Clinical trial NCT05578521: CerebrAlcare Pills on CereBral Small VesseL DiseasE（CABLE）
Official title: CerebrAlcare Pills on CereBral Small VesseL DiseasE（CABLE）：A Randomized, Double-blinded, Placebo-controlled, Multi-center Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Cerebral Small Vessel Diseases
Keywords: cerebral small vessel diseases
Cerebralcare Pills
cognitive function
randomized controlled trial
multicenter study
double blind study
placebo-controlled
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: Tasly Pharmaceutical Group Co., Ltd
First posted: 2022-10-13
Enrollment: 114
Sex: ALL
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 45-75 years old;
2. No gender limitation;
3. 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).
4. Mild or moderate vascular cognitive impairment(16 ≤ MoCA ≤ 24 score, for patients with primary school degree or below,15 ≤ MoCA ≤ 23 score).
5. Daily life independence (mRS ≤ 2).
6. Sign informed consent.

Note:

1. 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.
2. 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:

1. Cerebral hemorrhage and subarachnoid hemorrhage occurred within 30 days.
2. 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%.
3. Coronary CTA or coronary angiography showed severe three vessel lesions or frequent angina pectoris within 30 days.
4. Chronic kidney disease stage 4 or 5.
5. Resistant hypertension which could not be controlled by medicine (SBP \> 180mmHg or DBP \> 110mmHg).
6. Resistant hyperglycemia which could not be controlled by medicine（fasting blood glucose \> 10mmol/L or HB1AC \> 7%).
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.
8. Neurodegenerative diseases, such as AD and PD, have been diagnosed.
9. There are clear non angiogenic white matter lesions, such as multiple sclerosis, adult white matter dysplasia, metabolic encephalopathy diseases, etc.
10. Untreated cerebrovascular malformations or intracranial aneurysms (d \> 3mm).
11. Active gastrointestinal bleeding.
12. Coagulation dysfunction or history of systemic bleeding.
13. 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.
14. 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).
15. History of intracranial or intramedullary surgery within three months of randomization.
16. 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.
17. 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).
18. Other surgical or interventional therapy planned within 1 year requiring experimental drugs discontinuation.
19. Childbearing-age women who do not take effective methods of contraception without negative records of pregnancy tests.
20. Known to be allergic to CerebrAlcare pill/granule.
21. Contraindications of MRI examination (such as claustrophobia).
22. With severe organic diseases, such as malignant tumor, the expected survival time is less than 1 years.
23. Due to geographical or other reasons can not cooperate to complete the follow-up.
24. Patients also participated in other clinical trials.

Primary outcomes:
measure: Progression in cognition function
timeFrame: 6 months after randomization
Secondary outcomes:
measure: Changes in both systolic and diastolic blood pressure
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Rey auditory verbal learning test（RAVLT）
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Generalized Anxiety Disorder 7（GAD-7)
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Self-rating depression scale
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Dizziness handicap inventory（DHI）
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Headache impact test 6(HIT-6）
timeFrame: 3 months, 6 months and 1 year after randomization
measure: EuroQol five dimensions questionnaire (EQ-5D)
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Stroop Color Word Test
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Severity of white matter hyperintensities(WMHs)
timeFrame: 6 months and 1 year after randomization
measure: Changes of white matter hyperintensities(WMHs) volume
timeFrame: 6 months and 1 year after randomization
measure: Number of lacunes
timeFrame: 6 months and 1 year after randomization
measure: Number of cerebral microbleeds
timeFrame: 6 months and 1 year after randomization
measure: Number of enlarged perivascular space
timeFrame: 6 months and 1 year after randomization
measure: Changes in hemodynamic parameters
timeFrame: 6 months and 1 year after randomization
measure: changes in Chinese medical symptoms
timeFrame: 6 months and 1 year after randomization
measure: Difference of recurrent stroke between groups
timeFrame: 3 months, 6 months and 1 year after randomization
measure: changes in Blood-Brain Barrier (BBB) Permeability between groups
timeFrame: 6 months and 1 year after randomization
measure: Compare protein profiles observed among different groups.
timeFrame: 6 months and 1 year after randomization
measure: Composite vascular events
timeFrame: 3 months, 6 months and 1 year after randomization
measure: All-cause death
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Moderate and/or severe hemorrhage events
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Symptomatic and/or asymptomatic intracranial hemorrhage
timeFrame: 3 months, 6 months and 1 year after randomization
measure: Adverse events and severe adverse events
timeFrame: 3 months, 6 months and 1 year after randomization
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital
Study officials:
affiliation: Beijing Tiantan Hospital, Capital Medical University, Beijing, China
name: Yilong Wang, PhD，MD
role: PRINCIPAL_INVESTIGATOR
References: