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

Percutaneous Coronary Intervention Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04434365
• Other study ID #: BBRCADGM2019
• Secondary ID: 2016-I2M-1-011
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: June 21, 2019
• Est. completion date: December 30, 2020

Study information

• Verified date: June 2020
• Source: Peking Union Medical College Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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:

1. . Endothelial function, as measured by Flow mediated dilation (FMD) from baseline to 12-week follow-up;

2. . 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 24
• Est. completion date: December 30, 2020
• Est. primary completion date: November 18, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

Patients with stable coronary artery disease undergo elective PCI >8 weeks, but =40 weeks

Exclusion Criteria:

1. Planned coronary revascularization, including PCI and coronary artery bypass graft (CABG) during the study period.

2. Subjects with uncontrolled high blood pressure

3. Recent (within 4 weeks) dose adjustment of any standard therapy agents

4. Recent (within 4 weeks) use of berberine

5. History of intolerance to berberine.

6. Cr>1.5mg/dL; ALT level exceeds the upper limit of 3 times

7. Heart failure or LVEF <50%

8. Uncontrolled arrhythmia

9. Pregnancy or lactation

10. Malignant tumor or life expectancy is less than half a year

11. Subjects who can not complete the follow-up

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia
• Percutaneous Coronary Intervention
• Stable Coronary Artery Disease

Intervention

Drug:
• Berberine
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).
• Aspirin
Aspirin 100 mg once daily for 12±1 weeks.
• Clopidogrel
Clopidogrel 75 mg once daily for 12±1 weeks.
• Statin
Statins once daily for 12±1 weeks.

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital

Country where clinical trial is conducted

China, 

References & Publications (9)

Affuso F, Ruvolo A, Micillo F, Saccà L, Fazio S. Effects of a nutraceutical combination (berberine, red yeast rice and policosanols) on lipid levels and endothelial function randomized, double-blind, placebo-controlled study. Nutr Metab Cardiovasc Dis. 2010 Nov;20(9):656-61. doi: 10.1016/j.numecd.2009.05.017. Epub 2009 Aug 20. — View Citation

Cao Y, Pan Q, Cai W, Shen F, Chen GY, Xu LM, Fan JG. Modulation of Gut Microbiota by Berberine Improves Steatohepatitis in High-Fat Diet-Fed BALB/C Mice. Arch Iran Med. 2016 Mar;19(3):197-203. doi: 0161903/AIM.008. — View Citation

Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992 Nov 7;340(8828):1111-5. — View Citation

Karlsson FH, Fåk F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, Bäckhed F, Nielsen J. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun. 2012;3:1245. doi: 10.1038/ncomms2266. — View Citation

Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic Value of Flow-Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2015 Nov 13;4(11). pii: e002270. doi: 10.1161/JAHA.115.002270. Review. — View Citation

Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012 Sep 13;489(7415):242-9. doi: 10.1038/nature11552. Review. — View Citation

Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, Feng R, Ma C, Wen BY, Guo F, Yang XY, Han YX, Wang LL, Tong Q, You XF, Lin Y, Kong WJ, Si SY, Jiang JD. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism. 2017 May;70:72-84. doi: 10.1016/j.metabol.2017.02.003. Epub 2017 Feb 10. — View Citation

Xie W, Gu D, Li J, Cui K, Zhang Y. Effects and action mechanisms of berberine and Rhizoma coptidis on gut microbes and obesity in high-fat diet-fed C57BL/6J mice. PLoS One. 2011;6(9):e24520. doi: 10.1371/journal.pone.0024520. Epub 2011 Sep 6. — View Citation

You DG, Saravanakumar G, Son S, Han HS, Heo R, Kim K, Kwon IC, Lee JY, Park JH. Dextran sulfate-coated superparamagnetic iron oxide nanoparticles as a contrast agent for atherosclerosis imaging. Carbohydr Polym. 2014 Jan 30;101:1225-33. doi: 10.1016/j.carbpol.2013.10.068. Epub 2013 Oct 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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 a and ß 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
Primary	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	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
Secondary	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
Secondary	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