NCT01778556

Brief Summary

Background: \- Lipodystrophy is a condition where people do not have enough fat in the body. People with lipodystrophy can have problems such as diabetes or an enlarged liver. Researchers are looking at how leptin, a hormone produced by fat cells, can help people with these problems. Leptin helps control appetite and how the body stores food. Taking leptin can help people with lipodystrophy eat less food, which may help treat diabetes and other problems. To better understand how leptin works, researchers want to do an inpatient study on leptin treatment in people with lipodystrophy. Objectives: \- To study how leptin treatment affects lipodystrophy. Eligibility: \- Individuals between 14 and 70 years of age who have lipodystrophy. Design:

  • All participants will have a 19-day stay at the National Institutes of Health Clinical Center. One group of participants will have tests for 5 days before starting to take leptin. They will then take leptin for 2 weeks, and have more tests. The other group of participants will have tests for 5 days while taking leptin. They will then take stop taking leptin for 2 weeks, and have more tests, and then they will start taking leptin again.
  • Participants will have regular blood and urine tests during the visit. Some of the blood tests will look at insulin levels. Some will look at how the body metabolizes sugar and fat. Other tests will check hormone levels, especially of reproductive hormones.
  • During the visit, participants will spend 3 separate days in a metabolic chamber, a special room that measures how many calories the body uses. Urine samples will be collected during these stays.
  • Participants will also have several body imaging studies, including magnetic resonance imaging and a body composition scan.
  • Physical activity will be tested with an exercise bicycle and an electronic activity monitor.
  • Participants will be asked questions about hunger and comfort levels throughout the stay.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
25

participants targeted

Target at below P25 for phase_2

Timeline
Completed

Started Jan 2013

Longer than P75 for phase_2

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

January 26, 2013

Completed
Same day until next milestone

Study Start

First participant enrolled

January 26, 2013

Completed
3 days until next milestone

First Posted

Study publicly available on registry

January 29, 2013

Completed
5.1 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

February 23, 2018

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

February 23, 2018

Completed
1.7 years until next milestone

Results Posted

Study results publicly available

November 13, 2019

Completed
Last Updated

November 13, 2019

Status Verified

February 25, 2019

Enrollment Period

5.1 years

First QC Date

January 26, 2013

Results QC Date

June 24, 2019

Last Update Submit

October 21, 2019

Conditions

Lipodystrophy

Keywords

LipodystrophyLeptinEnergy ExpenditureDiabetesHypertriglyceridemia

Outcome Measures

Primary Outcomes (1)

  • Total Body Insulin Sensitivity

    Total body insulin sensitivity (measured as glucose disposal rate during a hyperinsulinemic, euglycemic clamp)

    Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)

Secondary Outcomes (2)

  • Insulin-mediated Suppression of Hepatic Glucose Production

    Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)

  • Endogenous Rate of Appearance of Palmitate

    Intervention 1 (5 days), Intervention 2 (14 days), and Long-term follow-up (6 months)

Study Arms (2)

Leptin naive

EXPERIMENTAL

Studied for 5 days without metreleptin, then 14 days while taking metreleptin

Biological: Metreleptin

On-leptin

EXPERIMENTAL

Studied for 5 days while taking metreleptin, then 14 days during metreleptin withdrawal

Biological: Metreleptin

Interventions

MetreleptinBIOLOGICAL

Recombinant analog of the human hormone, leptin

Leptin naiveOn-leptin

Eligibility Criteria

Age14 Years - 70 Years
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

  • Age 14-70 years (children under age 18 will only be enrolled in the leptin-naive arm of the study
  • Lipodystrophy identified by the study physician during physical examination as an absence of fat outside the range of normal
  • Circulating leptin levels \< 12.0 ng/mL in females and \< 8.0 ng/mL in males
  • Presence of at least one of the following metabolic abnormalities:
  • Diabetes as defined by the 2007 American Diabetes Association criteria
  • Fasting insulin \>30 microU/mL
  • Fasting hypertriglyceridemia \>200 mg/dL
  • Co-enrolled in protocol 02-DK-0022 and either:
  • Leptin naive, with plans to initiate leptin treatment during the current study. For the purpose of this study, leptin naive will be defined as having received no exogenous leptin in the 4 months prior to study participation. Thus, subjects who previously received leptin therapy, discontinued, and wish to restart are eligible.
  • Leptin treated, meaning the subject has taken a stable dose of exogenous leptin for a minimum of 4 months (adults over age 18, only)

You may not qualify if:

  • Poorly controlled diabetes at study entry (hemoglobin A1c greater than or equal to 9%)
  • Poorly controlled hypertriglyceridemia at study entry (serum triglycerides \> 800 mg/dL)
  • Extreme hypertriglyceridemia prior to leptin (triglycerides greater than 2000 mg/dL at initiation of leptin treatment)
  • History of chronic or recurrent acute pancreatitis (\> 1 episode), or a single episode of pancreatitis while receiving leptin treatment
  • Lipase greater than the upper limit of normal (491 units/L) at study entry
  • Known HIV infection or HIV-associated lipodystrophy
  • History of diabetic ketoacidosis
  • Active inflammatory disease (e.g. dermatomyositis)
  • Change in diabetes or lipid-lowering medications within the past 6 weeks
  • Estimated glomerular filtration rate \< 30 mL/minute
  • Current or recent (past 2 weeks) use of systemic glucocorticoids
  • Inadequately controlled hypothyroidism (TSH \< 0.4 or \>4 mcIU/L) or change in thyroid medication in the past 8 weeks.
  • Pregnancy or breast-feeding
  • Psychiatric disorder impeding competence or compliance
  • Any medical condition or medication that will increase risk to the subject (e.g. ischemic heart disease, decompensated liver disease) or that will interfere with interpretation of study data (e.g. Cushing s syndrome).

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (12)

  • Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest. 1997 Feb 1;99(3):391-5. doi: 10.1172/JCI119172.

    PMID: 9022071BACKGROUND

  • Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature. 1996 Jul 18;382(6588):250-2. doi: 10.1038/382250a0.

    PMID: 8717038BACKGROUND

  • Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 1996 Mar;12(3):318-20. doi: 10.1038/ng0396-318.

    PMID: 8589726BACKGROUND

  • Quaye E, Chacko S, Startzell M, Brown RJ. Leptin Decreases Gluconeogenesis and Gluconeogenic Substrate Availability in Patients With Lipodystrophy. J Clin Endocrinol Metab. 2023 Dec 21;109(1):e209-e215. doi: 10.1210/clinem/dgad445.

    PMID: 37515588DERIVED

  • 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: 34677608DERIVED

  • 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: 34223895DERIVED

  • Grover A, Quaye E, Brychta RJ, Christensen J, Startzell MS, Meehan CA, Valencia A, Marshall B, Chen KY, Brown RJ. Leptin Decreases Energy Expenditure Despite Increased Thyroid Hormone in Patients With Lipodystrophy. J Clin Endocrinol Metab. 2021 Sep 27;106(10):e4163-e4178. doi: 10.1210/clinem/dgab269.

    PMID: 33890058DERIVED

  • Baykal AP, Parks EJ, Shamburek R, Syed-Abdul MM, Chacko S, Cochran E, Startzell M, Gharib AM, Ouwerkerk R, Abd-Elmoniem KZ, Walter PJ, Walter M, Muniyappa R, Chung ST, Brown RJ. Leptin decreases de novo lipogenesis in patients with lipodystrophy. JCI Insight. 2020 Jul 23;5(14):e137180. doi: 10.1172/jci.insight.137180.

    PMID: 32573497DERIVED

  • Sekizkardes H, Chung ST, Chacko S, Haymond MW, Startzell M, Walter M, Walter PJ, Lightbourne M, Brown RJ. Free fatty acid processing diverges in human pathologic insulin resistance conditions. J Clin Invest. 2020 Jul 1;130(7):3592-3602. doi: 10.1172/JCI135431.

    PMID: 32191645DERIVED

  • 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: 31194872DERIVED

  • Brown RJ, Valencia A, Startzell M, Cochran E, Walter PJ, Garraffo HM, Cai H, Gharib AM, Ouwerkerk R, Courville AB, Bernstein S, Brychta RJ, Chen KY, Walter M, Auh S, Gorden P. Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy. J Clin Invest. 2018 Aug 1;128(8):3504-3516. doi: 10.1172/JCI95476. Epub 2018 Jul 16.

    PMID: 29723161DERIVED

  • 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: 28324110DERIVED

Related Links

MeSH Terms

Conditions

LipodystrophyDiabetes MellitusHypertriglyceridemia

Interventions

metreleptin

Condition Hierarchy (Ancestors)

Skin Diseases, MetabolicSkin DiseasesSkin and Connective Tissue DiseasesLipid Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesGlucose Metabolism DisordersEndocrine System DiseasesHyperlipidemiasDyslipidemias

Results Point of Contact

Title
Dr. Rebecca Brown
Organization
NIDDK
brownrebecca@mail.nih.gov
301-594-0609

Study Officials

  • Rebecca J Brown, 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
NON RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
CROSSOVER
Sponsor Type
NIH
Responsible Party
SPONSOR

Study Record Dates

First Submitted

January 26, 2013

First Posted

January 29, 2013

Study Start

January 26, 2013

Primary Completion

February 23, 2018

Study Completion

February 23, 2018

Last Updated

November 13, 2019

Results First Posted

November 13, 2019

Record last verified: 2019-02-25

Locations

US(1)