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Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00596934
Recruitment Status : Completed
First Posted : January 17, 2008
Results First Posted : December 9, 2016
Last Update Posted : November 24, 2017
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Michigan
Information provided by (Responsible Party):
Elif Oral, University of Michigan

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.

Condition or disease Intervention/treatment Phase
Fatty Liver Disease, Nonalcoholic Drug: metreleptin Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nonalcoholic Steatohepatitis: is Leptin an Etiological Factor (Phase 2).
Study Start Date : February 2006
Actual Primary Completion Date : March 2009
Actual Study Completion Date : March 2009

Arm Intervention/treatment
Experimental: Metreleptin treatment group
Treatment group
Drug: metreleptin
0.1 mg/kg/day once a day via subcutaneous injections
Other Name: (originally A100, recombinant-human-Methionyl-leptin

Primary Outcome Measures :
  1. Non-alcoholic Steatohepatitis Score as Determined by Liver Histopathology at 12 Months [ Time Frame: 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 Outcome Measures :
  1. Body Weight at 12 Months [ Time Frame: 1 year ]
    Body weight (kg) after one year of treatment on metreleptin for patients that completed 12 months of metreleptin treatment.

  2. Liver Fat Percentage by Magnetic Resonance Imaging (MRI - Dixon Method) at 12 Months [ Time Frame: 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.

  3. Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months [ Time Frame: 1 year ]
    ALT value in subjects that completed 12 months of metreleptin treatment.

  4. Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months [ Time Frame: 1 year ]
    AST value in subjects that completed 12 months of metreleptin treatment.

  5. Fasting Glucose Value at 12 Months [ Time Frame: 1 year ]
    Fasting glucose value in subjects that completed 12 months of metreleptin treatment.

  6. Fasting Triglycerides Value at 12 Months [ Time Frame: 1 year ]
    Fasting triglyceride value in subjects that completed 12 months of metreleptin treatment.

  7. Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months [ Time Frame: 1 year ]
    HOMA values in subjects that completed 12 months of metreleptin treatment.

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00596934

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United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
Elif Oral
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Michigan
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Principal Investigator: Elif A Oral, MD University of Michigan

Additional Information:
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Responsible Party: Elif Oral, Associate Prof of Medicine, University of Michigan Identifier: NCT00596934     History of Changes
Other Study ID Numbers: R03DK074488 ( U.S. NIH Grant/Contract )
R03DK074488 ( U.S. NIH Grant/Contract )
Protocol 2145 (MCRU)
Amylin Protocol 20050119
DRDA 643938K3
First Posted: January 17, 2008    Key Record Dates
Results First Posted: December 9, 2016
Last Update Posted: November 24, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Elif Oral, University of Michigan:
Nonalcoholic fatty liver disease
Insulin resistance
Leptin therapy
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases