Clinical trial NCT00596934: Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)
Official title: Nonalcoholic Steatohepatitis: is Leptin an Etiological Factor (Phase 2).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fatty Liver Disease, Nonalcoholic
Keywords: Nonalcoholic fatty liver disease
Insulin resistance
Obesity
Leptin therapy
NASH
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of Michigan
First posted: 2008-01-17
Enrollment: 9
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Non-alcoholic Steatohepatitis Score as Determined by Liver Histopathology at 12 Months
timeFrame: 1 year
Secondary outcomes:
measure: Body Weight at 12 Months
timeFrame: 1 year
measure: Liver Fat Percentage by Magnetic Resonance Imaging (MRI - Dixon Method) at 12 Months
timeFrame: 1 year
measure: Liver Function Test: Alanine Aminotransferase (ALT) Values at 12 Months
timeFrame: 1 year
measure: Liver Function Test: Aspartate Aminotransferase (AST) Values at 12 Months
timeFrame: 1 year
measure: Fasting Glucose Value at 12 Months
timeFrame: 1 year
measure: Fasting Triglycerides Value at 12 Months
timeFrame: 1 year
measure: Insulin Resistance: Homeostatic Model Assessment (HOMA) at 12 Months
timeFrame: 1 year
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: Elif A Oral, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. 2021 Jul 9;2(7):814-835. doi: 10.1016/j.medj.2021.04.001. Epub 2021 May 12.