Leptin to Treat Lipodystrophy

NCT00025883 | Completed Phase 2 Results

• 2 other identifiers: 02002202-DK-0022
• Study Type: interventional
• Target: 103
• Locations: 1 country
• Sites: 1

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.

Conditions

Lipodystrophy

Keywords

Lipoatrophic Diabetes; Diabetes Mellitus; Hypertriglyceridemia; NASH; Lipodystrophy; Leptin; Diabetes

Outcome Measures

Primary Outcomes (2)

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

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

  Baseline, 6 months, 12 months

• Triglycerides at Baseline, 6 Months, and 12 Months on Treatment With Metreleptin

  Baseline, 6 months, 12 months

Study Arms (1)

Metreleptin

EXPERIMENTAL

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

Drug: Metreleptin

Interventions

Metreleptin DRUG

Drug treatment

Also known as: Leptin

Metreleptin

Eligibility Criteria

• Age: 6 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Presence of diabetes as defined by the 2007 ADA criteria
• Fasting plasma glucose greater than or equal to 126 mg/dL, or
• hour plasma glucose greater than or equal to 200 mg/dL following a 75 gram (1.75gm/kg) oral glucose load, or
• Diabetic symptoms with a random plasma glucose greater than or equal to 200 mg/dl
• Fasting insulin greater than 30 micro units/ml.
• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (16)

• 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. doi: 10.1172/JCI119839.

  PMID: 9389757 BACKGROUND

• 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. doi: 10.1101/gad.12.20.3168.

  PMID: 9784492 BACKGROUND

• 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. doi: 10.1093/hmg/9.1.109.

  PMID: 10587585 BACKGROUND

• Okawa MC, Tuska RM, Lightbourne M, Abel BS, Walter M, Dai Y, Cochran E, Brown RJ. Insulin Signaling Through the Insulin Receptor Increases Linear Growth Through Effects on Bone and the GH-IGF-1 Axis. J Clin Endocrinol Metab. 2023 Dec 21;109(1):e96-e106. doi: 10.1210/clinem/dgad491.

  PMID: 37595266 DERIVED

• Meral R, Malandrino N, Walter M, Neidert AH, Muniyappa R, Oral EA, Brown RJ. Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients With Partial Lipodystrophy. J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1739-e1751. doi: 10.1210/clinem/dgab760.

  PMID: 34677608 DERIVED

• Nguyen ML, Sachdev V, Burklow TR, Li W, Startzell M, Auh S, Brown RJ. Leptin Attenuates Cardiac Hypertrophy in Patients With Generalized Lipodystrophy. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4327-e4339. doi: 10.1210/clinem/dgab499.

  PMID: 34223895 DERIVED

• Sekizkardes H, Cochran E, Malandrino N, Garg A, Brown RJ. Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3068-3076. doi: 10.1210/jc.2018-02787.

  PMID: 31194872 DERIVED

• Brown RJ, Meehan CA, Cochran E, Rother KI, Kleiner DE, Walter M, Gorden P. Effects of Metreleptin in Pediatric Patients With Lipodystrophy. J Clin Endocrinol Metab. 2017 May 1;102(5):1511-1519. doi: 10.1210/jc.2016-3628.

  PMID: 28324110 DERIVED

• Kassai A, Muniyappa R, Levenson AE, Walter MF, Abel BS, Ring M, Taylor SI, Biddinger SB, Skarulis MC, Gorden P, Brown RJ. Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy. J Clin Endocrinol Metab. 2016 Apr;101(4):1790-7. doi: 10.1210/jc.2015-3891. Epub 2016 Feb 22.

  PMID: 26900642 DERIVED

• Chan JL, Koda J, Heilig JS, Cochran EK, Gorden P, Oral EA, Brown RJ. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf). 2016 Jul;85(1):137-49. doi: 10.1111/cen.12980. Epub 2016 Feb 2.

  PMID: 26589105 DERIVED

• Diker-Cohen T, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab. 2015 May;100(5):1802-10. doi: 10.1210/jc.2014-4491. Epub 2015 Mar 3.

  PMID: 25734254 DERIVED

• Christensen JD, Lungu AO, Cochran E, Collins MT, Gafni RI, Reynolds JC, Rother KI, Gorden P, Brown RJ. Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy. J Clin Endocrinol Metab. 2014 Aug;99(8):E1493-500. doi: 10.1210/jc.2014-1353. Epub 2014 Jul 29.

  PMID: 25070319 DERIVED

• Joseph J, Shamburek RD, Cochran EK, Gorden P, Brown RJ. Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and triglycerides. J Clin Endocrinol Metab. 2014 Sep;99(9):E1676-80. doi: 10.1210/jc.2014-1878. Epub 2014 Jun 13.

  PMID: 24926953 DERIVED

• Kamran F, Rother KI, Cochran E, Safar Zadeh E, Gorden P, Brown RJ. Consequences of stopping and restarting leptin in an adolescent with lipodystrophy. Horm Res Paediatr. 2012;78(5-6):320-5. doi: 10.1159/000341398. Epub 2012 Sep 4.

  PMID: 22965160 DERIVED

• Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C, Gorden P. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract. 2011 Nov-Dec;17(6):922-32. doi: 10.4158/EP11229.OR.

  PMID: 22068254 DERIVED

• Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010 Jan;53(1):27-35. doi: 10.1007/s00125-009-1502-9. Epub 2009 Sep 2.

  PMID: 19727665 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lipodystrophy; Diabetes Mellitus, Lipoatrophic; Diabetes Mellitus; Hypertriglyceridemia

Interventions

metreleptin; Leptin

Condition Hierarchy (Ancestors)

Skin Diseases, Metabolic; Skin Diseases; Skin and Connective Tissue Diseases; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Endocrine System Diseases; Hyperlipidemias; Dyslipidemias

Intervention Hierarchy (Ancestors)

Adipokines; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Phillip Gorden
• Organization: National Institute of DIabetes and Digestive and Kidney Dseases, National Institutes of Health

phillipg@mail.nih.gov

301-402-7340

Study Officials

• Phillip Gorden, M.D.

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2001
• First Posted: October 29, 2001
• Study Start: October 1, 2001
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: August 16, 2016
• Results First Posted: August 16, 2016

Record last verified: 2016-08

Data Sharing

• IPD Sharing: Will share

Locations

US (1)