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

NCT04434365 | Unknown Phase 1 DMC

• 2 other identifiers: BBRCADGM20192016-I2M-1-011
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Stable Coronary Artery Disease; Percutaneous Coronary Intervention

Keywords

Berberine; Gut microbiota; Endothelial function

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Blood lipid levels

  On the baseline, 4th, 8th, 12th week of treatment

• Inflammatory factor levels

  On the 12th week of treatment

• Blood glucose levels

  On the baseline, 4th, 8th, 12th week of treatment

Study Arms (2)

Berberine+standard therapy Arm

EXPERIMENTAL

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; Drug: Aspirin; Drug: Clopidogrel; Drug: Statin

Standard therapy Arm

ACTIVE COMPARATOR

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; Drug: Clopidogrel; Drug: Statin

Interventions

Berberine DRUG

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).

Also known as: Berberine Hydrochloride Tablets

Berberine+standard therapy Arm

Aspirin DRUG

Aspirin 100 mg once daily for 12±1 weeks.

Also known as: Aspirin Enteric-coated Tablets

Berberine+standard therapy Arm; Standard therapy Arm

Clopidogrel DRUG

Clopidogrel 75 mg once daily for 12±1 weeks.

Also known as: Clopidogrel Hydrogen Sulphate Tablets, Plavix

Berberine+standard therapy Arm; Standard therapy Arm

Statin DRUG

Statins once daily for 12±1 weeks.

Also known as: Atorvastatin, Rosuvastatin

Berberine+standard therapy Arm; Standard therapy Arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with stable coronary artery disease undergo elective PCI \>8 weeks, but ≤40 weeks

You may not qualify if:

• 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

Sponsors & Collaborators

• Peking Union Medical College Hospital: lead

Study Sites (1)

Peking Union Medical College Hospital

Beijing, Beijing Municipality, 100730, China

Location

Related Publications (9)

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• 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. doi: 10.1016/0140-6736(92)93147-f.

  PMID: 1359209 BACKGROUND

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

  PMID: 22972297 BACKGROUND

• 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):e002270. doi: 10.1161/JAHA.115.002270.

  PMID: 26567372 BACKGROUND

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

  PMID: 23212374 BACKGROUND

• Affuso F, Ruvolo A, Micillo F, Sacca 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.

  PMID: 19699071 BACKGROUND

• 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.

  PMID: 21915347 BACKGROUND

• 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.

  PMID: 28403947 BACKGROUND

• 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.

  PMID: 26923892 BACKGROUND

MeSH Terms

Interventions

Berberine; Aspirin; Clopidogrel; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium

Intervention Hierarchy (Ancestors)

Berberine Alkaloids; Benzylisoquinolines; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds, 2-Ring; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Pyrroles; Azoles; Heptanoic Acids; Fatty Acids; Lipids; Sulfonamides; Amides; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Sulfones; Pyrimidines

Study Officials

• Ran Tian, M.D.

  Peking Union Medical College Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 27, 2019
• First Posted: June 16, 2020
• Study Start: June 21, 2019
• Primary Completion: November 18, 2019
• Study Completion: December 30, 2020
• Last Updated: June 16, 2020

Record last verified: 2020-06

Locations

CN (1)