Clinical trial NCT03770325: A Mechanistic Randomized Controlled Trial on the Cardiovascular Effect of Berberine
Official title: Effect of Berberine on Cardiovascular Disease Risk Factors: a Mechanistic Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Cardiovascular Risk Factor
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Food and Health Bureau, Hong Kong
First posted: 2018-12-10
Enrollment: 84
Sex: MALE
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Berberine is extracted from Coptis (Huanglian) and Phellodendron Chinese (Huangbai), to make into berberine tablets.1 Recent studies have shown that berberine has beneficial effects on cardiovascular disease (CVD) risk factors,1,2 such as lowering the risk of hyperlipidemia, diabetes, and hypertension.1 In a comprehensive systematic review and meta-analysis of 27 randomized controlled trials (RCTs), berberine effectively reduced low density lipoprotein cholesterol (LDL-c) (-0.65 mmol/L, 95% confidence interval (CI) -0.75 to -0.56), triglycerides (TG) (-0.39 mmol/L, 95% CI -0.59 to -0.19), total cholesterol (TC) (-0.66 mmol/L, 95% CI -1.02 to -0.31) and increased high density lipoprotein cholesterol (HDL-c) (0.07mmol/L, 95% CI 0.04 to 0.1).1 Notably, no serious adverse event has been reported in these trials,1 suggesting a good tolerability of berberine. The mechanism by which berberine exerts a protective role in atherosclerosis is unclear. Protoberberines have been identified as a new inhibitor of AKR1C3, an enzyme responsible for the regulation of steroid hormone action.3 The investigators propose to examine the effects of berberine on a set of well-established CVD risk factors including lipids, systolic and diastolic blood pressure, coagulation factors, adiposity, fasting glucose, insulin, and liver function, as well as to examine potential mediation via testosterone and/or sex hormone binding globulin using a mechanistic, randomized, double-blind, placebo-controlled trial in Chinese men with hyperlipidemia.

Detailed description: Objectives: to assess the effect of berberine on a set of well-established CVD risk factors, including lipids, systolic and diastolic blood pressure, coagulation factors, fasting glucose, insulin, adiposity (body mass index (BMI) and waist-hip ratio (WHR)) and the mediation via testosterone and/or sex hormone binding globulin using a mechanistic, parallel RCT.

Study design: a mechanistic, randomized, double-blind, placebo-controlled, parallel trial in 84 Chinese men in Hong Kong.

Interventions: the eligible participants will be randomized to take berberine (500 mg orally twice a day) or placebo for 12 weeks. Blood samples will be taken at baseline, 8-week and 12-week intervention.

Data analysis and expected results: the investigators will use an intention to treat analysis, with multiple imputation for missing data. The investigators will compare the baseline characteristics of participants in the two arms using analysis of variance. The investigators will assess the effects of berberine on changes in CVD risk factors using analysis of variance, and the mediation using causal mediation analysis. Compared to the placebo group, the participants receiving berberine are expected to have lower burden of cardiovascular disease risk factors at the end of the intervention. These effects may be mediated or partly mediated by lowering testosterone.

Eligibility criteria: Inclusion Criteria:

* Men, who are

  1. aged 20 to 65 years
  2. of Chinese ethnicity
  3. with hyperlipidemia, defined as TG greater than 150 mg/dl (1.70 mmol/L), TC greater than 200 mg/dl (5.16 mmol/L), and/or LDL-c greater than 100 mg/dl (2.58 mmol/L)
  4. willing to make return visits
  5. not currently receiving hormone replacement therapy, such as testosterone replacement therapy, in the past 12 months
  6. not currently taking berberine or traditional Chinese medicine that contains berberine, in the past 1 month
  7. free of any congenital diseases, including familial hypercholesterolemia
  8. free of any infectious diseases, e.g. seasonal influenza
  9. free of anemia and glucose-6-phosphate dehydrogenase deficiency
  10. with no history of any chronic diseases including ischemic heart disease, myocardial infarction (heart attack), stroke, diabetes, cancer, liver/renal dysfunction, and gastrointestinal disorders.

Exclusion Criteria:

* All women, and men, who did not meet the aforementioned inclusion criteria, and/or unable or unwilling to provide consent

Primary outcomes:
measure: lipid profile
timeFrame: change from baseline lipid profile at 8 weeks
measure: lipid profile
timeFrame: change from baseline lipid profile at 12 weeks
measure: blood pressure
timeFrame: change from baseline blood pressure at 8 weeks
measure: blood pressure
timeFrame: change from baseline blood pressure at 12 weeks
measure: thromboxane A2
timeFrame: change from baseline thromboxane A2 at 8 weeks
measure: thromboxane A2
timeFrame: change from baseline thromboxane A2 at 12 weeks
measure: testosterone
timeFrame: change from baseline testosterone at 8 weeks
measure: testosterone
timeFrame: change from baseline testosterone at 12 weeks
measure: body mass index (BMI)
timeFrame: change from baseline body mass index at 8 weeks
measure: body mass index (BMI)
timeFrame: change from baseline body mass index at 12 weeks
measure: waist hip ratio
timeFrame: change from baseline waist hip ratio at 8 weeks
measure: waist hip ratio
timeFrame: change from baseline waist hip ratio at 12 weeks
measure: fasting glucose
timeFrame: change from baseline fasting glucose at 8 weeks
measure: fasting glucose
timeFrame: change from baseline fasting glucose at 12 weeks
measure: fasting insulin
timeFrame: change from baseline fasting insulin at 8 weeks
measure: fasting insulin
timeFrame: change from baseline fasting insulin at 12 weeks
measure: liver function
timeFrame: change from baseline fasting insulin at 8 weeks
measure: liver function
timeFrame: change from baseline fasting insulin at 12 weeks
measure: sex hormone binding globulin (SHBG)
timeFrame: change from baseline SHBG at 8 weeks
measure: sex hormone binding globulin (SHBG)
timeFrame: change from baseline SHBG at 12 weeks
measure: thrombin time
timeFrame: change from baseline thrombin time at 8 weeks
measure: thrombin time
timeFrame: change from baseline thrombin time at 12 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Li Ka Shing Faculty of Medicine
Study officials:
affiliation: The University of Hong Kong
name: Jie Zhao, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol. 2015 Feb 23;161:69-81. doi: 10.1016/j.jep.2014.09.049. Epub 2014 Dec 10.
citation: Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res. 2008 Aug;22(8):999-1012. doi: 10.1002/ptr.2399.
citation: Skarydova L, Hofman J, Chlebek J, Havrankova J, Kosanova K, Skarka A, Hostalkova A, Plucha T, Cahlikova L, Wsol V. Isoquinoline alkaloids as a novel type of AKR1C3 inhibitors. J Steroid Biochem Mol Biol. 2014 Sep;143:250-8. doi: 10.1016/j.jsbmb.2014.04.005. Epub 2014 Apr 24.