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Nonalcoholic Fatty Liver DiseasePhase 2NCT00633282

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

A Phase 2 study testing Life style intervention, pioglitazone and berberine in people with Nonalcoholic Fatty Liver Disease, run by Xin Gao at 3 sites in China.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Nonalcoholic Fatty Liver Disease
What is being tested?
Life style intervention, pioglitazone and berberine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
184 participants
Where
3 sitesChina
Study dates
Mar 2008to Aug 2011
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have an age range between 18 to 65 years (inclusive).
  • Patients with fatty liver confirmed by ultrasound.
  • 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).
  • Course of diabetic mellitus no more than 1 years
  • 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
  • Patients have not received lipid-regulating drugs (statins, fibrates)for 4 weeks before the time of enrollment
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  • Blood pressure < 160/100 mmHg,after receiving lifestyle therapy and effective anti-hypertensive drugs.
  • 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.
  • 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).

Who cannot join

  • 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.);
  • Patients with significantly impaired liver function: ALT or AST ≥ 2 times upper limit of normal;
  • HBsAg (+) and/or HCV-Ab (+);
  • Patients with type 1 diabetes mellitus or gestational diabetes or special type diabetes, and patients with BMI < 22 Kg/m2;
  • Course of diabetes more than 1 years;
  • Diabetics patients who have taken or are taking oral glucose-lowering drugs or insulin;
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  • Diabetics patients with a HbA1c > 7.5% on initial visit;
  • Patients with severe diabetes complications (diabetes ketoacidosis, diabetes coma or with symptomatic of diabetes coma; dysfunction of nerve, retinopathy, dysfunction of kidney）;
  • Patients with serum creatinine ≥ 1.5 mg/dL (133 umol/L);
  • Patients with a history of clinically significant heart disease (myocardial infarct, heart failure, and or severe cardiac rhythm);
  • Complicating severe infection, within 6 months after operation, severe trauma;
  • Patients with excess alcohol consumption≥140g/week(male); ≥ 70g/week(female);
  • Patients have participated other clinical trials within 24 weeks;
  • Patients with a history of drug allergy to TZDs and berberine;
  • Patients wth gestation or possible gestation or lactation, or males or females who expecting gestation during clinical trial;
  • Mental diseases patients;
  • Those who refuse to sign informed consent;
  • Any other conditions, which, in the opinion of the investigators would impede competence or compliance or possibility of hindering completion of the study;
  • Patients with serum triglyceride ≥ 5.0 mmol/L;
  • Patients with thyroid disease, including hyperthyroidism or hypothyroidism.

Trial locations and contacts

3 sites in 1 country.

China3 sites

  • Endocrinology and Metabolism Department, Zhongshan Hospital, Fudan University,

    Shanghai, Shanghai Municipality, 200032

  • 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 Municipality, 200233

  • Department of Endocrinology and Metabolism,The Fifth People's Hospital，Fudan University

    Shanghai, Shanghai Municipality, 200240

Other trials in China

About this study

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

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.

Read the 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.

Being tested
Life style intervention, pioglitazone, berberine
Keywords
Nonalcoholic Fatty Liver Disease, Pioglitazone, Berberine, Impaired Glucose Metabolism
Medical subject headings
Non-alcoholic Fatty Liver Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Life style interventionBehavioural

    Also called calorie limited diet, aerobic exercise

    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

  • pioglitazoneDrug

    Also called Actlns, PPAR agonist, Thiazolidinediones, insulin sensitizer

    pioglitazone tablet,15mg qd ,30 minutes before breakfast,for 16 weeks

  • berberineDrug

    Also called traditional Chinese medicine, herb

    berberine tablet 0.5g tid,30 minutes before each meal,for 16 weeks

Study groups in NCT00633282
Study groupRoleWhat they receive
Lifestyle interventionExperimentalLife style intervention including aerobic exercise and reducing energy intake(-500kcal) without drug
Receives: Behavioral: Life style intervention
Life style intervention, pioglitazoneExperimentalLife style intervention with pioglitazone 15mg qd for 16 weeks
Receives: Behavioral: Life style intervention; Drug: pioglitazone
Life style intervention, berberineExperimentalLife style intervention with berberine 0.5g tid for 16 weeks
Receives: Behavioral: Life style intervention; Drug: berberine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Improved metabolic parameters(glucose, lipid, liver enzymes, etc.)

    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）.

    Measured: 16 weeks

Secondary outcomes (3)

  1. liver fat content

    improvement of liver fat content by 1H NMR spectroscopy

    Measured: 16 weeks

  2. serum insulin

    improvement of serum insulin including fasting insulin,2 hour insulin and area under insulin curve.

    Measured: 16 weeks

  3. the ratio of withdrawing because of inefficiency

    Measured: 16 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Mar 2008 (estimated)
  2. Study startMar 2008
  3. Primary completionAug 2011
  4. Study completionAug 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
184 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00633282
Sponsor's protocol ID
07JC14011
Status last verified
Jun 2012
First submitted
3 Mar 2008
Last updated
5 Jun 2012
Results posted
No
Data monitoring committee
Yes

Publications

  • Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005 Jul;42(1):44-52. doi: 10.1002/hep.20734.

    PubMed 15895401

  • Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, Li F, Chen SY. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol. 2005 Sep;43(3):508-14. doi: 10.1016/j.jhep.2005.02.042.

    PubMed 16006003

  • Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2004 Sep;89(9):4312-9. doi: 10.1210/jc.2004-0190.

    PubMed 15356026

  • Szapary PO, Bloedon LT, Samaha FF, Duffy D, Wolfe ML, Soffer D, Reilly MP, Chittams J, Rader DJ. Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome. Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):182-8. doi: 10.1161/01.ATV.0000195790.24531.4f. Epub 2005 Nov 10.

    PubMed 16284192

  • Shadid S, Stehouwer CD, Jensen MD. Diet/Exercise versus pioglitazone: effects of insulin sensitization with decreasing or increasing fat mass on adipokines and inflammatory markers. J Clin Endocrinol Metab. 2006 Sep;91(9):3418-25. doi: 10.1210/jc.2006-0015. Epub 2006 Jun 27.

    PubMed 16804048

  • Yoneda M, Endo H, Nozaki Y, Tomimoto A, Fujisawa T, Fujita K, Yoneda K, Takahashi H, Saito S, Iwasaki T, Yamamoto S, Tsutsumi S, Aburatani H, Wada K, Hotta K, Nakajima A. Life style-related diseases of the digestive system: gene expression in nonalcoholic steatohepatitis patients and treatment strategies. J Pharmacol Sci. 2007 Oct;105(2):151-6. doi: 10.1254/jphs.fm0070063. Epub 2007 Oct 6.

    PubMed 17928738

  • Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004 Dec;10(12):1344-51. doi: 10.1038/nm1135. Epub 2004 Nov 7.

    PubMed 15531889

  • Yan H, Wu W, Chang X, Xia M, Ma S, Wang L, Gao J. Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism. Biol Sex Differ. 2021 Jan 4;12(1):1. doi: 10.1186/s13293-020-00344-1.

    PubMed 33397443

  • Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.

    PubMed 33210751

  • Chang X, Wang Z, Zhang J, Yan H, Bian H, Xia M, Lin H, Jiang J, Gao X. Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease. J Transl Med. 2016 Sep 15;14:266. doi: 10.1186/s12967-016-0982-x.

    PubMed 27629750

  • 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.

    PubMed 26252777

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Life style intervention, pioglitazone and berberine in people with Nonalcoholic Fatty Liver Disease, run by Xin Gao at 3 sites in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Jun 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Improved metabolic parameters(glucose, lipid, liver enzymes, etc.) (time frame: 16 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00633282, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jun 2012.

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