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Insulin Resistance in Non-alcoholic Fatty Liver Disease

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ClinicalTrials.gov Identifier: NCT00252499
Recruitment Status : Terminated (Protocol drug change required new clinicaltrails.gov entry)
First Posted : November 11, 2005
Results First Posted : April 11, 2014
Last Update Posted : August 20, 2014
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development ( US Department of Veterans Affairs )

Tracking Information
First Submitted Date  ICMJE November 9, 2005
First Posted Date  ICMJE November 11, 2005
Results First Submitted Date  ICMJE November 12, 2013
Results First Posted Date  ICMJE April 11, 2014
Last Update Posted Date August 20, 2014
Study Start Date  ICMJE October 2005
Actual Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2014)
Liver/Spleen Ratio at 6 Months [ Time Frame: 6 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 9, 2005)
  • The 2 primary outcome measures are:
  • 1. Change in alanine aminotransferase (ALT) levels as a marker of hepatic inflammation
  • 2. Change in the liver spleen ration by CT scan as a measure of fat in the liver
Change History Complete list of historical versions of study NCT00252499 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 5, 2014)
  • Change in Alanine Aminotransferase (ALT) Levels From Baseline to 6 Months [ Time Frame: 6 months ]
  • 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 ]
  • Change in Peripheral Insulin Sensitivity From Baseline to 6 Months [ Time Frame: 6 months ]
    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 ]
    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 ]
    Hepatic insulin sensitivity was determined as the percent suppression of endogenous glucose production (EGP) at the end of the low dose insulin clamp.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 9, 2005)
Peripheral insulin sensitivityHepatic insulin sensitivityInflammatory cytokinesLipid profileGlucose toleranceBeta-cell function
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Insulin Resistance in Non-alcoholic Fatty Liver Disease
Official Title  ICMJE Insulin Resistance in Non-alcoholic Fatty Liver Disease
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE
  • Fatty Liver
  • Insulin Resistance
Intervention  ICMJE
  • Drug: rosiglitazone
    PPAR-gamma agonist, insulin sensitizer
  • Drug: fenofibrate
    PPAR-alpha agonist, reduces triglycerides
  • Drug: placebo for rosiglitazone
    placebo tablets that are matched to look like rosiglitazone
  • Drug: placebo for fenofibrate
    placebo matched to look like fenofibrate tablets
Study Arms  ICMJE
  • Placebo Comparator: Placebo Arm
    matching placebo for rosiglitazone, 1 po bid and placebo for fenofibrate 1 po qd
    Interventions:
    • Drug: placebo for rosiglitazone
    • Drug: placebo for fenofibrate
  • Experimental: Rosiglitazone Arm
    rosiglitazone 4 mg po bid and fenofibrate placebo 1 po qd
    Interventions:
    • Drug: rosiglitazone
    • Drug: placebo for fenofibrate
  • Experimental: Fenofibrate Arm
    micronized fenofibrate 200 mg 1 po qd and rosiglitazone placebo 1 po bid
    Interventions:
    • Drug: fenofibrate
    • Drug: placebo for rosiglitazone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 5, 2014)
13
Original Enrollment  ICMJE
 (submitted: November 9, 2005)
48
Actual Study Completion Date  ICMJE August 2010
Actual Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00252499
Other Study ID Numbers  ICMJE CDA-2-044-08S
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party VA Office of Research and Development ( US Department of Veterans Affairs )
Study Sponsor  ICMJE US Department of Veterans Affairs
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kristina Marie Utzschneider, MD VA Puget Sound Health Care System, Seattle
PRS Account VA Office of Research and Development
Verification Date August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP