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

NCT01679197 | Completed Phase 2 Results

• 2 other identifiers: MCRU 2834R01DK088114-02
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Fatty Liver Disease, Nonalcoholic; Nonalcoholic Steatohepatitis; Lipodystrophy

Keywords

Nonalcoholic fatty liver disease; NAFLD; Nonalcoholic steatohepatitis; NASH; Lipodystrophy; Leptin; Metreleptin; Hypertriglyceridemia; Diabetes mellitus

Outcome Measures

Primary Outcomes (1)

• Liver Histopathology

  Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.

  1 year

Secondary Outcomes (5)

• Liver Fat by MRI and MR Spectroscopy

  1 year

• Liver Function Tests

  1 year

• Fasting Lipids

  1 year

• Fasting Glucose

  1 year

• Body Weight

  1 year

Study Arms (1)

Treatment

EXPERIMENTAL

Metreleptin

Drug: Metreleptin

Interventions

Metreleptin DRUG

Also known as: (originally A100, recombinant-human-methionyl-leptin

Treatment

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Michigan: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (2)

• 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.

  PMID: 35291351 DERIVED

• Meral R, Malandrino N, Walter M, Neidert AH, Muniyappa R, Oral EA, Brown RJ. Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy. J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1739-e1751. doi: 10.1210/clinem/dgab760.

  PMID: 34677608 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Lipodystrophy; Hypertriglyceridemia; Diabetes Mellitus

Interventions

metreleptin; recombinant methionyl human leptin

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Skin Diseases, Metabolic; Skin Diseases; Skin and Connective Tissue Diseases; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Glucose Metabolism Disorders; Endocrine System Diseases

Results Point of Contact

• Title: Dr. Elif Oral
• Organization: University of Michigan

eliforal@med.umich.edu

7346157271

Study Officials

• Elif A Oral, MD, MS

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 31, 2012
• First Posted: September 5, 2012
• Study Start: October 8, 2012
• Primary Completion: July 13, 2016
• Study Completion: July 13, 2016
• Last Updated: June 14, 2017
• Results First Posted: June 14, 2017

Record last verified: 2017-05

Locations

US (1)