Effect of Berberine for Endothelial Function and Intestinal Microflora in Patients With Coronary Artery Disease

Study Overview
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Brief Summary
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The purpose of this study is to conduct a single-center, randomized, open-label, controlled, dose-escalating, parallel-group study, evaluating the effects and change of endothelial function and gut microbiota after berberine administration in patients with stable coronary artery disease who are at > 8 but ≤ 40 weeks after elective percutaneous coronary intervention

Detailed Description
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In the present study, about 48 patients with stable coronary artery disease who are at > 8 but ≤ 40 weeks after elective percutaneous coronary intervention. The total study duration is expected to be approximately 14 weeks per patient, including a screening period, a 12±1 week treatment period, Randomization was computer generated. After screening, eligible subjects will be randomly assigned into one of the following two groups: Berberine+therapy Arm or Standard therapy Arm. The primary objective is to determine whether a combination of berberine and coronary artery disease standard therapy is preferable to either berberine alone or standard therapy alone. The visit schedule will be as follows: Visit 1: Day -7 to Day -1, Screening/Enrolment; Visit 2: Day 1, Randomization/First dose; Visit 3: Week 4±1, Dose adjustment 1, BBR (100mg, tid); Visit 4: Week 8±1, Dose adjustment 2, BBR (200mg, tid); Visit 5: Week 12±1, End of Treatment (EOT) /Last dose, BBR (300mg, tid); Safety visit. We perform cross-sectional comparisons between the two arms and longitudinal comparisons within each arm to evaluate the indicators as follows: . Endothelial function, as measured by Flow mediated dilation (FMD) from baseline to 12-week follow-up; . Gut microbiota, as sequenced by metagenomic sequencing from baseline to 12-week follow-up. Blood and feces samples will be collected before and after treatment. Flow mediated dilation (FMD), HbA1C, fasting plasma glucose (FPG), lipids and cholesterol level, inflammatory factors, amino acids, bile acids and other metabolic related components and parameters will be measured. Furthermore, the change of gut microbiota will be evaluated too.

Official Title
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The Study of Berberine Affecting Metabolism, Inflammation Status, Endothelial Function and Thrombotic Events in Patients With Coronary Artery Disease by Remodeling Gut Microbiota

Conditions
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Stable Coronary Artery Disease, Percutaneous Coronary Intervention

Intervention / Treatment
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* Drug: Berberine
* Drug: Aspirin
* Drug: Clopidogrel
* Drug: Statin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with stable coronary artery disease undergo elective PCI >8 weeks, but ≤40 weeks Exclusion Criteria: Planned coronary revascularization, including PCI and coronary artery bypass graft (CABG) during the study period. Subjects with uncontrolled high blood pressure Recent (within 4 weeks) dose adjustment of any standard therapy agents Recent (within 4 weeks) use of berberine History of intolerance to berberine. Cr>1.5mg/dL; ALT level exceeds the upper limit of 3 times Heart failure or LVEF <50% Uncontrolled arrhythmia Pregnancy or lactation Malignant tumor or life expectancy is less than half a year Subjects who can not complete the follow-up

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: On the first day of the treatment period (Visit 1), eligible patients will be randomized into the Berberine Arm and the Control Arm. In the Berberine Arm, patients will receive berberine 200 mg twice daily for 4±1 weeks (Stage 1); then, 300 mg twice daily for 4±1 weeks (Stage 2); then, 400 mg twice daily for 4±1 weeks (Stage 3) in addition to standard treatment, including aspirin 100 mg once daily and clopidogrel 75 mg once daily for 12±1 weeks. In the Control Arm, patients will receive standard treatment, including aspirin 100 mg once daily and clopidogrel 75 mg once daily for 12±1 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Berberine+standard therapy Arm<br>In the Berberine Arm, patients will receive berberine 100 mg twice daily for 4±1 weeks (Stage 1); then, 200 mg twice daily for 4±1 weeks (Stage 2); then, 300 mg twice daily for 4±1 weeks (Stage 3) in addition to standard treatment, including aspirin (100mg/day), clopidogrel (75mg/day), statins, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, calcium channel blockers, beta-blockers, and/or antidiabetic therapy (including insulin or oral medication) was decided on an individual basis by the attending physician for 12±1 weeks. | Drug: Berberine<br>* Berberine 100 mg twice daily for 4±1 weeks (Stage 1); then, 200 mg twice daily for 4±1 weeks (Stage 2); then, 300 mg twice daily for 4 weeks (Stage 3).<br>* Other names: Berberine Hydrochloride Tablets;Drug: Aspirin<br>* Aspirin 100 mg once daily for 12±1 weeks.<br>* Other names: Aspirin Enteric-coated Tablets;Drug: Clopidogrel<br>* Clopidogrel 75 mg once daily for 12±1 weeks.<br>* Other names: Plavix;Drug: Statin<br>* Statins once daily for 12±1 weeks.<br>* Other names: Rosuvastatin;|
| Active Comparator: Standard therapy Arm<br>In the Control Arm, patients will receive standard treatment, including aspirin (100mg/day), clopidogrel (75mg/day), statins, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, calcium channel blockers, beta-blockers, and/or antidiabetic therapy (including insulin or oral medication) was decided on an individual basis by the attending physician for 12±1 weeks. | Drug: Aspirin<br>* Aspirin 100 mg once daily for 12±1 weeks.<br>* Other names: Aspirin Enteric-coated Tablets;Drug: Clopidogrel<br>* Clopidogrel 75 mg once daily for 12±1 weeks.<br>* Other names: Plavix;Drug: Statin<br>* Statins once daily for 12±1 weeks.<br>* Other names: Rosuvastatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial function measured by Flow mediated dilation (FMD) | Flow-mediated vasodilation measurement in the brachial artery was performed with subjects in the supine position for the evaluation of endothelial function. All imaging was performed by a single, highly skilled sonographer who was unaware of the study assignment.brachial artery diameter was imaged with a 5-12-MHz linear array transducer ultrasound system at a location 3 to 7 cm above the right elbow. The brachial artery diameters at baseline (D0) and after reactive hyperemia (D1) and sublingual nitroglycerine (D2) were recorded. The flow-mediated vasodilation [(D1-D0)/D0×100%] was used as a measure of endothelium-dependent vasodilation. | On the baseline, 4th, 8th, 12th week of treatment | 
| Gut microbiome | At baseline, we evaluate the bacterial diversity, different species, different genes, and different metabolic pathways in the BBR+Standard therapy group and the Standard therapy group . In addition, we mainly focused on α and β diversity variation in the remaining 3 visits of BBR+Standard therapy subjucts. Taxonomy alteration and bacterial metabolic pathways after BBR treatment were also observed. | On the baseline, 4th, 8th, 12th week of treatment | 
| Fecal metabolomics profile measurement | In aid of LC/MS and GC/MS technique, we will measure the metabolomics molecular profile in fecal samples at baseline, 4th, 8th, 12th week. We aimed to detect the profile of short chain fatty acids including Acetic acid, Propanoic acid, Isobutyric acid, Butyric acid, Ethylmethylacetic acid, Isovaleric acid, Valeric acid, 2-methylvaleric acid, 3-methylvaleric acid, 4-methylvaleric acid, Hexanoic acid-SCFA and 3_Hydroxyisovaleric acid. | On the baseline, 4th, 8th, 12th week of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood lipid levels | Total cholesterol (mmol/L), Triglyceride (mmol/L), HDL-C (mmol/L), LDL-C (mmol/L), Free fatty acids (umol/L), ApoA1(g/L), ApoB (g/L), Lp(a) (mg/L). | On the baseline, 4th, 8th, 12th week of treatment | 
| Inflammatory factor levels | hs-CRP (mg/L), IL-1b (pg/mL), IL-6 (pg/mL), IL-18 (pg/mL), TNF-a (pg/mL), IFN-r (pg/mL), IL-10 (pg/mL). | On the 12th week of treatment | 
| Blood glucose levels | Fasting glucose level (mmol/L), 2-hour postprandial glucose levels (mmol/L), HbA1c %. | On the baseline, 4th, 8th, 12th week of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Berberine, Gut microbiota, Endothelial function