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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK037948 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Very Low Density Lipoprotein - Triglyceride Production Rate | 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). | baseline cross-sectional data |
| Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate |
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Inclusion Criteria:
All
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Samuel Klein, MD | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
We screened 138 subjects. 80 would-be participants failed the screening. This was often due to not having Non-alcoholic Fatty Liver Disease. Other subjects were excluded due to use of various medications or the presence of some excluded disease such as type 2 diabetes. Of the 58 that passed screening 51 chose to enroll in the study.
Beginning and ending recruitment dates: Beginning - 10/20/04; Ending - 09/24/07. Recruitment occurred only at Washington University in St. Louis.
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| ID | Title | Description |
|---|---|---|
| FG000 | NAFLD - Niacin | subjects diagnosed with NAFLD were randomized to a sixteen week regimen of niacin. |
| FG001 | NAFLD - Fenofibrate | Subjects diagnosed with NAFLD were randomized to an eight week regimen of fenofibrate |
| FG002 | Controls | Subjects with normal intrahepatic fat triglyceride(IHTG) levels (<10%). IHTG was measured using magnetic resonance spectroscopy and defined as the extrapolated ratio of triglyceride signal to water signal at time t = 0. |
| FG003 | NAFLD - no Drug | Subjects with elevated intrahepatic triglyceride (IHTG) levels (>10%) who were measured only once (baseline). These subjects did not undergo drug therapy, in contrast to the NAFLD-niacin and NAFLD-fenofibrate group subjects. IHTG was measured using magnetic resonance spectroscopy and defined as the extrapolated ratio of triglyceride signal to water signal at time t = 0. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Controls | Subjects with normal intra-hepatic triglyceride content (defined by less than 10% lipid to water signal in magnetic resonance spectroscopy). |
| BG001 | NAFLD | Subjects diagnosed with Non-Alcoholic Fatty Liver Disease(NAFLD). Determination of NAFLD was by magnetic resonance spectroscopy of intra-hepatic triglyceride content (defined by greater than 10% lipid to water signal). This group included subjects later randomized into the NAFLD-Niacin, NAFLD-Fenofibrate, and NAFLD-no intervention arms. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | number of subjects determined by power calculations. Analysis was per protocol. Intrahepatic triglyceride was determined by magnetic resonance spectroscopy. | Posted | Mean | Standard Error | [10000/(μmol/min)x(mU/L)] | baseline cross-sectional data |
|
Adverse event data was collected from baseline testing through post-treatment testing. The "NAFLD - no drug" and control groups were only followed through the baseline testing.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | NAFLD - Fenofibrate | Subjects diagnosed with NAFLD were randomized to an weight week regimen of fenofibrate |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| elevation of liver enzymes | Hepatobiliary disorders | Systematic Assessment | assessment of liver dysfunction by ALT and/or AST counts in blood plasma |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Elisa Fabbrini, MD | Washington University School of Medicine | 314-362-8156 | efabbrini@dom.wustl.edu |
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| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| D009765 | Obesity |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D050177 | Overweight |
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| ID | Term |
|---|---|
| D009525 | Niacin |
| D011345 | Fenofibrate |
| ID | Term |
|---|---|
| D009539 | Nicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D006571 | Heterocyclic Compounds |
| D011725 | Pyridines |
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|
|
| fenofibrate | Drug | Subjects randomized to fenofibrate will be treated with 200 mgs per day for eight weeks. |
|
|
| placebo | Drug | Subjects randomized to placebo will be treated with one placebo pill per day for eight weeks. |
|
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) |
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. |
| baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) |
| Change From Baseline in VLDL-Tg Clearance Rate | Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute. | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
| Change From Baseline in VLDL-Tg Production Rate | VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute. | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
| Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration | Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg) | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
| BG002 | Total | Total of all reporting groups |
| participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m^2 |
|
| Body Weight | Mean | Standard Deviation | kilograms |
|
| fat as percentage of total body composition | fat as percentage of total body composition as characterized using whole body Dual Energy X-ray Absorptiometry (DEXA). | Mean | Standard Deviation | percentage of total body weight |
|
| plasma glucose level | fasting plasma glucose level | Mean | Standard Deviation | mg/dl |
|
| plasma insulin level | fasting plasma insulin | Mean | Standard Deviation | mU/L |
|
| OG001 | Controls | subjects with normal intra-hepatic triglyceride levels |
|
|
|
| Secondary | Very Low Density Lipoprotein - Triglyceride Production Rate | 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). | Posted | Mean | Standard Error | μmol/L/min | baseline cross-sectional data |
|
|
|
|
| Primary | 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. | Posted | Mean | Standard Error | percent increase | baseline cross-sectional data pre and post nine hour euglycemic clamp |
|
|
|
|
| Primary | 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. | Posted | Mean | Standard Error | percent decrease | baseline cross-sectional data pre and post nine hour euglycemic clamp |
|
|
|
|
| Primary | 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. | 10 (or more) subjects in each group would be sufficient for detecting changes in IHTG. | Posted | Mean | Standard Deviation | ratio | baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| Secondary | Change From Baseline in Very Low Density Lipoprotein Apolipoprotein B Production Rate | 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. | Posted | Mean | Standard Error | nmol/l/min | baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| Secondary | Change From Baseline in VLDL-Tg Clearance Rate | Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute. | Posted | Mean | Standard Error | (ml/min) | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| Secondary | Change From Baseline in VLDL-Tg Production Rate | VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute. | Posted | Mean | Standard Error | (μmol/L/min) | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| Secondary | Change From Baseline in Very Low-density Lipoprotein Triglyceride Concentration | Change from baseline in very low-density lipoprotein triglyceride concentration (VLDL-Tg) | Posted | Mean | Standard Error | mmol/l | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| Primary | 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 | Posted | Mean | Standard Error | percent decrease | baseline to post intervention: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| Primary | 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. | Posted | Mean | Standard Error | percent increase | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| Primary | 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. | Posted | Mean | Standard Error | [10000/(μmol/min)x(mU/L)] | baseline to end of treatment: 8 weeks (fenofibrate), 16 weeks (niacin) |
|
|
|
|
| 0 |
| 11 |
| 1 |
| 11 |
| EG001 | NAFLD - Niacin | subjects with intra-hepatic triglyceride signal greater than 10% placed on daily niacin for 16 weeks. The dose of medication will be gradually increased according to the protocol of most clinical trials (59): 500 mg/day during wk 1, 1000 mg/day during wk 2, 1500 mg/day during wks 3, and 2000mg/day during wks 4-16. | 0 | 11 | 0 | 11 |
| EG002 | NAFLD - no Drug | subjects with elevated hepatic triglyceride who did not receive any drug intervention | 0 | 12 | 0 | 12 |
| EG003 | Controls | subjects with normal hepatic triglyceride. | 0 | 17 | 0 | 17 |
|
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| D044343 |
| Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D058607 | Fibric Acids |
| D058610 | Isobutyrates |
| D002087 | Butyrates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D010647 | Phenyl Ethers |
| D004987 | Ethers |
| D001577 | Benzophenones |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D010636 | Phenols |
| D007659 | Ketones |
| A Student's t-test for paired samples was used to evaluate the effect of treatment. The null hypothesis was that the IHTG percentage for the NAFLD-niacin group at baseline and post-treatment would not change. | t-test, 2 sided | Treatment effects determined by repeated-measures ANOVA. When significant interactions between time and group were found, a Student's t-test was used. | .315 | A P-value < 0.05 was considered statistically significant. | 95 | Superiority or Other |
A Student's t-test for paired samples was used to evaluate the effect of treatment. Null hypothesis was that VLDL-apoB would be the same before and after 8 weeks on fenofibrate in subjects with NAFLD.
| t-test, 2 sided |
| .022 |
A P-value < 0.05 was considered statistically significant. |
| 95 |
| Superiority or Other |
| .358 |
a priori threshold for significance was <0.05. |
| 95 |
| Superiority or Other |
| t-test, 2 sided |
| .023 |
the a priori threshold for statistical significance was set at <0.05. |
| 95 |
| Superiority or Other |
The null hypothesis was that niacin would not affect VLDL-Tg concentration. We compare the pre and post-treatment results of subjects receiving a 16 week course of niacin.
| t-test, 2 sided |
| <0.001 |
the a priori threshold for statistical significance was p<0.05 |
| 95 |
| Superiority or Other |
Null hypothesis was that niacin would not affect adipose tissue insulin sensitivity. Here we compare the baseline and post-treatment adipose tissue insulin sensitivity results for subjects who received a 16 week course of niacin |
| t-test, 2 sided |
| .019 |
A priori threshold for significance was set for p<0.05. |
| 95 |
| Superiority or Other |
The null hypothesis was that niacin would not affect skeletal muscle insulin sensitivity. Here we compare the pre and post-treatment results for subjects receiving a 16 week course of niacin. |
| t-test, 2 sided |
| .025 |
The a priori threshold for significance was set at p<0.05. |
| 95 |
| Superiority or Other |
The null hypothesis was that niacin would not affect skeletal muscle insulin sensitivity. Here we compare the pre and post-treatment results of subjects receiving a 16 week course of niacin.
| t-test, 2 sided |
| .018 |
The a priori threshold for significance was set at p<0.05. |
| 95 |
| Superiority or Other |