Obesity and Nonalcoholic Fatty Liver Disease

• ClinicalTrials.gov Identifier: NCT00262964
• Recruitment Status: Completed
• First Posted: December 7, 2005
• Results First Posted: June 28, 2010
• Last Update Posted: July 11, 2018
• Sponsor: Washington University School of Medicine
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

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. 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 or disease	Intervention/treatment	Phase
Non-alcoholic Fatty Liver Disease	Drug: Niacin; Drug: fenofibrate; Drug: placebo	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Obesity and Nonalcoholic Fatty Liver Disease
• Study Start Date: October 2004
• Actual Primary Completion Date: December 2008
• Actual Study Completion Date: December 2008

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. Hepatic Insulin Sensitivity Index (HISI) [ Time Frame: baseline cross-sectional data ]
   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.
2. Percent Increase in Skeletal Muscle Insulin Sensitivity During Insulin Infusion. [ Time Frame: baseline cross-sectional data pre and post nine hour euglycemic clamp ]
   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.
3. Adipose Tissue Insulin Sensitivity [ Time Frame: baseline cross-sectional data pre and post nine hour euglycemic clamp ]
   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.
4. Hepatic Fat Content for Fenofibrate and Niacin Groups [ Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   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.
5. Adipose Tissue Insulin Sensitivity in Fenofibrate and Niacin Groups [ Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   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
6. Change From Baseline in Skeletal Muscle Insulin Sensitivity [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   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.
7. Change From Baseline in Hepatic Insulin Sensitivity Index [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   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 :

1. Very Low Density Lipoprotein - Triglyceride Production Rate [ Time Frame: baseline cross-sectional data ]
   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).
2. Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate [ Time Frame: baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   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.
3. Change From Baseline in VLDL-Tg Clearance Rate [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute.
4. Change From Baseline in VLDL-Tg Production Rate [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute.
5. Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration [ Time Frame: baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) ]
   Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• 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

Locations

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

Sponsors and Collaborators

Washington University School of Medicine

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Samuel Klein, MD; Washington University School of Medicine

More Information

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00262964
• Other Study ID Numbers: DK37948; R01DK037948 ( U.S. NIH Grant/Contract )
• First Posted: December 7, 2005
• Results First Posted: June 28, 2010
• Last Update Posted: July 11, 2018
• Last Verified: June 2018

Keywords provided by Washington University School of Medicine:

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

Additional relevant MeSH terms:

Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Obesity; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Digestive System Diseases; Niacin; Fenofibrate; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Vasodilator Agents; Vitamin B Complex; Vitamins; Micronutrients; Physiological Effects of Drugs