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

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Brief 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

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

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).
    

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.

        1. 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, AztraZeneca, Wilmington,
           DE). 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.

        2. 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Liver Histopathology

Secondary Outcome

 Liver Fat by MRI and MR Spectroscopy

Condition

Fatty Liver Disease, Nonalcoholic

Intervention

Metreleptin

Study Arms / Comparison Groups

 Treatment
Description:  Metreleptin

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

23

Start Date

October 8, 2012

Completion Date

July 13, 2016

Primary Completion Date

July 13, 2016

Eligibility 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.
      

Gender

All

Ages

5 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Elif A Oral, MD, MS, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01679197

Organization ID

MCRU 2834

Secondary IDs

R01DK088114-02

Responsible Party

Principal Investigator

Study Sponsor

University of Michigan

Collaborators

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

Study Sponsor

Elif A Oral, MD, MS, Principal Investigator, University of Michigan


Verification Date

May 2017