Leptin to Treat Lipodystrophy

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00025883
• Collaborator: (none)
• Enrollment: 103
• Location: 1
• Arm: 1
• Duration (Months): 160
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lipodystrophy	Drug: Metreleptin	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Long-Term Efficacy of Leptin Replacement in Treatment of Lipodystrophy
• Study Start Date: Oct 1, 2001
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metreleptin subcutaneous metreleptin injections in one to two daily doses ranging from 0.06 to 0.24 mg/kg per day.	Drug: Metreleptin; Drug treatment; Other Names: Leptin

Outcome Measures

Primary Outcome Measures

1. Percentage of Glycosylated Hemoglobin at Baseline, 6 Months, and 12 Months on Treatment With Metreleptin [Baseline, 6 months, 12 months]

   Percentage of glycosylated hemoglobin at Baseline, 6 months, and 12 months on treatment with metreleptin

2. Triglycerides at Baseline, 6 Months, and 12 Months on Treatment With Metreleptin [Baseline, 6 months, 12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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

2. Fasting plasma glucose greater than or equal to 126 mg/dL, or

3. 2 hour plasma glucose greater than or equal to 200 mg/dL following a 75 gram (1.75gm/kg) oral glucose load, or

4. Diabetic symptoms with a random plasma glucose greater than or equal to 200 mg/dl

5. Fasting insulin greater than 30 micro units/ml.

6. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

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

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Burant CF, Sreenan S, Hirano K, Tai TA, Lohmiller J, Lukens J, Davidson NO, Ross S, Graves RA. Troglitazone action is independent of adipose tissue. J Clin Invest. 1997 Dec 1;100(11):2900-8.
• Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000 Jan 1;9(1):109-12.
• Moitra J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Aoyama T, Eckhaus M, Reitman ML, Vinson C. Life without white fat: a transgenic mouse. Genes Dev. 1998 Oct 15;12(20):3168-81.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00025883
• Other Study ID Numbers: 020022; 02-DK-0022
• First Posted: Oct 28, 2001
• Last Update Posted: Aug 16, 2016
• Last Verified: Aug 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Lipoatrophic Diabetes; Diabetes Mellitus; Hypertriglyceridemia; NASH; Lipodystrophy; Leptin; Diabetes
• Additional relevant MeSH terms: Lipodystrophy

Study Results

Participant Flow

Arm/Group Title	Metreleptin
Arm/Group Description	subcutaneous metreleptin injections in one to two daily doses ranging from 0.06 to 0.24 mg/kg/day.
Period Title: Overall Study
STARTED	103
Generalized Lipodystrophy	63
Partial Lipodystrophy	40
COMPLETED	86
NOT COMPLETED	17

Baseline Characteristics

Arm/Group Title	Metreleptin With Generalized Lipodystrophy	Metreleptin With Patial Lipodystrophy	Total
Arm/Group Description	patients with generalized lipodystrophy with subcutaneous metreleptin injection (0.06-0.24 mg/kg/day)	patients with partial lipodystrophy with subcutaneous metreleptin injection (0.06-0.24 mg/kg/day)	Total of all reporting groups
Overall Participants	55	31	86
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	18 (12)	35 (14)	24 (15)
Sex: Female, Male (Count of Participants)
Female	42 76.4%	31 100%	73 84.9%
Male	13 23.6%	0 0%	13 15.1%
Pediatric patients (participants) [Number]
aged <20 years	42 76.4%	7 22.6%	49 57%
aged >=20 years	13 23.6%	24 77.4%	37 43%
Body mass index-standard deviation score (BMI-SDS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	0.26 (0.98)	0.66 (0.7)	0.41 (0.9)
Percentage body fat (percentage of body fat) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of body fat]	9 (2)	22 (4)	15 (7)
Leptin (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	1.13 (0.74)	6.23 (3.96)	3.03 (3.44)
Glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	180 (80)	182 (87)	181 (83)
HbA1c (percentage of glycated hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycated hemoglobin]	8.4 (2.3)	8.1 (2.2)	8.3 (2.3)
Fasting insulin (µU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [µU/mL]	122 (318)	82 (157)	108 (273)
C-peptide (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	5.61 (4.03)	3.56 (2.27)	4.82 (3.62)
Antidiabetic medications per patient (antidiabetic medications) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [antidiabetic medications]	1.13 (0.7)	1.79 (0.68)	1.36 (0.81)
Insulin users (participants) [Number]
Yes	30 54.5%	15 48.4%	45 52.3%
No	24 43.6%	14 45.2%	38 44.2%
not known	1 1.8%	2 6.5%	3 3.5%
Lipid-lowering medications per patient (lipid-lowering medications) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [lipid-lowering medications]	0.61 (0.84)	1.07 (1.04)	0.82 (0.93)
Total cholesterol (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	214 (110)	235 (147)	222 (126)
Triglycerides (mg/dL) [Geometric Mean (Inter-Quartile Range) ]
Geometric Mean (Inter-Quartile Range) [mg/dL]	467	483	473
HDL-C (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	29 (9)	31 (9)	30 (9)
LDL-C (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	104 (50)	101 (36)	103 (46)
Vitamin A (µg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [µg/dL]	57 (33)	73 (20)	61 (25)
Vitamin E (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	26 (32)	34 (21)	31 (28)
25-Hydroxyvitamin D (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	16 (11)	23 (13)	19 (12)
PT (sec) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [sec]	14.2 (1.2)	13.2 (0.6)	13.8 (1.1)
International Normalized Ratio (INR) (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	1.10 (0.14)	0.98 (0.06)	1.05 (0.13)
Daily total insulin units per patient (insulin units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [insulin units]	625 (1099)	278 (214)	362 (620)

Outcome Measures

1. Primary Outcome

Title	Percentage of Glycosylated Hemoglobin at Baseline, 6 Months, and 12 Months on Treatment With Metreleptin
Description	Percentage of glycosylated hemoglobin at Baseline, 6 months, and 12 months on treatment with metreleptin
Time Frame	Baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Generalized Lipodystrophy (GLD)	Partial Lipodystrophy (PLD)
Arm/Group Description	patients with generalized lipodystrophy (GLD) with initiation of subcutaneous metreleptin injection (0.06-0.24 mg/kg/day)	patients with partial lipodystrophy (PLD) with initiation of subcutaneous metreleptin injection (0.06-0.24 mg/kg/day)
Measure Participants	55	31
Baseline	8.4 (2.3)	8.1 (2.2)
6 months	6.6 (1.7)	7.2 (1.2)
12 months	6.4 (1.5)	7.3 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generalized Lipodystrophy (GLD)
	Comments	A null hypothesis of interest is there is no significant change over three time points (baseline, 6 months, 12 months) in response to metreleptin within GLD group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Partial Lipodystrophy (PLD)
	Comments	A null hypothesis of interest is there is no significant change over three time points (baseline, 6 months, 12 months) in response to metreleptin within PLD group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

Title	Triglycerides at Baseline, 6 Months, and 12 Months on Treatment With Metreleptin
Time Frame	Baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Generalized Lipodystrophy (GLD)	Partial Lipodystrophy (PLD)
Arm/Group Description	patients with generalized lipodystrophy (GLD) with initiation of subcutaneous metreleptin injection (0.06-0.24 mg/kg/day)	patients with partial lipodystrophy (PLD) with initiation of subcutaneous metreleptin injection (0.06-0.24 mg/kg/day)
Measure Participants	55	31
Baseline	467	483
6 months	198	339
12 months	180	326

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generalized Lipodystrophy (GLD)
	Comments	Triglycerides were log transformed for analysis due to non-normal distribution. Changes in triglycedies in response to metreleptin over three time points (baseline, 6 months, 12 months) are tested within GLD group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Partial Lipodystrophy (PLD)
	Comments	Triglycerides were log transformed for analysis due to non-normal distribution. Changes in triglycedies in response to metreleptin over three time points (baseline, 6 months, 12 months) are tested within PLD group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	1 year
Arm/Group Title	Metreleptin
Arm/Group Description	subcutaneous metreleptin injection (0.06-0.24 mg/kg/day)
All Cause Mortality
	Metreleptin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Metreleptin
	Affected / at Risk (%)	# Events
Total	10/103 (9.7%)
Cardiac disorders
Exacerbations of heart failure	2/103 (1.9%)	5
Gastrointestinal disorders
Abdominal pain requiring hospitalization	1/103 (1%)	5
Acute exacerbation of pancreatitis	1/103 (1%)	1
Osteomyelitis	1/103 (1%)	1
Infections and infestations
Severe acute bronchitis	1/103 (1%)	1
Pneumonia	2/103 (1.9%)	2
Cellulitis	1/103 (1%)	2
Group B streptococcus bacteremia	1/103 (1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian cyst requiring bilateral oophorectomy and total abdominal hysterectomy	1/103 (1%)	1
Pregnancy, puerperium and perinatal conditions
Miscarriage	1/103 (1%)	1
Other (Not Including Serious) Adverse Events
	Metreleptin
	Affected / at Risk (%)	# Events
Total	64/103 (62.1%)
Blood and lymphatic system disorders
Anemia	6/103 (5.8%)	6
Iron deficiency	4/103 (3.9%)	5
Endocrine disorders
Hypoglycemia	10/103 (9.7%)	12
Fatigue	7/103 (6.8%)	8
Gastrointestinal disorders
Abdominal pain	8/103 (7.8%)	9
Nausea	9/103 (8.7%)	9
Constipation	5/103 (4.9%)	5
Diarrhea	5/103 (4.9%)	5
Decreased appetite	4/103 (3.9%)	4
General disorders
Anxiety	6/103 (5.8%)	6
Insomnia	5/103 (4.9%)	5
Headache	4/103 (3.9%)	4
Depression	4/103 (3.9%)	4
Infections and infestations
Infection	7/103 (6.8%)	12
Metabolism and nutrition disorders
Weight loss	12/103 (11.7%)	12
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	15/103 (14.6%)	19
Joins pain	4/103 (3.9%)	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
tumor, benign	6/103 (5.8%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.