Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy - Full Text View

Purpose

This study involves research about an investigational medicine called metreleptin. The reason for this study is to find out how metreleptin can improve non-alcoholic steatohepatitis or nonalcoholic fatty liver disease associated with lipodystrophy, a rare disorder associated with abnormal loss of the body's fat tissue. In this study, metreleptin is considered to be investigational for the treatment of lipodystrophy. Metreleptin will be 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 (e.g. blood cholesterol, liver function, insulin resistance) and body composition characteristics (e.g. the pattern of fat distribution in the body).

Condition	Intervention	Phase
Fatty Liver Disease, Nonalcoholic Nonalcoholic Steatohepatitis Lipodystrophy	Drug: Metreleptin	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy

Resource links provided by NLM:

MedlinePlus related topics: Liver Diseases

U.S. FDA Resources

Further study details as provided by University of Michigan:

Primary Outcome Measures:

Liver histopathology [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Primary outcome will be the Total NASH score read histopathologically from the liver biopsy samples, as determined by the NIH NASH Clinical Network criteria. At baseline and at the end of the year, patients will undergo a transcutaneous liver biopsy and the specimen will be graded for the severity of NAFLD/NASH pathology.

Secondary Outcome Measures:

Liver fat by MRI and MR spectroscopy [ Time Frame: 1 year ] [ Designated as safety issue: No ]
All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. 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 tests [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Fasting lipids [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Fasting glucose [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Body weight [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	October 2012
Estimated Primary Completion Date:	September 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Treatment Metreleptin	Drug: Metreleptin Other Name: (originally A100, recombinant-human-methionyl-leptin

Detailed Description:

The goal is to test the efficacy of restorative leptin therapy on the degree of hepatic steatosis and on amelioration of pathological features of NASH/NAFLD. In addition, the study will evaluate the impact of leptin therapy on total body insulin sensitivity and lipid levels as well as energy expenditure. In order to accomplish this aim, we now propose an efficacy study with recombinant human leptin therapy in patients with all forms of lipodystrophy who also have NASH/NAFLD.

AIM 1: To determine the efficacy of leptin in promoting amelioration of body composition, hepatic steatosis and histopathological scores in patients with all forms of lipodystrophy and NAFLD/NASH. We will conduct a 1 year, open-label study, to assess the metabolic effects of recombinant human leptin (METRELEPTIN, Amylin Pharmaceuticals, San Diego, CA). The primary outcome measure will be NASH scores. We will also explore body weight, insulin sensitivity, glucose and lipid control, body composition, and free fatty acid levels.
AIM 2: To Investigate molecular effects of leptin therapy. In parallel to our preliminary studies, gene expression will be performed on individuals participating in Aim 1 at baseline and following 1 year of leptin. We will combine this with measures of liver metabolite levels to provide novel insights into alterations in metabolism that occur secondary to leptin therapy. We will also measure plasma metabolites at baseline and after 2 (optional), 24 and 48 weeks of therapy to assess the dynamic changes induced by leptin and correlate these changes with phenotypic measures.

Eligibility

Ages Eligible for Study:	5 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Is male or female ≥ 5 years old at baseline.
Is male, female not of childbearing potential, or meets all the following criteria if female of childbearing potential (including perimenopausal women who have had a menstrual period within one year):
- Not breastfeeding
- Negative pregnancy test result (human chorionic gonadotropin, beta subunit [βhCG]) at baseline (not applicable to hysterectomized females).
- Must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate when use consistently and correctly, such as implants, injectables, oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a vasectomized partner) during the entire duration of metreleptin treatment.
Has physician-confirmed lipodystrophy as defined by evidence of generalized (whole body) or partial (limbs) loss of body fat outside the range of normal variation.
Alcohol consumption of less than 40 grams/week.
A liver ultrasound confirming non-alcoholic fatty liver disease, or previous liver biopsy confirming NASH status.
If ≥ 18 years of age, is able to read, understand and sign the U of M IRBMED approved informed consent form (ICF), communicate with study physician and study team, understand and comply with protocol requirements.
If < 18 and ≥ 7 years of age, is able to read, understand and sign the appropriate U of M IRBMED approved assent form and has a parent or legal guardian that is able to read, understand and sign the ICF.
If < 7 and ≥ 5 years of age or unable to read, the appropriate assent form must be explained to the child.
If previously treated with thiazolidinediones or Vitamin E, stable dose of these medications for at least 3 months.

Exclusion Criteria:

Presence of advanced liver disease (as evidenced by abnormal synthetic function, abnormal PT or albumin).
Evidence of other etiologies of viral hepatitis.
Presence of clinically significant hematologic abnormalities (such as neutropenia and/or lymphadenopathy).
Presence of HIV infection.
Very poorly controlled diabetes; HbA1c >10%
Inability to give informed consent.
Presence of ESRD, 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.
Active infection (may be transient).
Has known allergies to E. coli-derived proteins or hypersensitivity to any component of metreleptin treatment.
Any other condition in the opinion of the investigators that may impede successful data collection.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01679197

Contacts

Contact: Adam Neidert, MS	734-615-0539	aneidert@med.umich.edu
Contact: Elif A Oral, MD, MS	734-615-7271	eliforal@med.umich.edu

Locations

United States, Michigan
University of Michigan	Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Adam Neidert, MS 734-615-0539 aneidert@med.umich.edu
Principal Investigator: Elif A Oral, MD, MS
Sub-Investigator: Charles Burant, MD, PhD
Sub-Investigator: Barbara McKenna, MD
Sub-Investigator: Hari Conjeevaram, MPH
Sub-Investigator: Thomas Chenevert, PhD
Sub-Investigator: Hero Hussain, MD
Sub-Investigator: Nevin Ajluni, MD

Sponsors and Collaborators

University of Michigan

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

Principal Investigator:

Elif A Oral, MD, MS

University of Michigan

More Information

No publications provided

Responsible Party:	Elif Oral, Associate Professor, University of Michigan
ClinicalTrials.gov Identifier:	NCT01679197 History of Changes
Other Study ID Numbers:	MCRU 2834, R01DK088114-02
Study First Received:	August 31, 2012
Last Updated:	April 24, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Michigan:

Nonalcoholic fatty liver disease
NAFLD
Nonalcoholic steatohepatitis
NASH
Lipodystrophy

Leptin
Metreleptin
Hypertriglyceridemia
Diabetes mellitus

Additional relevant MeSH terms:

Fatty Liver
Lipodystrophy
Liver Diseases
Digestive System Diseases

Skin Diseases, Metabolic
Skin Diseases
Lipid Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on May 23, 2013