Brief Title
Leptin to Treat Lipodystrophy
Official Title
Efficacy of Leptin Replacement in Treatment of Lipodystrophy
Brief Summary
This study will evaluate the safety and effectiveness of the leptin replacement therapy in
treating lipoatrophy or lipodystrophy-a condition in which there is a total or partial loss
of fat cells. Patients with lipodystrophy lack sufficient leptin, because this hormone 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, uncontrolled appetite, and liver disease due to fat accumulation.
Patients 15 years and older with lipodystrophy are eligible for this study. Candidates are
screened with a medical history and physical examination, and fasting blood tests. Those
enrolled undergo the following additional procedures:
- Ultrasound of the liver and, if abnormalities are found, possibly a liver biopsy
- Resting metabolic rate measurement - measures the amount of oxygen breathed at rest in
order to calculate how many calories are required to maintain resting body functions
- Magnetic resonance imaging of the liver and other organs, and of muscle and fat
- Estimation of body fat - measurements of height, weight, hip size, and skin folds over
the arms and abdomen to estimate body fat content
- Insulin tolerance test - measures blood glucose levels after administration of insulin.
Insulin is given through an intravenous (IV) catheter (a thin tube placed in a vein) and
blood is drawn 5 minutes before the test begins, when the test begins, and 5, 10, 15, 20
and 30 minutes into the test
- Oral glucose tolerance test - measures blood glucose and insulin levels after drinking a
glucose (sugar) solution. Blood samples are drawn through an IV catheter 15 minutes
before the test begins, at the time the test begins, and 30, 60, 90 and 180 minutes into
the test
- Intravenous glucose tolerance test - measures tissue response to insulin and glucose
after glucose is injected into a vein. The glucose injection is followed by a short
infusion of insulin and then blood samples are taken over 3 hours to measure insulin and
glucose levels
- Appetite level and food intake - measures hunger level and caloric intake. Patients are
questioned about their hunger level, given a variety of foods they may choose to eat and
questioned again at various intervals about hunger level. On another day, patients are
given breakfast (usually a milkshake) and when they want to eat again, the appetite
level and caloric intake study is repeated.
- Hormone function tests - the function of three hormones influenced by leptin
(corticotropin-releasing hormone, thyrotropin-releasing hormone and luteinizing
hormone-releasing hormone) are assessed. The hormones are injected intravenously and
then blood samples are drawn.
When all the tests are completed, leptin therapy begins. The drug is injected under the skin
twice a day for 4 months by the patient or a caregiver (similar to self-administered insulin
injections for diabetes). Blood is drawn once a month to monitor the effects of treatment and
drug side effects. At clinic visits scheduled 1, 2 and 4 months after therapy starts,
patients have a physical examination and meet with a dietitian. Medication dosage is also
increased at these visits. At the end of 4 months, all baseline studies described above are
repeated. Throughout the study, all patients complete a form once a week, in which they
record their symptoms. Patients with diabetes also measure their blood glucose levels at home
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. To what extent does leptin
deficiency cause diabetes in lipoatrophic patients? In one mouse model of lipoatrophy, leptin
administration reversed the diabetes and liver disease. In a different, more severely
adipose-deficient mouse, the effects of leptin treatment were detectable, but more modest.
In this protocol, to be carried out at both the NIH and the University of Texas in Dallas, we
test the hypotheses that leptin can be safely administered to patients with lipoatrophic
diabetes and they will benefit from treatment with A-100 (recombinant form of human leptin
provided by Amgen). We will study patients with lipoatrophy, low leptin levels, and at least
one of the following metabolic abnormalities: severe insulin resistance, diabetes, and/or
hypertriglyceridemia.
We will treat patients with A-100 injections for four months, with inpatient studies at
baseline, 1, 2, and 4 months of treatment. In the core protocol, we will monitor metabolic
control (e.g. glucose, insulin, free fatty acid, and triglyceride levels). Ancillary studies
will evaluate the effect of A-100 on the gonadal axis and on liver pathology.
After 8 months of treatment, we will offer a withdrawal study to the patient requiring an
inpatient admission and controlled diet. Afterwards leptin therapy will resume in a long-term
extension study with follow up visits every 6 months. Metabolic parameters will continue to
be followed, along with body fat imaging studies, gonadotropin monitoring, and liver function
analysis.
Study Phase
Phase 2
Study Type
Interventional
Condition
Lipodystrophy
Intervention
hu Leptin (A-100)
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
20
Start Date
June 2000
Completion Date
April 2003
Eligibility Criteria
INCLUSION CRITERIA:
All ethnic groups
Males and females
Age greater than 14 years
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 4.0 ng/ml in females and less than 3.0 ng/ml in males
as measured by Linco assay on at least 2 occasions.
Presence of at least one of the following metabolic abnormalities:
Presence of diabetes as defined by the 1997 ADA criteria: a) fasting plasma glucose greater
than or equal to 126 mg/dL, or b) 2 hour plasma glucose greater than or equal to 200 mg/dL
following a 75 gram oral glucose load, or c) diabetic symptoms with a random plasma glucose
greater than or equal to 200 mg/dL.
Fasting insulin greater than 30 micrograms/ml;
Fasting hypertriglyceridemia greater than 200 mg/dl.
EXCLUSION
General: Pregnant women, women in their reproductive years who do not use an effective
method of birth control, women currently nursing or lactating within 6 weeks of having
completed nursing, and persons who are unable to provide informed consent will be excluded
from the study.
Exclusions for underlying disease likely to increase side effects or to hinder objective
data collection:
Known liver disease due to causes other than non-alcoholic steatohepatitis
Current alcohol or substance abuse
Psychiatric disorder impeding competence or compliance
Active tuberculosis
Use of anorexiogenic drugs
Other condition which in the opinion of the clinical investigators would impede completion
of the study
Subjects who have a known hypersensitivity to E. Coli derived proteins
Gender
All
Ages
N/A - N/A
Accepts Healthy Volunteers
No
Contacts
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Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00005905
Organization ID
000146
Secondary IDs
00-DK-0146
Study Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study Sponsor
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Verification Date
April 2003