Obesity and Nonalcoholic Fatty Liver Disease

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00262964
First received: December 6, 2005
Last updated: July 2, 2010
Last verified: July 2010
  Purpose

The primary goal of this study is to provide a better understanding of: 1) the pathogenesis and pathophysiology of non-alcoholic fatty liver disease (NAFLD) in obese subjects, and 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. The following hypotheses will be tested:

  1. obesity causes hepatic fat accumulation because of excessive fatty acid release from fat tissue and increased free fatty acid availability,
  2. increased hepatic (liver) fat content causes insulin-resistant glucose (sugar) production by the liver and altered liver protein synthesis,
  3. increased hepatic fat content causes increased lipid (fat) peroxidation, hepatic inflammation, necrosis and fibrosis, and
  4. marked weight loss improves NAFLD once patients are weight stable.

Condition Intervention
Non-Alcoholic Fatty Liver Disease
Drug: Niacin
Drug: fenofibrate
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Factorial Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Obesity and Nonalcoholic Fatty Liver Disease

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Hepatic Insulin Sensitivity Index (HISI) [ Time Frame: baseline cross-sectional data ] [ Designated as safety issue: No ]
    Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index(HISI) is the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.

  • Percent Increase in Skeletal Muscle Insulin Sensitivity During Insulin Infusion. [ Time Frame: baseline cross-sectional data pre and post nine hour euglycemic clamp ] [ Designated as safety issue: No ]
    A precise measure of the ability of insulin to stimulate glucose uptake by skeletal muscle. Skeletal muscle insulin sensitivity, measured as the increase from baseline in skeletal muscle glucose uptake during insulin infusion(percentage)as part of a nine hour euglycemic hyperinsulinemic clamp study.

  • Adipose Tissue Insulin Sensitivity [ Time Frame: baseline cross-sectional data pre and post nine hour euglycemic clamp ] [ Designated as safety issue: No ]
    The ability of insulin to suppress the release of fatty acids from adipose tissue: Adipose tissue insulin sensitivity, measured as the suppression from baseline of free fatty acid release from adipose tissue (lipolysis) during insulin infusion as part of a nine hour euglycemic hyperinsulinemic clamp study.

  • Hepatic Fat Content for Fenofibrate and Niacin Groups [ Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    Hepatic fat content as measured by magnetic resonance spectroscopy. A PRESS sequence was used. The results from three 10 cubic centimeter voxels positioned within the liver were averaged. The measure is a ratio of triglyceride signal to total signal.

  • Adipose Tissue Insulin Sensitivity in Fenofibrate and Niacin Groups [ Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    The baseline and post-treatment measures of adipose tissue insulin sensitivity (ATIS) were compared. ATIS at both timepoints is the suppression from fasting levels of free fatty acid release from adipose tissue (lipolysis) during an insulin infusion as part of a euglycemic clamp study. It is the percent decrease from time zero to the end of the nine hour euglycemic hyperinsulinemic clamp

  • Change From Baseline in Skeletal Muscle Insulin Sensitivity [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    Changes in skeletal muscle insulin sensitivity (SMIS). SMIS was measured as the increase in skeletal muscle glucose uptake from time zero to the end of a nine hour euglycemic clamp and insulin infusion study. This increase is the percentage change from time zero to end of insulin infusion at nine hours.

  • Change From Baseline in Hepatic Insulin Sensitivity Index [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index (HISI) is measured as the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.


Secondary Outcome Measures:
  • Very Low Density Lipoprotein - Triglyceride Production Rate [ Time Frame: baseline cross-sectional data ] [ Designated as safety issue: No ]
    Very low density lipoprotein triglyceride (VLDL-TG) production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute (μmol/L/min).

  • Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate [ Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    VLDL-apolipoprotein B (apoB) concentrations were measured as part of a VLDL metabolism study utilizing stable isotope tracers. VLDL apoB production rate, a measure of hepatic secretion of VLDL-apolipoproteinB-100 per liter of plasma per minute.

  • Change From Baseline in VLDL-Tg Clearance Rate [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute.

  • Change From Baseline in VLDL-Tg Production Rate [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute.

  • Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ] [ Designated as safety issue: No ]
    Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg)


Enrollment: 51
Study Start Date: October 2004
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NAFLD-Niacin
Subjects, having previously diagnosed with NAFLD, were given Niacin for 16 weeks. The dosage was 500mg/day for week 1, 1000mg/day for week 2, 1500mg/day for week three and 2000mg/day for weeks 4 through 16.
Drug: Niacin
Subjects randomized to Niacin therapy will be treated with Niacin at night for 16 wks to reduce plasma free fatty acid concentrations. The dose of medication will be gradually increased: 500 mg/day during week 1, 1000 mg/day during week 2, 1500 mg/day during week 3, and 2000mg/day during weeks 4-16.
Other Name: niaspan
No Intervention: Control
Subjects were found to have intrahepatic triglyceride levels below the threshold for Non-Alcoholic Fatty Liver Disease (NAFLD). For this study that threshold was set at 10% intrahepatic triglyceride content as determined by magnetic resonance spectroscopy. These control subjects did not participate in any intervention. Only baseline features were characterized for this arm.
Experimental: NAFLD-fenofibrate
Subjects diagnosed with NAFLD were randomized to fenofibrate, an oral medication, nightly for eight weeks. Subjects will be given a dose of 200mg/day.
Drug: fenofibrate
Subjects randomized to fenofibrate will be treated with 200 mgs per day for eight weeks.
Other Name: Tricor
Placebo Comparator: NAFLD-placebo
These subjects were diagnosed with Non-Alcoholic Fatty Liver Disease (NAFLD) and received an 8 week course of a placebo pill. Their baseline characteristics were averaged into the overall NAFLD baseline characteristics along with the baseline data for the two intervention groups.
Drug: placebo
Subjects randomized to placebo will be treated with one placebo pill per day for eight weeks.

Detailed Description:

Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD), which represents a spectrum of liver diseases. NAFLD is a major health problem in the US because of its high prevalence and causal relationship with serious liver abnormalities. However, the mechanism(s)responsible for developing NAFLD in obese persons and the effects on liver function are not known. This gap in knowledge has made it difficult to identify effective therapy. The results from these studies will lay the groundwork for the development of novel therapeutic interventions for NAFLD in obese patients.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All

  • 18 - 45 years old
  • Class I obesity, i.e. Body Mass Index (BMI) between 30 and 45.
  • weight less than 300 lbs.

Exclusion Criteria:

  • Active or previous infection with hepatitis B or C, as well as other liver disease.
  • History of alcohol abuse
  • Diabetes
  • Medications that cause liver damage or steatosis.
  • Women who are pregnant or lactating.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00262964

Locations
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Samuel Klein, MD Washington University School of Medicine
  More Information

No publications provided

Responsible Party: Samuel Klein, MD, William H. Danforth Professor of Medicine and Nutritional Science, Washington University
ClinicalTrials.gov Identifier: NCT00262964     History of Changes
Other Study ID Numbers: DK37948, R01DK037948
Study First Received: December 6, 2005
Results First Received: March 15, 2010
Last Updated: July 2, 2010
Health Authority: United States: Federal Government

Keywords provided by Washington University School of Medicine:
non-alcoholic fatty liver disease
obesity
fatty liver disease

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Obesity
Digestive System Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Niacin
Fenofibrate
Nicotinic Acids
Niacinamide
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Vasodilator Agents
Cardiovascular Agents
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 25, 2014