Leptin to Treat Lipodystrophy
Condition: Lipodystrophy
MeSH terms: Lipodystrophy
Intervention: Metreleptin
Intervention description: Drug treatment
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 103.0
Sex: All
Minimum age: 6 Months
Healthy volunteers: No
Keywords: Lipoatrophic Diabetes; Diabetes Mellitus; Hypertriglyceridemia; NASH; Lipodystrophy; Leptin; Diabetes

Summary:

      This study will evaluate the safety and effectiveness of leptin replacement therapy in
      patients with lipodystrophy (also called lipoatrophy). Patients have a total or partial loss
      of fat cells. They also lack the hormone leptin, which is produced by fat cells. The leptin
      deficiency usually causes high blood lipid (fat) levels and insulin resistance that may lead
      to diabetes. Patients may have hormone imbalances, fertility problems, large appetite, and
      liver disease due to fat accumulation.

      Patients age greater than or equal to 6 months with significant lipodystrophy may be eligible
      for this study. Participants will be admitted to the NIH Clinical Center for 10 days for the
      following studies before beginning 12 months of leptin therapy:

        -  Insulin tolerance test

        -  Ultrasound of the liver and, if abnormalities are found, possibly liver biopsies.

        -  Fasting blood tests

        -  Resting metabolic rate

        -  Magnetic resonance imaging of the liver and other organs, and of muscle and fat.

        -  Pelvic ultrasound in women to detect ovarian cysts.

        -  Estimation of body fat

        -  Oral glucose tolerance test

        -  Intravenous glucose tolerance test

        -  Appetite level and food intake

        -  Hormone function tests

        -  Questionnaires to assess activity and mood

        -  24-hour urine collections

      Additional studies may include blood tests for genetic studies of lipodystrophy, a muscle
      biopsy to study muscle proteins involved in regulating energy expenditure before and after
      leptin replacement, and examination of a surgical specimen (if available) to study molecules
      that may be involved in energy storage and use.

      When the above tests are completed, leptin therapy begins. The drug is injected under the
      skin twice a day for 4 months and then once a day, if feasible. The dose is increased at the
      1- and 2-month visits. Follow-up visits at 1, 2, 4, 6, 8 and 12 months after therapy starts
      include a physical examination, blood tests and a meeting with a dietitian. At the end of 12
      months, all baseline studies described above are repeated. Patients record their symptoms
      weekly throughout the study. Those with diabetes measure their blood glucose levels daily
      before each meal and at bedtime.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        All ethnic groups.

        Males and females.

          -  Age greater than or equal to 6 months.

          -  Clinically significant lipodystrophy, identified by the study physician during the
             physical examination as an absence of fat outside the range of normal variation and/or
             identified as a disfiguring factor by the patient.

        Circulating leptin levels less than 12.0 ng/ml in females and less than 8.0 ng/ml in males
        as measured by Linco assay on a specimen obtained after an overnight fast. In children ages
        6 months 5 years, a circulating leptin level of less than 6 ng/mL will be used. Leptin
        samples will be run through Millipore Laboratories, who use the Linco Assay, which has been
        the assay previously used to measure leptin levels throughout this study period.

        Presence of at least one of the following metabolic abnormalities:

          1. Presence of diabetes as defined by the 2007 ADA criteria

               1. Fasting plasma glucose greater than or equal to 126 mg/dL, or

               2. 2 hour plasma glucose greater than or equal to 200 mg/dL following a 75 gram
                  (1.75gm/kg) oral glucose load, or

               3. Diabetic symptoms with a random plasma glucose greater than or equal to 200 mg/dl

          2. Fasting insulin greater than 30 micro units/ml.

          3. Fasting hypertriglyceridemia greater than 200 mg/dL or postprandially elevated
             triglycerides greater than 500 mg/dL when fasting is clinically not indicated (e.g. in
             infants)

             -Persons with impaired decision-making capacity and who may be unable to provide
             informed consent may participate in this study per the discretion of the Principal
             Investigator.

             EXCLUSION CRITERIA:

             Pregnant women, women in their reproductive years who do not use an effective method
             of birth control, and women currently nursing or lactating within 6 weeks of having
             completed nursing.

             Exclusions for underlying diseases likely to increase side effects or hinder objective
             data collection:

               -  Known infectious liver disease

               -  Known HIV infection

               -  Current alcohol or substance abuse

               -  Psychiatric disorder impeding competence or compliance

               -  Active tuberculosis

               -  Use of anorexiogenic drugs

               -  Other condition(s) which in the opinion of the clinical investigators would
                  impede completion of the study

               -  Subjects who have known hypersensitivity to E. Coli derived proteins.

               -  Subjects with acquired lipodystrophy and a hematologic abnormality such as
                  neutropenia and/or lymphadenopathy