Leptin to Treat Lipodystrophy

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Brief Title

Leptin to Treat Lipodystrophy

Official Title

Long-Term Efficacy of Leptin Replacement in Treatment of Lipodystrophy

Brief 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.
    

Detailed Description

      Lipoatrophic diabetes is a syndrome characterized by insulin resistance in association with a
      paucity of adipose tissue. Patients with severe lipoatrophy die prematurely, typically from
      the complications of diabetes or liver disease. Experiments with lipoatrophic mice suggest
      that the insulin resistance is caused by the lack of adipose tissue. Adipose tissue normally
      produces leptin, a hormone that increases insulin action. For the last fourteen years, we
      have been studying the extent to which leptin deficiency causes diabetes in lipoatrophic
      patients. In fact, in our initial study we have seen nearly 60% amelioration of fasting
      glucose, triglycerides and free fatty acid levels and about 2% actual decreases from baseline
      HbA1c levels with 4 months of leptin replacement therapy. This response has continued to be
      sustained, as we continue to follow patients that have now received leptin replacement
      therapy for fourteen years.

      This is an open-labeled study. The study monitors the safety and efficacy of recombinant
      methionyl human leptin (A-100) replacement in children and adults. We are looking at the
      long-term effects of leptin replacement on extended therapy. In this long-term replacement
      protocol, we will monitor metabolic control (e.g. glucose, insulin, and triglyceride levels)
      as primary outcome measures. Ancillary studies will evaluate the effect of Metreleptin on
      other hormonal axes, growth and development and on liver pathology.

      We continue to evaluate the efficacy in a broader leptin deficient population of patients
      with lipodystrophy. Current inclusion criteria in patients greater than or equal to 5 years
      include female patients with leptin levels < 12 ng/mL and male patients with leptin levels <
      8 ng/mL. We continue to seek patients who meet these criteria. In children ages 6 months 5
      years, we will use a cut-off leptin level of 6 ng/mL in both genders.

      Patients who are greater than or equal to age 5 years will be evaluated every 6 months during
      the first year of therapy. If no improvements are seen after 6 months of therapy, then the
      study medication may be increased to 150% of the predicted dose (0.09mg/kg/day for males and
      girls less than 10 years of age/ 0.12mg/kg/day for females 10 years of age and older) from 6
      months to 1 year on therapy. If no improvements are seen after increasing to 150% of the
      predicted dose, then the study medication will be withdrawn. If the patient shows
      improvements in his/her metabolic parameters while on leptin, the patient will be invited to
      continue taking the study medication. The investigators will strive for all patients
      responding to leptin to bring their metabolic parameters into the normal range. The maximum
      dose of leptin that will be given is 0.24 mg/kg/day for females 10 and older, and 0.12
      mg/kg/day for males and females less than 10 years of age. After the first year of treatment,
      the patient will be evaluated every 6 months through the second year of treatment, and then
      the study period will end. After two years of treatment, extending the treatment period on an
      annual basis will be the decision of the patient, principal investigator and Bristol-Myers
      Squibb (BMS)/AstraZeneca Pharmaceuticals (AZ). Leptin is supplied by BMS/AZ, and is currently
      only available through research studies. Neither the NIH nor BMS/AZ can guarantee that leptin
      will be available indefinitely and/or after the study ends. However, leptin was recently
      approved by the FDA on February 25, 2014, for use in patients with generalized lipodystrophy.

      All patient referrals for acceptance into the protocol, are initiated by the physician/health
      care provider.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Percentage of Glycosylated Hemoglobin at Baseline, 6 Months, and 12 Months on Treatment With Metreleptin


Condition

Lipodystrophy

Intervention

Metreleptin

Study Arms / Comparison Groups

 Metreleptin
Description:  subcutaneous metreleptin injections in one to two daily doses ranging from 0.06 to 0.24 mg/kg per day.

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

103

Start Date

October 2001

Completion Date

February 2015

Primary Completion Date

February 2015

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
      

Gender

All

Ages

6 Months - N/A

Accepts Healthy Volunteers

No

Contacts

Phillip Gorden, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00025883

Organization ID

020022

Secondary IDs

02-DK-0022

Responsible Party

Sponsor

Study Sponsor

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


Study Sponsor

Phillip Gorden, M.D., Principal Investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


Verification Date

August 2016