Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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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.

Official Title
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Nonalcoholic Steatohepatitis: is Leptin an Etiological Factor (Phase 2).

Conditions
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Fatty Liver Disease, Nonalcoholic

Intervention / Treatment
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* Drug: metreleptin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metreleptin treatment group<br>Treatment group | Drug: metreleptin<br>* 0.1 mg/kg/day once a day via subcutaneous injections<br>* Other names: (originally A100, recombinant-human-Methionyl-leptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight at 12 Months | Body weight (kg) after one year of treatment on metreleptin for patients that completed 12 months of metreleptin treatment. | 1 year | 
| 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. | 1 year | 
| Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months | ALT value in subjects that completed 12 months of metreleptin treatment. | 1 year | 
| Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months | AST value in subjects that completed 12 months of metreleptin treatment. | 1 year | 
| Fasting Glucose Value at 12 Months | Fasting glucose value in subjects that completed 12 months of metreleptin treatment. | 1 year | 
| Fasting Triglycerides Value at 12 Months | Fasting triglyceride value in subjects that completed 12 months of metreleptin treatment. | 1 year | 
| Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months | HOMA values in subjects that completed 12 months of metreleptin treatment. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonalcoholic fatty liver disease, Insulin resistance, Obesity, Leptin therapy, NASH