limit of normal or eGFR<40 ml/min/1.73m2; severe heat insufficiency refers to NYHA stage 3 and 4). History of intracranial or intramedullary surgery within three months of randomization. The patient has used or is using chinese medicine with similar components to CerebrAlcare pill/granule (including Tianshu capsule, Toutongning capsule, Naoxintong capsule, Danzhen Toutou capsule, Yindanxinnaotong soft capsule, Naoxinqing Tablet, Bazhen pill and Shiquandabu pill) within 14 days. Definite indications for anticoagulation (suspicion of cardioembolism, e.g. atrial fibrillation, known heart valve prosthesis, atrial myxoma, endocarditis, etc.) or definite indications for dual antiplatelet therapy (e.g. recent coronary or cerebral artery stent implantation). Other surgical or interventional therapy planned within 1 year requiring experimental drugs discontinuation. Childbearing-age women who do not take effective methods of contraception without negative records of pregnancy tests. Known to be allergic to CerebrAlcare pill/granule. Contraindications of MRI examination (such as claustrophobia). With severe organic diseases, such as malignant tumor, the expected survival time is less than 1 years. Due to geographical or other reasons can not cooperate to complete the follow-up. Patients also participated in other clinical trials.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cerebralcare pills placebo group<br>This group will receive Cerebralcare pills placebo, 2 packages, twice a day, from the day of randomization to 6 months. | Drug: Cerebralcare pills placebo<br>* Cerebralcare pills placebo will be administrated at the same rate with experimental group<br>|
| Experimental: Cerebralcare pills group<br>This group will receive Cerebralcare pills, 2 packages, twice a day, from the day of randomization to 6 months. | Drug: Cerebralcare pills<br>* a dose of 2 packages, twice a day of Cerebralcare pills<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression in cognition function | Cognition function assessed by Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.. | 6 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in both systolic and diastolic blood pressure | Including systolic and diastolic blood pressure (mmHg). | 3 months, 6 months and 1 year after randomization | 
| Rey auditory verbal learning test（RAVLT） | The Rey Auditory Verbal Learning Test (RAVLT) provides a standardized procedure to evaluate a range of aspects of verbal learning and memory of supra-span lists of words. The test requires recalling as many words as possible in any order from a standard list of 15 unrelated words read out by the examiner. The total score ranges from 0-120, with a lower score indicating a worse outcome. | 3 months, 6 months and 1 year after randomization | 
| Generalized Anxiety Disorder 7（GAD-7) | Generalized Anxiety disorder (GAD) is a widespread psychiatric syndrome involving significant consequences on people's health, with a total score of 21, where a higher score means a worse outcome. However, recent data show that this disorder has received little attention when compared to other anxiety disorders. | 3 months, 6 months and 1 year after randomization | 
| Self-rating depression scale | The Zung Self-Rating Depression Scale (SDS) consists of 20 items with a Likert type scale after each item. Each item is rated from 1 to 4, with scores ranging from 20 to 80, where higher scores mean worse results | 3 months, 6 months and 1 year after randomization | 
| Dizziness handicap inventory（DHI） | The DHI has 25 items with 3 response levels, sub-grouped into three domains: functional, emotional, and physical. A shortened version, the Dizziness Handicap Inventory short form (DHIsf), reduced to 13 items with 2 response levels, has been shown to compare favourably to the original version. Scores range from 0-100, with higher scores indicating worse outcomes. | 3 months, 6 months and 1 year after randomization | 
| Headache impact test 6(HIT-6） | The HIT-6 consists of six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress.Total HIT-6 score that ranges from 36 to 78, where a lower score indicates a greater impact of headache on the daily life of the respondent. | 3 months, 6 months and 1 year after randomization | 
| EuroQol five dimensions questionnaire (EQ-5D) | It includes a descriptive system(DS) and a visual analogue scale(VAS). Two indicators are index value(ranged 0-1) and visual score(ranged 0-100) with higher scores corresponding to better health status. | 3 months, 6 months and 1 year after randomization | 
| Stroop Color Word Test | The Stroop Color and Word Test (SCWT) is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. Shorter the test time, the better the outcome. | 3 months, 6 months and 1 year after randomization | 
| Severity of white matter hyperintensities(WMHs) | Fazekas score is used to describe the different types of hyperintense signal abnormalities surrounding the ventricles and in the deep white matter. Periventricular hyperintensity (PVH) is graded as 0 = absence, 1 = caps or pencil-thin lining, 2 = smooth halo, 3 = irregular PVH extending into the deep white matter. Separate deep white matter hyperintensity (DWMH) is rated as 0 = absence, 1 = punctate foci, 2 = beginning confluence of foci, 3 = large confluent areas. Higher scores indicats a worse outcome. | 6 months and 1 year after randomization | 
| Changes of white matter hyperintensities(WMHs) volume | WMH volume is assessed on 3D fluid attenuated inversion recovery (FLAIR) sequence in mm3 or cm3. Larger volume indicates a worse outcome. | 6 months and 1 year after randomization | 
| Number of lacunes | Lacunes were defined as rounded or ovoid lesions in the subcortical, basal ganglia, or brainstem, ranging from 3mm to 20mm in diameter, presenting with cerebral spinal fluid signal intensity on T2 and FLAIR, generally featuring a hyperintense rim on FLAIR and no increased signal on diffusion weighted imaging (DWI). Higher number of lacunae means a worse outcome. | 6 months and 1 year after randomization | 
| Number of cerebral microbleeds | Cerebral microbleeds are defined as rounded, hypodense foci within brain parenchyma on susceptibi lity weighted imaging (SWI) sequence, up to 10 mm in diameter, and were differentiated from microbleed mimics based on current guidelines. Higher number of cerebral microbleeds means a worse outcome. | 6 months and 1 year after randomization | 
| Number of enlarged perivascular space | Enlarged perivascular space was defined as small punctate or linear hyperintensities on T2 images in the basal ganglia or centrum semiovale. Higher number of enlarged perivascular spaces means a worse outcome. | 6 months and 1 year after randomization | 
| Changes in hemodynamic parameters | Lower cerebrovascular reactivity (CVR), cerebral blood flow (CBF), and reduced radial peripapillary capillary network density, and parafoveal vessel densities of the superficial retinal capillary plexuses mean worse outcomes. | 6 months and 1 year after randomization | 
| changes in Chinese medical symptoms | Chinese medical symptoms assessed by Blood Deficiency and Liver Hyperactivity Syndrome score. Scores range 0-21 and higher scores mean a worse outcome. | 6 months and 1 year after randomization | 
| Difference of recurrent stroke between groups | stroke included ischemic stroke, hemorrhagic stroke, TIA, et al. | 3 months, 6 months and 1 year after randomization | 
| changes in Blood-Brain Barrier (BBB) Permeability between groups | BBB permeability is assessed by MRI and biomarker (including NSE, GFAP, S100β). | 6 months and 1 year after randomization | 
| Compare protein profiles observed among different groups. | Blood was collected from the healthy (n=6), experimental (n=6) and placebo (n=6) groups at baseline, 3 months, and 12 months post-dosing. Alterations in protein profiles were detected by high performance liquid chromatography-mass spectrometry (HPLC-MS). GO classification and pathway enrichment were performed to analyse relevant protein changes. Serum metabolomics was determined using untargeted assays, and metabolite patterns in different groups were distinguished using orthogonal partial least squares analysis (OPLS-DA), compared with databases, and validated with the help of standards to finalise qualitative and quantitative analysis of metabolites and to identify differential metabolites. The Cell Counting Bead Analysis (CBA) Flex Set Flow Multifactor Assay Kit is used to detect serum levels of the inflammatory factors IL-1β, IL-6, IL-10, IL-12 and TNF-α. Western blot analysis is used to validate changes in the expression of 20 key proteins obtained from proteomic analysis. | 6 months and 1 year after randomization | 
| Composite vascular events | Incidence of symptomatic stroke, myocardial infarction and vascular death. | 3 months, 6 months and 1 year after randomization | 
| All-cause death | Deaths from all causes to the research subjects | 3 months, 6 months and 1 year after randomization | 
| Moderate and/or severe hemorrhage events | According to Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria which classifies the severity of bleeding complications as follows: 1) severe or life-threatening bleeding-intracranial bleeding or bleeding that causes substantial hemodynamic compromise requiring treatment; 2) moderate bleeding-bleeding which needs blood transfusion; 3) minor bleeding-other bleeding, neither requiring transfusion nor causing hemodynamic compromise. | 3 months, 6 months and 1 year after randomization | 
| Symptomatic and/or asymptomatic intracranial hemorrhage |  | 3 months, 6 months and 1 year after randomization | 
| Adverse events and severe adverse events | renal failure, hepatic failure, death. | 3 months, 6 months and 1 year after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cerebral small vessel diseases, Cerebralcare Pills, cognitive function, randomized controlled trial, multicenter study, double blind study, placebo-controlled