Obesity and Nonalcoholic Fatty Liver Disease

NCT00262964 | Completed Results DMC

• 2 other identifiers: DK37948R01DK037948
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Non-alcoholic Fatty Liver Disease

Keywords

non-alcoholic fatty liver disease; obesity; fatty liver disease

Outcome Measures

Primary Outcomes (7)

• Hepatic Insulin Sensitivity Index (HISI)

  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.

  baseline cross-sectional data

• Percent Increase in Skeletal Muscle Insulin Sensitivity During Insulin Infusion.

  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.

  baseline cross-sectional data pre and post nine hour euglycemic clamp

• Adipose Tissue Insulin Sensitivity

  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.

  baseline cross-sectional data pre and post nine hour euglycemic clamp

• Hepatic Fat Content for Fenofibrate and Niacin Groups

  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.

  baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)

• Adipose Tissue Insulin Sensitivity in Fenofibrate and Niacin Groups

  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

  baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)

• Change From Baseline in Skeletal Muscle Insulin Sensitivity

  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.

  baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

• Change From Baseline in Hepatic Insulin Sensitivity Index

  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.

  baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Secondary Outcomes (5)

• Very Low Density Lipoprotein - Triglyceride Production Rate

  baseline cross-sectional data

• Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate

  baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin)

• Change From Baseline in VLDL-Tg Clearance Rate

  baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

• Change From Baseline in VLDL-Tg Production Rate

  baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

• Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration

  baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin)

Study Arms (4)

NAFLD-Niacin

EXPERIMENTAL

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

Control

NO INTERVENTION

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.

NAFLD-fenofibrate

EXPERIMENTAL

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

NAFLD-placebo

PLACEBO COMPARATOR

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

Interventions

Niacin DRUG

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.

Also known as: niaspan

NAFLD-Niacin

fenofibrate DRUG

Subjects randomized to fenofibrate will be treated with 200 mgs per day for eight weeks.

Also known as: Tricor

NAFLD-fenofibrate

placebo DRUG

Subjects randomized to placebo will be treated with one placebo pill per day for eight weeks.

NAFLD-placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Obesity

Interventions

Niacin; Fenofibrate

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Fibric Acids; Isobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Phenyl Ethers; Ethers; Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Ketones

Results Point of Contact

• Title: Elisa Fabbrini, MD
• Organization: Washington University School of Medicine

efabbrini@dom.wustl.edu

314-362-8156

Study Officials

• Samuel Klein, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2005
• First Posted: December 7, 2005
• Study Start: October 1, 2004
• Primary Completion: December 1, 2008
• Study Completion: December 1, 2008
• Last Updated: July 11, 2018
• Results First Posted: June 28, 2010

Record last verified: 2018-06

Locations

US (1)