Official Title: “Role of Pioglitazone and Berberine in the Treatment of Non-Alcoholic Fatty Liver Disease(NAFLD) Patients With Impaired Glucose Regulation or Type 2 Diabetes Mellitus”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: November 2008

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 LDLR expression through a post-transcriptional mechanism that stabilizes the 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.

Intervention(s) in this Clinical Trial

• Behavioral: Life style intervention
  • calorie limited diet: to subtract 500 kcal from daily mean calorie intake before 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
• Drug: pioglitazone
  • pioglitazone tablet 15mg qd for 16 weeks
• Drug: berberine
  • berberine tablet 0.5g tid for 16 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Life style intervention including activity and reducing energy intake without drug
• Experimental: 2
  • Life style intervention with pioglitazone 15mg qd for 16 weeks
• Experimental: 3
  • Life style intervention with berberine 0.5g tid for 16 weeks

Primary Measures

• OGTT (glucose, insulin, AUC of insulin), HbA1c; lipid profile（TC, TG, HDL-c, LDL-c, ApoA, ApoB, ApoE, Lpa); liver enzymes (ALT, AST, γ-GT, ALP)
  • Time Frame: 16 weeks
    Safety Issue?: Yes

Secondary Measures

• liver fat content by 1H NMR spectroscopy
  • Time Frame: 16 weeks
    Safety Issue?: Yes

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).Patients with a HbA1c > 7.5% will be excluded from the study.
• 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 assessed by 1H MRS ≥ 15%.

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Fudan University

Overall Clinical Trial Officials and Contacts

Xin GAO, master Principal Investigator unaffiliated  

Overall Contact: Xin GAO, master 86-021-64041990 gao.xin@zs-hospital.sh.cn

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00633282

Study ID Number: 07JC14011

ClinicalTrials.gov Identifier: NCT00633282

Health Authority: China: State Food and Drug Administration