Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Insulin Resistance in Non-alcoholic Fatty Liver Disease

This study has been terminated.
(Protocol drug change required new clinicaltrails.gov entry)
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00252499
First received: November 9, 2005
Last updated: August 18, 2014
Last verified: August 2014
  Purpose

The purpose of this study is to determine whether nonalcoholic fatty liver disease (NAFLD) is associated with altered peripheral and hepatic insulin sensitivity and to investigate potential mechanisms underlying insulin resistance in NAFLD by determining associations between hepatic and peripheral insulin sensitivity, hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, beta-cell function and body fat distribution.


Condition Intervention
Fatty Liver
Insulin Resistance
Drug: rosiglitazone
Drug: fenofibrate
Drug: placebo for rosiglitazone
Drug: placebo for fenofibrate

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: Insulin Resistance in Non-alcoholic Fatty Liver Disease

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Liver/Spleen Ratio at 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Liver fat was estimated by non-contrast CT scan measuring the density ratio between the liver and spleen by Hounsfield units (liver/spleen ratio), which has been previously correlated with liver fat quantification by magnetic resonance spectroscopy.Ten separate measurements equally distributed throughout the liver and spleen were obtained and the Hounsfield units averaged. In subjects with more than one slice through the liver and spleen, the values for all slices were averaged.


Secondary Outcome Measures:
  • Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in the Liver Spleen Ratio by CT Scan From Baseline to 6 Months as a Measure of Fat in the Liver [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in Peripheral Insulin Sensitivity From Baseline to 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    A two-step stable isotope labeled, hyperinsulinemic-euglycemic clamp procedure was performed with a low dose insulin infusion (20 mU/m2/min) for 3 hours followed by a primed high dose insulin infusion (160 mU/m2/min x 5 minutes then 80 mU/m2/min) for two hours. D20 was infused and adjusted to maintain the blood glucose at 90 mg/dl. Samples for glucose, insulin and 6,6 2d glucose were drawn every 15 minutes during the final half hour of the basal, low dose and high dose insulin periods. Whole body insulin sensitivity was calculated as the rate of glucose disposal (Rd)/lean body mass during the high dose insulin infusion.

  • Changes in Intra-abdominal Fat Area From Baseline to 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Unenhanced CT scan images were obtained on a General Electric Discovery HD750 CT scanner. Intra-abdominal (IAF) areas were measured at the top of the iliac crest and quantified using the Tomovision program (SliceOMatic V4.3) by one trained technologist.

  • Change in Hepatic Insulin Sensitivity From Baseline to 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Hepatic insulin sensitivity was determined as the percent suppression of endogenous glucose production (EGP) at the end of the low dose insulin clamp.


Enrollment: 13
Study Start Date: October 2005
Study Completion Date: August 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo Arm
matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
Drug: placebo for rosiglitazone
placebo tablets that are matched to look like rosiglitazone
Drug: placebo for fenofibrate
placebo matched to look like fenofibrate tablets
Experimental: Rosiglitazone Arm
rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
Drug: rosiglitazone
PPAR-gamma agonist, insulin sensitizer
Drug: placebo for fenofibrate
placebo matched to look like fenofibrate tablets
Experimental: Fenofibrate Arm
micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid
Drug: fenofibrate
PPAR-alpha agonist, reduces triglycerides
Drug: placebo for rosiglitazone
placebo tablets that are matched to look like rosiglitazone

Detailed Description:

NAFLD and nonalcoholic steatohepatitis (NASH) are common liver disorders that are strongly associated with obesity, type 2 diabetes and dyslipidemia. The underlying pathophysiology of fatty infiltration of the liver is thought to be related to insulin resistance, which is an almost universal finding in patients with NAFLD. It is also possible that fat infiltration and inflammation in the liver may impair insulin sensitivity, either locally in the liver, or peripherally via the actions of inflammatory cytokines. We hypothesize that insulin resistance is a major causal factor leading to fat deposition in the liver and NAFLD, and thus interventions aimed at improving insulin sensitivity will result in a reduction of hepatic inflammation and steatosis.

Specific Aim 1: To determine in a cross-sectional study whether NAFLD is associated with altered peripheral and hepatic insulin sensitivity and to study their relationships with hepatic steatosis, dyslipidemia, inflammatory cytokines, glucose metabolism, -cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with rosiglitazone, an insulin sensitizer, or fenofibrate, a triglyceride lowering agent, will improve both hepatic as well as peripheral insulin sensitivity and thereby improve hepatic steatosis and inflammation in subjects with NAFLD.

The results of the proposed study will have important implications for our understanding of the mechanisms underlying insulin resistance and abnormalities in lipid and glucose metabolism in subjects with NAFLD and for the design of future studies aimed at the prevention and treatment of this condition.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18-80 years old Controls:

    • otherwise healthy Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated ALT and fatty liver by CT or ultrasound
  • Able to comply with taking 3 pills a day for 6 months and follow-up safety visits

Exclusion Criteria:

  • Controls:

    • history or evidence of hepatic steatosis
  • Cases:

    • Cirrhosis on liver biopsy or by clinical exam or fibrosis score
    • Causes of liver dysfunction other than NASH
  • Use of medications associated with hepatic steatosis:

    • glucocorticoids
    • estrogens
    • tamoxifen
    • amiodarone
    • accutane
    • sertraline
  • Use of medications that cause insulin resistance:

    • niacin
    • glucocorticoids
    • anti-HIV drugs or atypical antipsychotics
  • Use of lipid-lowering medications except stable dose statin
  • Use of anti-NASH drugs such as:

    • ursodeoxycholic acid
    • betaine milk thistle
  • Use of coumadin
  • Use of nitrates
  • Significant alcohol consumption:

    • Average >20 grams/day
  • In subjects with diabetes

    • a HbA1c >7.5% or use of insulin
    • metformin
    • rosiglitazone or pioglitazone
  • Liver transaminases:

    • Cases: ALT >5x upper limit of normal
    • Controls: ALT or AST above the normal range
  • Iron saturation >50%
  • Creatinine >1.5 mg/dl for men and >1.4 mg/dl for women
  • Hematocrit <33%
  • Pregnancy or lactation
  • Significant weight loss within the past 6 months for controls, or since the liver biopsy for case subjects, history of significant coronary artery disease or congestive heart failure
  • Retinopathy
  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: NCT00252499

Locations
United States, Washington
VA Puget Sound Health Care System, Seattle
Seattle, Washington, United States, 98108
Sponsors and Collaborators
Investigators
Principal Investigator: Kristina Marie Utzschneider, MD VA Puget Sound Health Care System, Seattle
  More Information

Additional Information:
Publications:
Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00252499     History of Changes
Other Study ID Numbers: CDA-2-044-08S
Study First Received: November 9, 2005
Results First Received: November 12, 2013
Last Updated: August 18, 2014
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
beta cell function
fenofibrate
non-alcoholic steatohepatitis
rosiglitazone
insulin sensitivity

Additional relevant MeSH terms:
Fatty Liver
Insulin Resistance
Liver Diseases
Digestive System Diseases
Glucose Metabolism Disorders
Hyperinsulinism
Metabolic Diseases
Fenofibrate
Insulin
Rosiglitazone
Antimetabolites
Hypoglycemic Agents
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014