Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)

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

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.

Study Overview

• Status: Completed
• Conditions: Fatty Liver Disease, Nonalcoholic
• Intervention / Treatment: Drug: metreleptin

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Elif Oral
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Michigan

Publications and helpful links

General Publications

• Akinci B, Subauste A, Ajluni N, Esfandiari NH, Meral R, Neidert AH, Eraslan A, Hench R, Rus D, McKenna B, Hussain HK, Chenevert TL, Tayeh MK, Rupani AR, Innis JW, Mantzoros CS, Conjeevaram HS, Burant CL, Oral EA. Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings. Med (N Y). 2021 Jul 9;2(7):814-835. doi: 10.1016/j.medj.2021.04.001. Epub 2021 May 12.

Helpful Links

• PIs Web site

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (ACTUAL): March 1, 2009
• Study Completion (ACTUAL): March 1, 2009

Study Registration Dates

• First Submitted: January 8, 2008
• First Submitted That Met QC Criteria: January 16, 2008
• First Posted (ESTIMATE): January 17, 2008

Study Record Updates

• Last Update Posted (ACTUAL): November 24, 2017
• Last Update Submitted That Met QC Criteria: October 19, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Obesity; Insulin resistance; NASH; Nonalcoholic fatty liver disease; Leptin therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: R03DK074488 (NIH); Protocol 2145 (MCRU); Amylin Protocol 20050119; DRDA 643938K3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED