Fatty Liver Disease, Nonalcoholic
Conditions
Keywords
Nonalcoholic fatty liver disease, Insulin resistance, Obesity, Leptin therapy, NASH
Brief summary
Nonalcoholic steatohepatitis (or NASH) is known to be caused by deposition of fat in the liver and development of scarring. This condition occurs more frequently in overweight and obese persons. It is often associated with resistance to the actions of insulin hormone. Fat cells secrete a hormone called leptin. Recently, we have learned that obese or overweight persons make too much leptin, which may contribute to insulin resistance. Paradoxically, patients who do not have any fat cells, also have insulin resistance. In these patients, insulin resistance is caused by the absence of leptin and leptin replacement significantly improves insulin resistance and fat deposition in the liver. In an earlier study, we determined the leptin levels in patients with NASH and how these levels are related to body fat levels as well as responsiveness to insulin. We saw that a subgroup of patients with NASH have relatively low levels of leptin in contrast to the amount of body fat they had. We now would like to see if restoring leptin levels to normal will improve the disease process in these patients. Our study patients will be male patients, aged between 18 and 65 (inclusive), who do not have any other cause for their liver disease. We have put some restrictions in body size such that a spectrum of patients from normal weight to obese range would be included. They will also demonstrate low leptin levels (levels similar to only 25% of normal population). We will use a genetically engineered form of leptin manufactured by Amylin Inc. given via injections under the skin. We plan to continue therapy for a period of one year and evaluate the change in liver disease by a liver biopsy. We will also follow the metabolic parameters and body composition characteristics that we examined in our earlier study. We expect that patients with low blood leptin levels will show improvement in their liver disease and insulin resistance when their blood leptin levels are restored to normal.
Interventions
DRUGmetreleptin
0.1 mg/kg/day once a day via subcutaneous injections
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Michigan
Elif Oral
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Biopsy proven NASH * Circulating fasting leptin \<9 ng/mL (staggered criteria for different BMI levels)
Exclusion criteria
* Presence of advanced liver disease (as evidenced by abnormal synthetic function, abnormal prothrombin time or albumin) * Presence of clinical lipodystrophy * Presence of other liver disease * Presence of clinical diabetes (fasting \>126 mg/dL or 2 hour post 75 g-glucose \>200 mg/dL or random glucose \>200 mg/dL with presence of diabetes symptoms or known history of diabetes) * Any medication for treatment of NASH or obesity * Presence of HIV * Inability to give informed consent * Presence of end-stage renal disease, any type of active cancer, or \>class 2 congestive heart failure ((New York Heart Association Functional Classification System), based on medical history and physical examination * Presence of any other condition that limits life expectancy to \<2 years * Active infection (may be transient) * Any other condition in the opinion of the investigators that may impede successful data collection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Non-alcoholic Steatohepatitis Score as Determined by Liver Histopathology at 12 Months | 1 year | Non-alcoholic steatohepatitis (NASH) score after approximately one year of treatment with metreleptin. Total NASH scores can range from 0 to 14. The higher the NASH score the more severe the liver disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Triglycerides Value at 12 Months | 1 year | Fasting triglyceride value in subjects that completed 12 months of metreleptin treatment. |
| Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months | 1 year | HOMA values in subjects that completed 12 months of metreleptin treatment. |
| Body Weight at 12 Months | 1 year | Body weight (kg) after one year of treatment on metreleptin for patients that completed 12 months of metreleptin treatment. |
| Liver Fat Percentage by Magnetic Resonance Imaging (MRI - Dixon Method) at 12 Months | 1 year | For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals. |
| Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months | 1 year | ALT value in subjects that completed 12 months of metreleptin treatment. |
| Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months | 1 year | AST value in subjects that completed 12 months of metreleptin treatment. |
| Fasting Glucose Value at 12 Months | 1 year | Fasting glucose value in subjects that completed 12 months of metreleptin treatment. |
Countries
United States
Participant flow
Recruitment details
Patient recruitment occurred from February 2007 and concluded in October 2007.
Pre-assignment details
One of ten enrolled participants screen failed during baseline visit, liver biopsy showed no non-alcoholic steatohepatitis. Therefore he is not included in any tables or analyses.
Participants by arm
| Arm | Count |
|---|---|
| Metreleptin Treatment Arm Treatment group
metreleptin : 0.1 mg/kg/day once a day via subcutaneous injections | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Metreleptin Treatment Arm |
|---|---|
| Age, Continuous | 44.3 years |
| Body Weight | 90.9 kg STANDARD_DEVIATION 9 |
| Fasting glucose | 98.1 mg/dL STANDARD_DEVIATION 7.2 |
| Fasting triglycerides | 129.4 mg/dL STANDARD_DEVIATION 66.2 |
| Insulin Resistance: homeostatic model assessment (HOMA) | 7.4 mU/L x mg/dL STANDARD_DEVIATION 3.2 |
| Liver fat percentage by Magnetic Resonance Imaging (MRI - Dixon method) | 19.0 liver fat percentage STANDARD_DEVIATION 7.7 |
| Liver function test: Alanine aminotransferase (ALT) | 50.9 IU/L STANDARD_DEVIATION 19.4 |
| Liver function test: Aspartate aminotransferase (AST) | 33.5 IU/L STANDARD_DEVIATION 13.3 |
| Non-alcoholic steatohepatitis (NASH) score | 8.1 units on a scale STANDARD_DEVIATION 3.3 |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 9 |
| serious Total, serious adverse events | 1 / 9 |
Outcome results
Primary
Non-alcoholic Steatohepatitis Score as Determined by Liver Histopathology at 12 Months
Non-alcoholic steatohepatitis (NASH) score after approximately one year of treatment with metreleptin. Total NASH scores can range from 0 to 14. The higher the NASH score the more severe the liver disease.
Time frame: 1 year
Population: Individuals who completed the year of metreleptin treatment and had follow-up liver biopsies after one year.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Non-alcoholic Steatohepatitis Score as Determined by Liver Histopathology at 12 Months | 5 units on a scale | Standard Deviation 1.73 |
Comparison: Differences in each collected parameter will be evaluated using a paired t-test. If data are skewed such as in triglyceride levels, nonparametric tests will be used. P\<0.05 will be considered significant. If a significant difference can be demonstrated between baseline and 1-year results, a large scale, placebo-controlled trial will be designed using the data obtained from this pilot studyp-value: 0.015t-test, 2 sided
Secondary
Body Weight at 12 Months
Body weight (kg) after one year of treatment on metreleptin for patients that completed 12 months of metreleptin treatment.
Time frame: 1 year
Population: Subjects that completed 12 months of metreleptin treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Body Weight at 12 Months | 86.4 kg | Standard Deviation 9.9 |
p-value: <0.0001t-test, 2 sided
Secondary
Fasting Glucose Value at 12 Months
Fasting glucose value in subjects that completed 12 months of metreleptin treatment.
Time frame: 1 year
Population: 7 subjects who completed 12 months of metreleptin treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Fasting Glucose Value at 12 Months | 92.1 mg/dL | Standard Deviation 5.9 |
p-value: 0.023t-test, 2 sided
Secondary
Fasting Triglycerides Value at 12 Months
Fasting triglyceride value in subjects that completed 12 months of metreleptin treatment.
Time frame: 1 year
Population: 7 subjects who completed 12 months of metreleptin treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Fasting Triglycerides Value at 12 Months | 146.4 mg/dL | Standard Deviation 75.7 |
p-value: 0.195t-test, 2 sided
Secondary
Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months
HOMA values in subjects that completed 12 months of metreleptin treatment.
Time frame: 1 year
Population: 7 subjects who completed 12 months of metreleptin treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months | 4.1 mU/L x mg/dL | Standard Deviation 3 |
p-value: 0.026t-test, 2 sided
Secondary
Liver Fat Percentage by Magnetic Resonance Imaging (MRI - Dixon Method) at 12 Months
For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Liver Fat Percentage by Magnetic Resonance Imaging (MRI - Dixon Method) at 12 Months | 13.7 liver fat percentage | Standard Deviation 9.1 |
p-value: 0.074t-test, 2 sided
Secondary
Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months
ALT value in subjects that completed 12 months of metreleptin treatment.
Time frame: 1 year
Population: 7 subjects who completed 12 months of metreleptin treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months | 44.3 IU/L | Standard Deviation 29.1 |
p-value: 0.003t-test, 2 sided
Secondary
Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months
AST value in subjects that completed 12 months of metreleptin treatment.
Time frame: 1 year
Population: 7 subjects who completed 12 months of metreleptin treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metreleptin Treatment Arm | Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months | 34.9 IU/L | Standard Deviation 13.9 |
p-value: 0.006t-test, 2 sided