Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Short-term Effects of Leptin in People With Lipodystrophy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01778556
Recruitment Status : Completed
First Posted : January 29, 2013
Last Update Posted : February 28, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

Tracking Information
First Submitted Date  ICMJE January 26, 2013
First Posted Date  ICMJE January 29, 2013
Last Update Posted Date February 28, 2019
Study Start Date  ICMJE January 26, 2013
Actual Primary Completion Date February 23, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 29, 2014)
  • Total body insulin sensitivity [ Time Frame: 6 moths ]
  • Rate of lipolysis [ Time Frame: 6 months ]
  • Total 24 hour energy expenditure [ Time Frame: 6 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2013)
  • Total body insulin sensitivity [ Time Frame: 19 days ]
  • Rate of lipolysis [ Time Frame: 19 days ]
  • Total 24 hour energy expenditure [ Time Frame: 19 days ]
Change History Complete list of historical versions of study NCT01778556 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2016)
  • Fatty acid turnover, Liver & muscle triglyceride, IGFBP2; Physical activity; thyroid function; catecholamines; cardiac autonomic nervous system tone; body temperature; thermal comfort; LH pulsatility; blood pressure, hunger and satiety. [ Time Frame: 6 months ]
  • Hepatic insulin sensitivity; fasting plasma glucose, C-peptide, triglycerides, resting energy expenditure; Skeletal muscle work efficiency. [ Time Frame: 6 months ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Short-term Effects of Leptin in People With Lipodystrophy
Official Title  ICMJE Short Term Effects of Leptin Withdrawal or Initiation in Lipodystrophy Independent of Energy Intake
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.
Detailed Description

Background

Leptin is an adipocyte-derived hormone that can be thought of as a signal from adipose tissue to the rest of the body conveying information about long-term nutritional status. Patients with lipodystrophy have leptin deficiency secondary to lack of adipose tissue, and thus represent a natural model for studying the effects of leptin deficiency and replacement in humans. Leptin replacement in lipodystrophy ameliorates metabolic and endocrine abnormalities, including reducing food intake, improving insulin resistance and diabetes, reducing ectopic lipid, and normalizing reproduction. The reduction in energy intake induced by leptin replacement is likely responsible for part of the improvements observed in glucose and lipid metabolism. The clinical effects of leptin that are independent of changes in energy intake, and the mechanisms underlying these effects, have been poorly explored in humans.

Aim

The primary aim of this study is to determine the energy intake-independent effects of leptin on energy metabolism in lipodystrophic subjects. The major aspects of energy metabolism to be studied are:

  1. Lipid metabolism, including fasting lipids, lipolysis and fatty acid turnover, and ectopic lipid storage.
  2. Glucose metabolism, including fasting glucose, endogenous glucose production, and insulin sensitivity
  3. Energy expenditure, including total and resting energy expenditure, skeletal muscle work efficiency, and spontaneous physical activity

In addition, the effects of leptin on endocrine and autonomic function will be examined, including effects on the thyroid, gonadal, and adrenal axes, as well as blood pressure, body temperature, and heart rate variability.

Methods

This is a non-randomized, parallel group study. Two groups of patients aged 14 to 70 years with lipodystrophy will be studied: leptin naive and leptin treated. Minors will only be included in the leptin naive arm. All subjects will be stabilized on a weight maintenance diet for 5 days (Period 1). After this, leptin will be withdrawn from leptin treated subjects, and leptin will be initiated in leptin naive subjects for a period of 14 days (Period 2). The same isocaloric diet will be continued throughout both Periods, permitting study of leptin s effects independent of energy intake.

All subjects will undergo metabolic testing on admission, at the end of Period 1, and throughout Period 2, to generate a detailed short-term time course of the effects of leptin initiation or withdrawal. At the end of Period 2, leptin will be continued in the leptin naive subjects, and restarted in the leptin treated subjects. Repeat metabolic testing will be performed 6-12 months after leptin initiation in the leptin-naive cohort to generate information on leptin s long-term effects.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lipodystrophy
Intervention  ICMJE Biological: Metreleptin
Recombinant analog of the human hormone, leptin
Study Arms  ICMJE
  • Experimental: Leptin naive
    Studied for 5 days without metreleptin, then 14 days while taking metreleptin
    Intervention: Biological: Metreleptin
  • Experimental: On-leptin
    Studied for 5 days while taking metreleptin, then 14 days during metreleptin withdrawal
    Intervention: Biological: Metreleptin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 26, 2019)
27
Original Estimated Enrollment  ICMJE
 (submitted: January 26, 2013)
40
Actual Study Completion Date  ICMJE February 23, 2018
Actual Primary Completion Date February 23, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Age 14-70 years (children under age 18 will only be enrolled in the leptin-naive arm of the study
  • Clinically-significant lipodystrophy as defined in protocol 02-DK-0022 (Long Term Efficacy of Leptin Replacement in the Treatment of Lipodystrophy). Relevant inclusion criteria for enrollment in protocol 02-DK-0022 are (summarized):

    • 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:

      1. Diabetes as defined by the 2007 American Diabetes Association criteria
      2. Fasting insulin >30 microU/mL
      3. Fasting hypertriglyceridemia >200 mg/dL
  • Co-enrolled in protocol 02-DK-0022 and either:

    • Leptin na(SqrRoot) ve, 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.

Or

--Leptin treated, meaning the subject has taken a stable dose of exogenous leptin for a minimum of 4 months (adults over age 18, only)

EXCLUSION CRITERIA:

In leptin treated subjects only, the following exclusion criteria apply:

  • 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

In all subjects (leptin treated and leptin naive), the following exclusion criteria apply:

  • 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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 14 Years to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01778556
Other Study ID Numbers  ICMJE 130057
13-DK-0057
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )
Study Sponsor  ICMJE National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Rebecca J Brown, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date February 25, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP