Role of Pioglitazone and Berberine in Treatment of Non-Alcoholic Fatty Liver Disease

This study has been completed.
Sponsor:
Collaborators:
Shanghai Jiao Tong University School of Medicine
Shanghai Municipal Science and Technology Commission
Information provided by (Responsible Party):
Xin Gao, Fudan University
ClinicalTrials.gov Identifier:
NCT00633282
First received: March 3, 2008
Last updated: June 3, 2012
Last verified: June 2012
  Purpose

The purpose of this study is to evaluate the effects and safety of pioglitazone and berberine on the basis of lifestyle intervention to non-alcoholic fatty liver disease patients with impaired glucose regulation or type 2 diabetes mellitus.


Condition Intervention Phase
Nonalcoholic Fatty Liver Disease
Behavioral: Life style intervention
Drug: pioglitazone
Drug: berberine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Role of Pioglitazone and Berberine in Treatment of Non-alcoholic Fatty Liver Disease(NAFLD) Patients With Impaired Glucose Regulation or Type 2 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Fudan University:

Primary Outcome Measures:
  • Improved metabolic parameters(glucose, lipid, liver enzymes, etc.) [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    improvement of the metabolic parameters, including serum glucose of OGTT, fasting glucose,2 hour glucose,area under the glucose curve and HbA1c,lipid profile(TC、TG、HDL-c、LDL-c、ApoA、ApoB、ApoE and Lpa),liver enzymes(ALT,AST,ALP,γ-GT).


Secondary Outcome Measures:
  • liver fat content [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    improvement of liver fat content by 1H NMR spectroscopy

  • serum insulin [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    improvement of serum insulin including fasting insulin,2 hour insulin and area under insulin curve.

  • the ratio of withdrawing because of inefficiency [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Enrollment: 184
Study Start Date: March 2008
Study Completion Date: August 2011
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lifestyle intervention
Life style intervention including aerobic exercise and reducing energy intake(-500kcal) without drug
Behavioral: Life style intervention

calorie limited diet: to subtract 500 kcal from daily mean calorie intake when entering the treatment

activity: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate; or higher-intensity aerobic exercise for more than 90min per week with heart rate around 70% of the maximal heart rate

Other Names:
  • calorie limited diet
  • aerobic exercise
Experimental: Life style intervention, pioglitazone
Life style intervention with pioglitazone 15mg qd for 16 weeks
Behavioral: Life style intervention

calorie limited diet: to subtract 500 kcal from daily mean calorie intake when entering the treatment

activity: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate; or higher-intensity aerobic exercise for more than 90min per week with heart rate around 70% of the maximal heart rate

Other Names:
  • calorie limited diet
  • aerobic exercise
Drug: pioglitazone
pioglitazone tablet,15mg qd ,30 minutes before breakfast,for 16 weeks
Other Names:
  • Actlns
  • PPAR agonist
  • Thiazolidinediones
  • insulin sensitizer
Experimental: Life style intervention, berberine
Life style intervention with berberine 0.5g tid for 16 weeks
Behavioral: Life style intervention

calorie limited diet: to subtract 500 kcal from daily mean calorie intake when entering the treatment

activity: medium intensity aerobic exercise for more than 150 min per week with heart rate around 50-70% of the maximal heart rate; or higher-intensity aerobic exercise for more than 90min per week with heart rate around 70% of the maximal heart rate

Other Names:
  • calorie limited diet
  • aerobic exercise
Drug: berberine
berberine tablet 0.5g tid,30 minutes before each meal,for 16 weeks
Other Names:
  • traditional Chinese medicine
  • herb

Detailed Description:

Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic and increasing the risk for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is a group of diseases with too much fat in liver in the absence of excess alcohol consumption. NAFLD encompasses a histological spectrum ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. NAFLD is estimated to affect 25% of the worldwide population[1] and 15.35% of adults in shanghai urban area[2]. Epidemiological data showed that the fatty liver may predict, independent of other factors, the metabolic syndrome, type 2 diabetes, and cardiovascular disease. Therefore, we may prevent those diseases by treating NAFLD.Life style intervention including activity and reducing energy intake is recommended by health care providers for optimal health and is the most common prescribed therapy for individuals diagnosed with NAFLD.

TZDs are oral glucose-lowering medications used to treat type 2 diabetes that enhance insulin sensitivity. The strong relationship between insulin resistance and NAFLD suggests that insulin sensitizing therapies such as TZDs might be beneficial in the prevention or improvement in NAFLD.TZDs bind to the peroxisome proliferator-activated receptors (PPARs), in part, by facilitating enhanced TG storage by adipocytes, suppressing the ectopic storage of lipids into liver and skeletal muscle. In addition, TZDs appear to have anti-inflammatory properties, inhibiting adipocyte gene expression and reducing circulating levels of TNFα[3] and resistin[4], and increasing adiponectin concentrations[5]. Some researches demonstrated that pioglitazone(a TZD) significantly reduced liver fat content of NAFLD, and ameliorated biological parameters and liver histology of NASH[6]. However, there have not been similar data of treating chinese NAFLD with pioglitazone.

Berberine (BBR), a compound isolated from a Chinese herb was identified by Weijia [7] as a new cholesterol-lowering drug with a mechanism different from that of statin drugs. BBR elevates LDL receptor(LDLR) expression through a post-transcriptional mechanism that stabilizes the LDLR-mRNA. Considering the close relationship between NAFLD and lipid metabolism, we assume that BBR may be effective for NAFLD by improving lipid metabolism.

In order to evaluate these hypotheses, we plan to treat a group of NAFLD patients with impaired glucose regulation (IGR) or T2DM with pioglitazone or BBR in a randomized, open, controlled trial for 16 weeks.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have an age range between 18 to 65 years (inclusive).
  2. Patients with fatty liver confirmed by ultrasound.
  3. Patients must meet the criteria for impaired glucose regulation or type 2 diabetes mellitus (FPG ≥ 5.6 mmol/L and/or a two hour glucose value ≥ 7.8 mmol/L).
  4. Course of diabetic mellitus no more than 1 years
  5. Diabetic patients have not received anti-diabetic drugs, including insulin, biguanides, sulfonylureas, thiazolidinediones, Alpha-glucosidase inhibitors, or glinides for 4 weeks before the time of enrollment
  6. Patients have not received lipid-regulating drugs (statins, fibrates)for 4 weeks before the time of enrollment
  7. Blood pressure < 160/100 mmHg,after receiving lifestyle therapy and effective anti-hypertensive drugs.
  8. Patients must stopped other drugs medications for four weeks prior to entering the treatment period, such as: silybin, ursodeoxycholic acid, Polyene Phosphatidylcholine, vitamin E, some herbs with effect of regulating lipid and protecting liver function, etc.
  9. Liver fat content(LFC) assessed by 1H MRS ≥ 13%(LFC was calculated by dividing the integral of the methylene groups in fatty acid chains of the hepatic triglycerides by the sum of methylene groups and water).

Exclusion Criteria:

  1. Any causes of chronic liver disease other than NAFLD (such as - but not restricted to - alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, etc.);
  2. Patients with significantly impaired liver function: ALT or AST ≥ 2 times upper limit of normal;
  3. HBsAg (+) and/or HCV-Ab (+);
  4. Patients with type 1 diabetes mellitus or gestational diabetes or special type diabetes, and patients with BMI < 22 Kg/m2;
  5. Course of diabetes more than 1 years;
  6. Diabetics patients who have taken or are taking oral glucose-lowering drugs or insulin;
  7. Diabetics patients with a HbA1c > 7.5% on initial visit;
  8. Patients with severe diabetes complications (diabetes ketoacidosis, diabetes coma or with symptomatic of diabetes coma; dysfunction of nerve, retinopathy, dysfunction of kidney);
  9. Patients with serum creatinine ≥ 1.5 mg/dL (133 umol/L);
  10. Patients with a history of clinically significant heart disease (myocardial infarct, heart failure, and or severe cardiac rhythm);
  11. Complicating severe infection, within 6 months after operation, severe trauma;
  12. Patients with excess alcohol consumption≥140g/week(male); ≥ 70g/week(female);
  13. Patients have participated other clinical trials within 24 weeks;
  14. Patients with a history of drug allergy to TZDs and berberine;
  15. Patients wth gestation or possible gestation or lactation, or males or females who expecting gestation during clinical trial;
  16. Mental diseases patients;
  17. Those who refuse to sign informed consent;
  18. Any other conditions, which, in the opinion of the investigators would impede competence or compliance or possibility of hindering completion of the study;
  19. Patients with serum triglyceride ≥ 5.0 mmol/L;
  20. Patients with thyroid disease, including hyperthyroidism or hypothyroidism.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00633282

Locations
China, Shanghai
Department of Endocrinology and Metabolism,Shanghai Clinical Center of Diabetes,Shanghai Institute of Diabetes,The sixth people's Hospital Affiliated to Shanghai Jiaotong University
Shanghai, Shanghai, China, 200233
Department of Endocrinology and Metabolism,The Fifth People's Hospital,Fudan University
Shanghai, Shanghai, China, 200240
Endocrinology and Metabolism Department, Zhongshan Hospital, Fudan University,
Shanghai, Shanghai, China, 200032
Sponsors and Collaborators
Xin Gao
Shanghai Jiao Tong University School of Medicine
Shanghai Municipal Science and Technology Commission
Investigators
Principal Investigator: Xin GAO, MD Fudan University
  More Information

Publications:

Responsible Party: Xin Gao, MD. and Professor, Vice-President of Zhongshan Hospital, Director of Department of Endocrinology & Metabolism of Zhongshan Hospital Fudan University, Fudan University
ClinicalTrials.gov Identifier: NCT00633282     History of Changes
Other Study ID Numbers: 07JC14011
Study First Received: March 3, 2008
Last Updated: June 3, 2012
Health Authority: China: Food and Drug Administration

Keywords provided by Fudan University:
Nonalcoholic Fatty Liver Disease
Pioglitazone
Berberine
Impaired Glucose Metabolism

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Digestive System Diseases
Pioglitazone
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 23, 2014