Effects of Berberine in Reducing Abdominal Visceral Adipose Tissue Among Individuals With Obesity and NAFLD (BRAVO)

Assess the Effects of Berberine in Reducing Abdominal Visceral Adipose Tissue Among Individuals With Obesity and Non-alcoholic Fatty Liver Disease

This multicenter, double-blinded, randomized controlled trial aims to evaluate the effect of berberine in reducing visceral and liver adipose tissue among individuals with obesity and non-alcoholic fatty liver disease (NAFLD) in China.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; NAFLD; Obesity, Abdominal
• Intervention / Treatment: Drug: Berberine plus lifestyle intervention; Behavioral: Placebo plus lifestyle intervention

Detailed Description

The trial aims to evaluate the efficacy and safety of berberine treatment for obesity and NAFLD. Potential eligible patients will be recruited from 10-20 medical centers in China. After a 4-week run-in period with berberine, all the eligible participants will be randomized (1:1) to berberine 1.0 g per day plus lifestyle intervention (Arm A) or placebo plus lifestyle intervention (Arm B). The participants will be asked to attend the visit at least once every 2 months, and be followed up for 6 months.

• Study Type: Interventional
• Enrollment (Anticipated): 326
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Haibo Zhang, MD; Phone Number: +86 60866781; Email: zhanghaibo@fuwai.org
• Study Contact Backup: Name: Bin Wang, PhD; Phone Number: +86 60866718; Email: wangbin@fuwai.org

Study Locations

• China
  • Beijing, China
    • Fuwai Hospital, Chinese Academy of Medical Sciences, National Center for Cardiovascular Diseases
    • Contact: Haibo Zhang, MD; Phone Number: +86 60866781; Email: zhanghaibo@fuwai.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants aged ≥18 years
• Participants with obesity (i.e., BMI ≥ 28 kg/m2) and abdominal obesity (i.e., waist circumference ≥85 cm in female or waist circumference ≥90 cm in male)
• Participants with NAFLD diagnosed by ultrasound, computed tomography or magnetic resonance imaging

Exclusion Criteria:

• Patients with established coronary heart disease, stroke, or peripheral arterial disease
• Patients diagnosed with diabetes or taking oral glucose-lowering drugs
• Patients with severely uncontrolled hypertension (i.e., SBP≥180mmHg and/or DBP ≥110mmHg)
• Excess alcohol consumption (i.e., alcohol ≥ 20 g/day in female or alcohol ≥ 30 g/day in male)
• Other causes of fatty liver disease, including alcohol or drug abuse, hepatitis B or C, autoimmune, hepatolenticular degeneration, total parenteral nutrition, inflammatory bowel disease, celiac disease, hypothyroidism, Cushing syndrome, β -lipoprotein deficiency, lipid atrophy diabetes, Mauriac syndrome, etc.
• Patients with thyroid disease, including hyperthyroidism or hypothyroidism
• Patients with cardiac insufficiency
• ALT or AST ≥ 3 times upper limit of normal, liver cirrhosis or hepatic insufficiency
• Patients with renal insufficiency: estimated glomerular filtration rate (eGFR) < 60 ml/(min×1.73m2)
• Patients who had weight loss surgery, or are currently taking drugs for weight loss, or plan to have weight loss surgery or drugs in the following 6 months
• Patients diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Taking berberine or drug containing berberine in the past 1 month
• Any adverse reaction to berberine
• Severe constipation, diarrhea, and/or severe chronic intestinal diseases (e.g., ulcerative colitis, Crohn's disease, irritable bowel syndrome, etc.)
• Patients who had to use long-term or intermittent corticosteroids, immunosuppressants, antibiotics, or other drugs that affect inflammatory biomarkers
• Women who are pregnant or breastfeeding, or those who plan to be pregnant during the trial
• Patients with malignant tumors
• Patients with mental disorders, cognitive disorders, and/or other serious diseases
• Those who participated or have been participating other trials during the last 3 months
• Any other conditions that may hinder the compliance to the study intervention or follow-up visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: berberine group; Berberine hydrochloride plus lifestyle intervention	Drug: Berberine plus lifestyle intervention; berberine hydrochloride 500mg twice a day for 6 months plus lifestyle intervention. Lifestyle intervention is based on "Guidelines of prevention and treatment for non-alcoholic fatty liver disease (2018 update)" and "China Blue Paper on Obesity Prevention and Control", including health education on diet, physical activity and weight loss, etc.
Placebo Comparator: placebo group; Placebo plus lifestyle intervention	Behavioral: Placebo plus lifestyle intervention; Placebo with identical shape, colour, odour and taste twice a day plus lifestyle intervention. Lifestyle intervention is based on "Guidelines of prevention and treatment for non-alcoholic fatty liver disease (2018 update)" and "China Blue Paper on Obesity Prevention and Control", including health education on diet, physical activity and weight loss, etc.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of visceral fat content	Measurement of visceral fat by computed tomography	6 months
Change of liver fat content	Measurement of liver fat content by computed tomography	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of fasting plasma glucose	Measurement of fasting plasma glucose (FPG)	6 months
Change of HbA1c	Measurement of HbA1c	6 months
Change of 2-hour postprandial blood glucose	Measurement of 2-hour postprandial blood glucose (2hPG)	6 months
Change of homeostatic model assessment-insulin resistance	Homeostatic model assessment-insulin resistance (HOMA-IR)= (fasting insulin (mIU/L) * FPG (mmol/L)) / 22.5	6 months
Change of homeostasis model assessment-β cell	Homeostatic model assessment (HOMA-β) = (20 x fasting insulin (mIU/L)) / (FPG (mmol/L) - 3.5)	6 months
Change of homeostasis model assessment-insulin sensitivity	Homeostatic model assessment-insulin sensitivity (HOMA-IS)= 1/ HOMA-IR	6 months
Change of serum triglyceride	Measurement of serum triglyceride (TG)	6 months
Change of high-density lipoprotein cholesterol	Measurement of high-density lipoprotein cholesterol	6 months
Change of low-density lipoprotein cholesterol	Measurement of low-density lipoprotein cholesterol	6 months
Change of total cholesterol	Measurement of total cholesterol	6 months
Change of lipoprotein (a)	Measurement of lipoprotein (a)	6 months
Change of apolipoprotein	Measurement of apolipoprotein	6 months
Normalization of glucose parameters among participants with prediabetes	Meeting all three criteria: 1) FPG<6.1 mmol/L; 2) 2hPG<7.8 mmol/L; 3) HbA1c<5.7%	6 months
Change of metabolic syndrome z-score	Metabolic syndrome z-score calculated by the five components, including waist circumference, HDL-C, blood pressure, TG and FPG. Higher score indicates greater severity of metabolic syndrome	6 months
Change of visceral fat index	Visceral fat index calculated by waist circumference, body mass index, TG, HDL-C. Higher index indicates higher content of visceral fat	6 months
Change of fat liver index	Fat liver index (FLI) calculated by TG, body mass index, gamma-glutamyltransferase (γ-GGT), waist circumference. Higher index indicates higher content of liver fat	6 months
Change of triglyceride glucose index	Triglyceride glucose index (TyG) calculated by TG and FPG. Higher index indicates higher insulin resistance	6 months
Change of serum urine acid	Measurement of serum urine acid	6 months
Change of serum homocysteine	Measurement of serum homocysteine	6 months
Change of body weight	Measurement of body weight in kg	6 months
Change of body mass index	Weight and height will be combined to report BMI in kg/m^2	6 months
Change of waist circumference	Measurement of waist circumference in cm	6 months
Change of waist-hip ratio	Waist circumference and hip circumference will be combined to report waist-hip ratio.	6 months
Change of waist-height ratio	Waist circumference and height will be combined to report waist-height ratio.	6 months
Change of systolic blood pressure	Measurement of systolic blood pressure (SBP)	6 months
Change of diastolic blood pressure	Measurement of diastolic blood pressure (DBP)	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of alanine aminotransferase	Measurement of alanine aminotransferase (ALT)	6 months
Change of aspartate aminotransferase	Measurement of aspartate aminotransferase (AST)	6 months
Change of γ-GGT	Measurement of γ-GGT	6 months
Change of fibrosis-4 score	Fibrosis-4 score (FIB-4) calculated by age, ALT, AST, platelet count. Higher score indicates higher extent of liver fibrosis.	6 months
Change of NAFLD fibrosis score	NAFLD fibrosis score (NFS) calculated by age, BMI, status of dysglycemia, ALT, AST, platelet count, serum albumin concentration. Higher score indicates higher extent of liver fibrosis.	6 months
Change of hypersensitive C-reactive protein	Measurement of hypersensitive C-reactive protein	6 months
Change of interleukin-6	Measurement of interleukin-6 (IL-6)	6 months
Change of tumor necrosis factor-α	Measurement of tumor necrosis factor-α (TNF-α)	6 months
Change of transforming growth factor-β	Measurement of transforming growth factor-β (TGF-β)	6 months
Change of leptin	Measurement of leptin	6 months
Change of adiponectin	Measurement of adiponectin	6 months
Change of short chain fatty acids	Measurement of short chain fatty acids	6 months
Change of trimethylamine	Measurement of trimethylamine (TMA)	6 months
Change of trimethylamine oxide	Measurement of trimethylamine oxide (TMAO)	6 months
Improvement of left ventricular diastolic function (LVDF) among participants with abnormal LVDF at baseline	Measurement of LVDF by echocardiogram	6 months
Change of pericardial fat among participants with abnormal LVDF	Measurement of pericardial fat by computed tomography	6 months

Collaborators and Investigators

• Sponsor: China National Center for Cardiovascular Diseases
• Investigators: Principal Investigator: Jing Li, PhD, National Center for Cardiovascular Diseases; Principal Investigator: Haibo Zhang, MD, National Center for Cardiovascular Diseases

Publications and helpful links

General Publications

• Yan HM, Xia MF, Wang Y, Chang XX, Yao XZ, Rao SX, Zeng MS, Tu YF, Feng R, Jia WP, Liu J, Deng W, Jiang JD, Gao X. Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease. PLoS One. 2015 Aug 7;10(8):e0134172. doi: 10.1371/journal.pone.0134172. eCollection 2015.
• Harrison SA, Gunn N, Neff GW, Kohli A, Liu L, Flyer A, Goldkind L, Di Bisceglie AM. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nat Commun. 2021 Sep 17;12(1):5503. doi: 10.1038/s41467-021-25701-5.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 15, 2022
• Primary Completion (Anticipated): December 15, 2023
• Study Completion (Anticipated): December 15, 2023

Study Registration Dates

• First Submitted: November 16, 2022
• First Submitted That Met QC Criteria: December 4, 2022
• First Posted (Estimate): December 13, 2022

Study Record Updates

• Last Update Posted (Estimate): December 13, 2022
• Last Update Submitted That Met QC Criteria: December 4, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: berberine hydrochloride
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Obesity, Abdominal
• Other Study ID Numbers: 2021-CXGC04-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No