Role of Leptin in the Neuroendocrine and Immune Response to Fasting

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00140231
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Center for Research Resources (NCRR) (NIH), Amgen (Industry)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Months): 170
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study will be to determine whether giving leptin (r-metHuLeptin) to a person when he or she is fasting will reverse changes in metabolism, and hormone levels, and immune function associated with fasting, which decreases leptin levels.

Condition or Disease	Intervention/Treatment	Phase
Fasting	Drug: r-metHuLeptin; Other: placebo	Phase 1/Phase 2

Detailed Description

Leptin is a hormone secreted by fat cells under normal conditions and acts in the brain to decrease appetite and increase energy use. Leptin levels usually go down with fasting. This study will evaluate the secretion of an investigational agent called leptin in lean and overweight individuals while fasting and investigate the potential role of leptin as a regulator of immune function and mediator of the neuroendocrine response to food deprivation in humans. Data derived from these studies will provide insights into the mechanisms underlying altered hormone levels and immune function in malnutrition and obesity and thus may provide the basis for future therapeutic interventions for obesity.

Comparison: fed state vs. fasting state vs. fasting + leptin state

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Role of Leptin in the Neuroendocrine and Immune Response to Fasting in Humans
• Study Start Date: Oct 1, 2002
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Metreleptin r-metHuLeptin self-administered subcutaneously	Drug: r-metHuLeptin; recombinant human leptin; Other Names: metreleptin ; Other: placebo; placebo (no active drug)
Placebo Comparator: Placebo Placebo, administered in same method as active arm.	Drug: r-metHuLeptin; recombinant human leptin; Other Names: metreleptin ; Other: placebo; placebo (no active drug)

Outcome Measures

Primary Outcome Measures

1. Cortisol [four days]

2. ACTH Mean Level [4 days]

   Response of ACTH to leptin administration in fed and fasting state from baseline was measured

3. Immune Function CD3 Count [4 days]

Secondary Outcome Measures

1. %Fat Mass [four days]

2. (RMR) [four days]

   Resting Metabolic rate using calorimetry

3. Autonomic Function [four days]

   aldosterone level were measured on day 4 in response to leptin in fed and fasting states and compared with baseline level on day 1

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy lean women (with body mass indices [BMI] < 25 kg/m2)

• Overweight otherwise healthy men (with BMI > 27 kg/m2)

• Overweight otherwise healthy women (with BMI > 27 kg/m2).

Exclusion Criteria:

• A history of any illness that may affect the concentrations of the hormones to be studied, e.g. infectious diseases, renal or hepatic failure, type 1 or type 2 diabetes mellitus, cancer or lymphoma, hypogonadism, malabsorption or malnourishment, hypo- or hyperthyroidism, hypercortisolism, alcoholism or drug abuse, anemia, or eating disorder

• On medications known to affect the hormones to be measured (glucocorticoids, anti-seizure medications, and thyroid hormones)

• A known history of anaphylaxis or anaphylactoid-like reactions, or a known hypersensitivity to E. coli derived proteins

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Center for Research Resources (NCRR)
• Amgen

Investigators

• Principal Investigator: Christos S Mantzoros, MD, DSc, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about the Mantzoros Research Group.
• Click here for more information about Beth Israel Deaconess Medical Center.

Publications

• Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003 May;111(9):1409-21.

• Responsible Party: Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT00140231
• Other Study ID Numbers: 2002P000049; 2M01RR001032-30; 5R01DK058785-07
• First Posted: Sep 1, 2005
• Last Update Posted: Jun 7, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center: leptin; fasting; reproductive; neuroendocrine; immune function; energy deficiency associated with short-term fasting

Study Results

Participant Flow

Arm/Group Title	Iso Fed, Then Fasting w/ Metreleptin, Then Fasting w/ Placebo	Iso Fed, Then Fasting w/ Placebo, Then Fasting w/ Met
Arm/Group Description	Six young, healthy, and lean women (age, 22.8,; BMI,21.7kg/m2) who were eumenor- rheic were enrolled in a clinical researchcenter- based, randomized, cross-over interventional study involving three separate 5-day-long inpatient admissions (22). Six subjects with a cross-over design, enabling paired comparisons, would provide 80% power to detect a difference of 1.4 SD between different conditionsat the conventional a=0.05 level. In thefirst admission, the subjects were studied in the isocaloric fed state, whereas in the following two admissions the subjects were studied in the prolonged fasting state for 72 h and were randomized to receive either placebo or metreleptin at replacement doses. A cross-over to the opposite arm took place in the later admission so that all six subjects received both placebo and metreleptin. r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)
Period Title: Fed State 1 Day- day5
STARTED	7	6
COMPLETED	7	6
NOT COMPLETED	0	0
Period Title: Fed State 1 Day- day5
STARTED	7	6
COMPLETED	7	6
NOT COMPLETED	0	0
Period Title: Fed State 1 Day- day5
STARTED	7	6
COMPLETED	7	6
NOT COMPLETED	0	0
Period Title: Fed State 1 Day- day5
STARTED	7	6
COMPLETED	7	6
NOT COMPLETED	0	0
Period Title: Fed State 1 Day- day5
STARTED	7	6
COMPLETED	7	6
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Iso Fed, Then Fasting w/ Metreleptin, Then Fasting w/ Placebo	Iso Fed, Then Fasting w/ Placebo, Then Fasting w/ Metreleptin	Total
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)	Total of all reporting groups
Overall Participants	7	6	13
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	6 100%	13 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26 (5)	25 (5)	25.5 (0.5)
Sex: Female, Male (Count of Participants)
Female	7 100%	6 100%	13 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	6 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	Cortisol
Time Frame	four days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metreleptin	Placebo
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)
Measure Participants	13	13
Mean (Standard Deviation) [ug/dl]	17.5 (0.9)	16.9 (1.9)

2. Primary Outcome

Title	ACTH Mean Level
Description	Response of ACTH to leptin administration in fed and fasting state from baseline was measured
Time Frame	4 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metreleptin	Placebo
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)
Measure Participants	13	13
baseline fed	10.48 (1.28)	9.33 (1.23)
fasting	9.89 (2.01)	8.74 (1.75)

3. Primary Outcome

Title	Immune Function CD3 Count
Time Frame	4 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metreleptin	Placebo
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)
Measure Participants	13	13
Mean (Standard Error) [cells/ul]	302 (185)	838 (268)

4. Secondary Outcome

Title	%Fat Mass
Time Frame	four days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metreleptin	Placebo
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)
Measure Participants	13	13
Mean (Standard Deviation) [fat%]	29.1 (2.2)	29.3 (1.9)

5. Secondary Outcome

Title	(RMR)
Description	Resting Metabolic rate using calorimetry
Time Frame	four days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metreleptin	Placebo
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)
Measure Participants	13	13
Mean (Standard Deviation) [kcal/d]	1.344 (34)	1.352 (43)

6. Secondary Outcome

Title	Autonomic Function
Description	aldosterone level were measured on day 4 in response to leptin in fed and fasting states and compared with baseline level on day 1
Time Frame	four days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Metreleptin	Placebo
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin	Placebo, administered in same method as active arm. placebo: placebo (no active drug)
Measure Participants	13	13
Day 4	132 (27.0)	112 (23.5)
day 1 baseline	66.1 (11.7)	66.0 (12.8)

Adverse Events

Arm/Group Title	Metreleptin		Placebo
Arm/Group Description	r-metHuLeptin self-administered subcutaneously r-metHuLeptin: recombinant human leptin		Placebo, administered in same method as active arm. placebo: placebo (no active drug)
All Cause Mortality
	Metreleptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Serious Adverse Events
	Metreleptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Metreleptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)

Limitations/Caveats

Our study is confined to lean, healthy female subjects; therefore, our results should not be generalized to male, obese,or diabetic subjects

More Information

Certain Agreements

Principal Investigators are NOT 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.