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Insulin Resistance in Non-alcoholic Fatty Liver Disease

This study has been terminated.
(Low recruitment in intervention study. Baseline data published.)
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01289639
First received: January 21, 2011
Last updated: October 10, 2014
Last verified: October 2014
  Purpose

The study is designed to investigate the relationship between insulin resistance and non-alcoholic fatty liver disease (NAFLD) 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
Drug: fenofibrate
Drug: pioglitazone
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Insulin Resistance in Non-alcoholic Fatty Liver Disease (Protocol Drug Change From Project Career Development Award (CDA)-2-044-08S)

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Liver/Spleen Ratio Measured as the Ratio in Hounsfield Units Between the Liver and the Spleen on Computed Tomography (CT) Scan [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in Alanine Aminotransferase (ALT) Levels [ Time Frame: 0-6 months ] [ Designated as safety issue: No ]
  • Change in Liver/Spleen Ratio Measure by the Density Ratio in Hounsfield Units Between the Liver and the Spleen by CT [ Time Frame: 0-6 months ] [ Designated as safety issue: No ]
  • Change in Peripheral Insulin Sensitivity [ Time Frame: 0-6 months ] [ Designated as safety issue: No ]
    Change in the rate of glucose disposal (Rd) during the low dose clamp. During a clamp procedure, insulin is infused at a dose based on body size and a glucose solution is infused and the rate adjusted every 5 minutes based on a blood glucose reading to maintain the blood glucose stable at 90 mg/dl (normal level). Using glucose isotopes and the rate of the glucose infusion, we are then able to calculate how much glucose the liver is producing and how much glucose is being taken up into tissues. This provides a measure of insulin sensitivity.

  • Change in Intra-abdominal Fat Area by CT Scan [ Time Frame: 0-6 months ] [ Designated as safety issue: No ]
  • Change in Hepatic Insulin Sensitivity [ Time Frame: 0-6 months ] [ Designated as safety issue: No ]
    Hepatic insulin sensitivity was determined using stable glucose isotope measurements during the low dose hyperinsulinemic euglycemic clamp to determine the rate of endogenous glucose production in the fasting state and in response to a low dose glucose infusion. The ability of insulin to suppress glucose, which is mainly produced by the liver, thus provides a measure of hepatic insulin sensitivity and is expressed as a percentage of the basal state. Change in the ability of low dose insulin to suppress endogenous glucose production during a labeled hyperinsulinemic euglycemic clamp.


Enrollment: 11
Study Start Date: October 2005
Estimated Study Completion Date: August 2015
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
matching placebo 1 po qd
Drug: placebo
placebo 1 capsule po qd
Other Name: placebo
Experimental: Fenofibrate
micronized fenofibrate 200 mg 1 po qd
Drug: fenofibrate
micronized fenofibrate 200 mg 1 po qd
Other Name: micronized fenofibrate
Experimental: Pioglitazone
pioglitazone 30 mg po qd
Drug: pioglitazone
pioglitazone 30 mg po qd
Other Name: Actos

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, beta-cell function and body fat distribution. Specific Aim 2: To determine in a 6 month placebo-controlled double-blinded treatment study if treatment with pioglitazone, 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:

Control subjects: nl liver enzymes and no history of liver disease Case subjects: NAFLD on liver biopsy within the past 3 years or presumed NAFLD with otherwise unexplained elevated alanine aminotransferase (ALT) and fatty liver by computerized tomography (CT) scan or ultrasound

  • Able to comply with taking 1 pill a day for 6 months and follow-up safety visits

Exclusion Criteria:

  • 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 hemoglobin A1c (HbA1c) >7.5% or use of insulin, metformin, rosiglitazone or pioglitazone
  • Liver transaminases: ALT >5x upper limit of normal,
  • 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 or since the liver biopsy
  • 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: NCT01289639

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

Publications:
Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01289639     History of Changes
Other Study ID Numbers: CDA-2-044-08S-2
Study First Received: January 21, 2011
Results First Received: October 1, 2014
Last Updated: October 10, 2014
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
non-alcoholic fatty liver disease
non-alcoholic steatohepatitis
insulin resistance
pioglitazone
fenofibrate

Additional relevant MeSH terms:
Fatty Liver
Insulin Resistance
Liver Diseases
Digestive System Diseases
Glucose Metabolism Disorders
Hyperinsulinism
Metabolic Diseases
Fenofibrate
Insulin
Pioglitazone
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 25, 2014