<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03770325</url>
  </required_header>
  <id_info>
    <org_study_id>15162621</org_study_id>
    <nct_id>NCT03770325</nct_id>
  </id_info>
  <brief_title>A Mechanistic Randomized Controlled Trial on the Cardiovascular Effect of Berberine</brief_title>
  <official_title>Effect of Berberine on Cardiovascular Disease Risk Factors: a Mechanistic Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Food and Health Bureau, Hong Kong</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Berberine is extracted from Coptis (Huanglian) and Phellodendron Chinese (Huangbai), to make&#xD;
      into berberine tablets.1 Recent studies have shown that berberine has beneficial effects on&#xD;
      cardiovascular disease (CVD) risk factors,1,2 such as lowering the risk of hyperlipidemia,&#xD;
      diabetes, and hypertension.1 In a comprehensive systematic review and meta-analysis of 27&#xD;
      randomized controlled trials (RCTs), berberine effectively reduced low density lipoprotein&#xD;
      cholesterol (LDL-c) (-0.65 mmol/L, 95% confidence interval (CI) -0.75 to -0.56),&#xD;
      triglycerides (TG) (-0.39 mmol/L, 95% CI -0.59 to -0.19), total cholesterol (TC) (-0.66&#xD;
      mmol/L, 95% CI -1.02 to -0.31) and increased high density lipoprotein cholesterol (HDL-c)&#xD;
      (0.07mmol/L, 95% CI 0.04 to 0.1).1 Notably, no serious adverse event has been reported in&#xD;
      these trials,1 suggesting a good tolerability of berberine. The mechanism by which berberine&#xD;
      exerts a protective role in atherosclerosis is unclear. Protoberberines have been identified&#xD;
      as a new inhibitor of AKR1C3, an enzyme responsible for the regulation of steroid hormone&#xD;
      action.3 The investigators propose to examine the effects of berberine on a set of&#xD;
      well-established CVD risk factors including lipids, systolic and diastolic blood pressure,&#xD;
      coagulation factors, adiposity, fasting glucose, insulin, and liver function, as well as to&#xD;
      examine potential mediation via testosterone and/or sex hormone binding globulin using a&#xD;
      mechanistic, randomized, double-blind, placebo-controlled trial in Chinese men with&#xD;
      hyperlipidemia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objectives: to assess the effect of berberine on a set of well-established CVD risk factors,&#xD;
      including lipids, systolic and diastolic blood pressure, coagulation factors, fasting&#xD;
      glucose, insulin, adiposity (body mass index (BMI) and waist-hip ratio (WHR)) and the&#xD;
      mediation via testosterone and/or sex hormone binding globulin using a mechanistic, parallel&#xD;
      RCT.&#xD;
&#xD;
      Study design: a mechanistic, randomized, double-blind, placebo-controlled, parallel trial in&#xD;
      84 Chinese men in Hong Kong.&#xD;
&#xD;
      Interventions: the eligible participants will be randomized to take berberine (500 mg orally&#xD;
      twice a day) or placebo for 12 weeks. Blood samples will be taken at baseline, 8-week and&#xD;
      12-week intervention.&#xD;
&#xD;
      Data analysis and expected results: the investigators will use an intention to treat&#xD;
      analysis, with multiple imputation for missing data. The investigators will compare the&#xD;
      baseline characteristics of participants in the two arms using analysis of variance. The&#xD;
      investigators will assess the effects of berberine on changes in CVD risk factors using&#xD;
      analysis of variance, and the mediation using causal mediation analysis. Compared to the&#xD;
      placebo group, the participants receiving berberine are expected to have lower burden of&#xD;
      cardiovascular disease risk factors at the end of the intervention. These effects may be&#xD;
      mediated or partly mediated by lowering testosterone.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 1, 2019</start_date>
  <completion_date type="Actual">November 1, 2020</completion_date>
  <primary_completion_date type="Actual">November 1, 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>lipid profile</measure>
    <time_frame>change from baseline lipid profile at 8 weeks</time_frame>
    <description>LDL-cholesterol, HDL-cholesterol, triglycerides and total cholesterol in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>lipid profile</measure>
    <time_frame>change from baseline lipid profile at 12 weeks</time_frame>
    <description>LDL-cholesterol, HDL-cholesterol, triglycerides and total cholesterol in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>blood pressure</measure>
    <time_frame>change from baseline blood pressure at 8 weeks</time_frame>
    <description>systolic blood pressure and diastolic blood pressure in mmHg</description>
  </primary_outcome>
  <primary_outcome>
    <measure>blood pressure</measure>
    <time_frame>change from baseline blood pressure at 12 weeks</time_frame>
    <description>systolic blood pressure and diastolic blood pressure in mmHg</description>
  </primary_outcome>
  <primary_outcome>
    <measure>thromboxane A2</measure>
    <time_frame>change from baseline thromboxane A2 at 8 weeks</time_frame>
    <description>thromboxane A2 in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>thromboxane A2</measure>
    <time_frame>change from baseline thromboxane A2 at 12 weeks</time_frame>
    <description>thromboxane A2 in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>testosterone</measure>
    <time_frame>change from baseline testosterone at 8 weeks</time_frame>
    <description>testosterone in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>testosterone</measure>
    <time_frame>change from baseline testosterone at 12 weeks</time_frame>
    <description>testosterone in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>body mass index (BMI)</measure>
    <time_frame>change from baseline body mass index at 8 weeks</time_frame>
    <description>weight and height will be combined to report BMI in kg/m^2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>body mass index (BMI)</measure>
    <time_frame>change from baseline body mass index at 12 weeks</time_frame>
    <description>weight and height will be combined to report BMI in kg/m^2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>waist hip ratio</measure>
    <time_frame>change from baseline waist hip ratio at 8 weeks</time_frame>
    <description>waist circumstance and hip circumstance will be combined to report waist hip ratio</description>
  </primary_outcome>
  <primary_outcome>
    <measure>waist hip ratio</measure>
    <time_frame>change from baseline waist hip ratio at 12 weeks</time_frame>
    <description>waist circumstance and hip circumstance will be combined to report waist hip ratio</description>
  </primary_outcome>
  <primary_outcome>
    <measure>fasting glucose</measure>
    <time_frame>change from baseline fasting glucose at 8 weeks</time_frame>
    <description>fasting glucose in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>fasting glucose</measure>
    <time_frame>change from baseline fasting glucose at 12 weeks</time_frame>
    <description>fasting glucose in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>fasting insulin</measure>
    <time_frame>change from baseline fasting insulin at 8 weeks</time_frame>
    <description>fasting insulin in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>fasting insulin</measure>
    <time_frame>change from baseline fasting insulin at 12 weeks</time_frame>
    <description>fasting insulin in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>liver function</measure>
    <time_frame>change from baseline fasting insulin at 8 weeks</time_frame>
    <description>Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), total bilirubin, Gamma-glutamyltransferase, total protein and albumin in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>liver function</measure>
    <time_frame>change from baseline fasting insulin at 12 weeks</time_frame>
    <description>Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), total bilirubin, Gamma-glutamyltransferase, total protein and albumin in mmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>sex hormone binding globulin (SHBG)</measure>
    <time_frame>change from baseline SHBG at 8 weeks</time_frame>
    <description>SHBG in nmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>sex hormone binding globulin (SHBG)</measure>
    <time_frame>change from baseline SHBG at 12 weeks</time_frame>
    <description>SHBG in nmol/L</description>
  </primary_outcome>
  <primary_outcome>
    <measure>thrombin time</measure>
    <time_frame>change from baseline thrombin time at 8 weeks</time_frame>
    <description>thrombin time in sec</description>
  </primary_outcome>
  <primary_outcome>
    <measure>thrombin time</measure>
    <time_frame>change from baseline thrombin time at 12 weeks</time_frame>
    <description>thrombin time in sec</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">84</enrollment>
  <condition>Cardiovascular Risk Factor</condition>
  <arm_group>
    <arm_group_label>Berberine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>berberine (500 mg orally twice a day)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo (500 mg orally twice a day)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Berberine</intervention_name>
    <description>Purified berberine (500 mg orally twice a day) in tablets for 12 weeks</description>
    <arm_group_label>Berberine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo tablets, prepared with the same appearance, for 12 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men, who are&#xD;
&#xD;
               1. aged 20 to 65 years&#xD;
&#xD;
               2. of Chinese ethnicity&#xD;
&#xD;
               3. with hyperlipidemia, defined as TG greater than 150 mg/dl (1.70 mmol/L), TC&#xD;
                  greater than 200 mg/dl (5.16 mmol/L), and/or LDL-c greater than 100 mg/dl (2.58&#xD;
                  mmol/L)&#xD;
&#xD;
               4. willing to make return visits&#xD;
&#xD;
               5. not currently receiving hormone replacement therapy, such as testosterone&#xD;
                  replacement therapy, in the past 12 months&#xD;
&#xD;
               6. not currently taking berberine or traditional Chinese medicine that contains&#xD;
                  berberine, in the past 1 month&#xD;
&#xD;
               7. free of any congenital diseases, including familial hypercholesterolemia&#xD;
&#xD;
               8. free of any infectious diseases, e.g. seasonal influenza&#xD;
&#xD;
               9. free of anemia and glucose-6-phosphate dehydrogenase deficiency&#xD;
&#xD;
              10. with no history of any chronic diseases including ischemic heart disease,&#xD;
                  myocardial infarction (heart attack), stroke, diabetes, cancer, liver/renal&#xD;
                  dysfunction, and gastrointestinal disorders.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  All women, and men, who did not meet the aforementioned inclusion criteria, and/or&#xD;
             unable or unwilling to provide consent&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jie Zhao, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Li Ka Shing Faculty of Medicine</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <reference>
    <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>
    <PMID>25498346</PMID>
  </reference>
  <reference>
    <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>
    <PMID>18618524</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>24769118</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 6, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>November 2, 2020</last_update_submitted>
  <last_update_submitted_qc>November 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03770325
org study id: 15162621
nct id: NCT03770325
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: lipid profile
time frame: change from baseline lipid profile at 8 weeks
description: LDL-cholesterol, HDL-cholesterol, triglycerides and total cholesterol in mmol/L
measure: lipid profile
time frame: change from baseline lipid profile at 12 weeks
description: LDL-cholesterol, HDL-cholesterol, triglycerides and total cholesterol in mmol/L
measure: blood pressure
time frame: change from baseline blood pressure at 8 weeks
description: systolic blood pressure and diastolic blood pressure in mmHg
measure: blood pressure
time frame: change from baseline blood pressure at 12 weeks
description: systolic blood pressure and diastolic blood pressure in mmHg
measure: thromboxane A2
time frame: change from baseline thromboxane A2 at 8 weeks
description: thromboxane A2 in mmol/L
measure: thromboxane A2
time frame: change from baseline thromboxane A2 at 12 weeks
description: thromboxane A2 in mmol/L
measure: testosterone
time frame: change from baseline testosterone at 8 weeks
description: testosterone in mmol/L
measure: testosterone
time frame: change from baseline testosterone at 12 weeks
description: testosterone in mmol/L
measure: body mass index (BMI)
time frame: change from baseline body mass index at 8 weeks
description: weight and height will be combined to report BMI in kg/m^2
measure: body mass index (BMI)
time frame: change from baseline body mass index at 12 weeks
description: weight and height will be combined to report BMI in kg/m^2
measure: waist hip ratio
time frame: change from baseline waist hip ratio at 8 weeks
description: waist circumstance and hip circumstance will be combined to report waist hip ratio
measure: waist hip ratio
time frame: change from baseline waist hip ratio at 12 weeks
description: waist circumstance and hip circumstance will be combined to report waist hip ratio
measure: fasting glucose
time frame: change from baseline fasting glucose at 8 weeks
description: fasting glucose in mmol/L
measure: fasting glucose
time frame: change from baseline fasting glucose at 12 weeks
description: fasting glucose in mmol/L
measure: fasting insulin
time frame: change from baseline fasting insulin at 8 weeks
description: fasting insulin in mmol/L
measure: fasting insulin
time frame: change from baseline fasting insulin at 12 weeks
description: fasting insulin in mmol/L
measure: liver function
time frame: change from baseline fasting insulin at 8 weeks
description: Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), total bilirubin, Gamma-glutamyltransferase, total protein and albumin in mmol/L
measure: liver function
time frame: change from baseline fasting insulin at 12 weeks
description: Alanine transaminase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), total bilirubin, Gamma-glutamyltransferase, total protein and albumin in mmol/L
measure: sex hormone binding globulin (SHBG)
time frame: change from baseline SHBG at 8 weeks
description: SHBG in nmol/L
measure: sex hormone binding globulin (SHBG)
time frame: change from baseline SHBG at 12 weeks
description: SHBG in nmol/L
measure: thrombin time
time frame: change from baseline thrombin time at 8 weeks
description: thrombin time in sec
measure: thrombin time
time frame: change from baseline thrombin time at 12 weeks
description: thrombin time in sec
arm group label: Berberine
arm group type: Experimental
description: berberine (500 mg orally twice a day)
arm group label: Placebo
arm group type: Placebo Comparator
description: placebo (500 mg orally twice a day)
intervention type: Drug
intervention name: Berberine
description: Purified berberine (500 mg orally twice a day) in tablets for 12 weeks
arm group label: Berberine
intervention type: Drug
intervention name: Placebo
description: Placebo tablets, prepared with the same appearance, for 12 weeks
arm group label: Placebo
criteria: 
gender: Male
minimum age: 20 Years
maximum age: 65 Years
healthy volunteers: No
last name: Jie Zhao, PhD
role: Principal Investigator
affiliation: The University of Hong Kong
facility: 
country: Hong Kong
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.
PMID: 25498346
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.
PMID: 18618524
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.
PMID: 24769118
responsible party type: Sponsor