Leptin to Treat Lipodystrophy
Leptin to Treat Lipodystrophy
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.
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.
-  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