Study of Leptin for the Treatment of Hypothalamic Amenorrhea

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00130117
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), National Center for Research Resources (NCRR) (NIH), Amgen (Industry)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 80
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether administration of an investigational medication called leptin (r-metHuLeptin) in replacement doses can improve bone health, reproductive function, hormone levels, immune function, and overall sense of well-being in women with hypothalamic (exercise-induced) amenorrhea (HA) who are being treated with oral contraceptive pills (OCPs), compared to placebo. Women with hypothalamic amenorrhea have low leptin levels. This study is based on the hypothesis that the relative leptin deficiency in women with hypothalamic (exercise-induced) amenorrhea may be the reason for the lack of menstrual cycles, hormone abnormalities, and bone loss associated with this condition.

Condition or Disease	Intervention/Treatment	Phase
Amenorrhea	Drug: r-metHuLeptin; Drug: Oral Contraceptive Pills (OCPs); Other: Placebo	Phase 2

Detailed Description

Leptin is a hormone secreted by fat cells under normal conditions and acts in the brain to regulate energy usage and hormone levels. Women with HA who do not have regular periods have low leptin levels and may also have other hormone abnormalities as well as loss of bone density (osteopenia or osteoporosis). This study will evaluate how leptin (a fat cell hormone that normally circulates in the blood) affects bone density, menstrual periods, hormone levels, bone metabolism (how bone forms and turns over), immune function (how well the body can fight infection), metabolic rate (how many calories are used at rest), and overall sense of well-being and appetite in women with HA (i.e. no regular menstrual periods due to low levels of pituitary hormones that regulate estrogen production from the ovary). It will also investigate whether leptin replacement can be used as an adjunct to the current standard of care for HA patients, i.e. OCPs.

Part A is a Randomized, placebo-controlled 36-week study. Part B is an Optional open-label 52-week study. There will also be an optional Reward Sub-study, including healthy controls, designed to investigate leptin's relation to reward processing by collecting participants' brain and behavioral responses to images (e.g., pictures of food vs. non-food). Brain responses will be collected and will also be assessed via functional Magnetic Resonance Imaging (fMRI).

Comparison: Part A = leptin-treated group to placebo-treated group and Part B optional sub study = leptin-treated group to health controls

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Placebo-controlled Trial of Human Recombinant Leptin (r-metHuLeptin) for the Treatment of Hypothalamic (Exercise-Induced) Amenorrhea
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: r-metHuLeptin r-metHuLeptin administered subcutaneously.	Drug: r-metHuLeptin; Starting dose: 0.08mg/kg once daily Subcutaneous injection.; Other Names: metreleptin ; Drug: Oral Contraceptive Pills (OCPs); Sprintec taken orally once daily.; Other Names: OCPs
Placebo Comparator: Oral Contraceptive Pills (OCPs) PLACEBO	Drug: Oral Contraceptive Pills (OCPs); Sprintec taken orally once daily.; Other Names: OCPs ; Other: Placebo; placebo (no active medication)

Outcome Measures

Primary Outcome Measures

1. the Difference Between the Placebo and Leptin Treated Groups in the Change in Bone Mineral Content(BMC) at the Anteroposterior (AP) Spine From Baseline to 36 Weeks [36 weeks]

Secondary Outcome Measures

1. Bone Markers - Ctx and Sclerostin [36 weeks]

2. Body Composition BMI [36 weeks]

3. Total Body BMD [36 weeks]

4. Body Fat [36 weeks]

5. Total Body BMD [9 months]

6. Lumbar BMD [9 months]

7. Radial BMD [9 months]

8. Hip BMD [9months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion criteria for HA subjects

• Hypothalamic amenorrhea of at least 6 months duration with low or normal LH and FSH, e.g. due to strenuous exercise (running >20 miles per week or equivalent) or low weight

• Can be secondary HA OR primary HA with some pubertal development and normal screening labs

• Age 18-35 years old

• Body weight within +/- 15% of ideal body weight and stable for 6 months (no change > 5 lbs)

• Baseline leptin <5 ng/mL (except for the Cognitive Sub-Study Baseline visit where baseline leptin will be greater than 5ng/mL)

Inclusion criteria for eumenorrheic controls for Reward Sub-study

• Normal menstrual cycles (between 25 and 35 days)

• Age 18-35

• Body weight within +/- 15% of ideal body weight and stable 6 months (no change > 5 lbs)

• Baseline leptin >5 ng/mL

Exclusion criteria:

• We will exclude subjects with:

• Significant medical history that may affect the concentrations of the hormones to studied or ability to participate in the study

• renal or hepatic disease (creatinine > 1.4, AST/ALT > 2x upper limit of normal)

• diagnosed diabetes mellitus

• myocardial ischemia

• malignancy (other than basal cell carcinoma of the skin or in situ carcinoma of the cervix)

• malabsorption

• alcoholism, drug abuse, or smoking

• active eating disorder

• depression or other psychiatric disease

• anemia (Hb10 gm/dL on 2 occasions)

• Conditions that are contraindicated for oral contraceptive use:

• Thrombophlebitis or thromboembolic disorders

• A past history of deep vein thrombophlebitis or thromboembolic disorders

• Cerebral vascular or coronary artery disease

• Known or suspected carcinoma of the breast

• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia

• Undiagnosed abnormal genital bleeding

• Hepatic adenomas or carcinomas

• Cholestatic jaundice of pregnancy or jaundice with prior OCP use

• Other endocrine causes of amenorrhea, e.g.

• hyperprolactinemia

• hypothyroidism or hyperthyroidism

• Cushing's syndrome

• congenital adrenal hyperplasia (elevated 17 OH progesterone)

• polycystic ovarian syndrome (elevated androgens or LH/FSH ratio >1.5)

• primary ovarian failure (elevated FSH)

• On medications known to affect the hormones to be measured such as

• glucocorticoids

• anti seizure medications

• thyroid hormones

• estrogen (must be off at least 3 months prior to participating in the study)

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

• Breast feeding, pregnant, or wanting to become pregnant during the next 6 months.

• We will screen for these conditions through a detailed history and systems review, physical examination, laboratory evaluation (as described above in Screening Methods), and EKG.

• In the Reward Sub-study subjects will be asked to fill out a standard BIDMC MRI safety screening form prior to entering the magnet.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• National Center for Research Resources (NCRR)
• Amgen

Investigators

• Principal Investigator: Christos S Mantzoros, MD, ScD, Beth Israel Deaconess Medical Center, Harvard Medical School

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

• Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab. 2011 Oct;301(4):E567-84. doi: 10.1152/ajpendo.00315.2011. Epub 2011 Jul 26. Review.
• Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004 Sep 2;351(10):987-97.

• Responsible Party: Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT00130117
• Other Study ID Numbers: 2004P000123; 1R34HD048526-01; 5M01RR001032-32
• First Posted: Aug 15, 2005
• Last Update Posted: May 17, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Christos Mantzoros, Professor of Medicine, Beth Israel Deaconess Medical Center: leptin; hypothalamic amenorrhea; exercise-induced amenorrhea; neuroendocrine function; bone metabolism
• Additional relevant MeSH terms: Amenorrhea; Contraceptive Agents; Contraceptives, Oral; Contraceptives, Oral, Combined

Study Results

Participant Flow

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Period Title: Overall Study
STARTED	11	9
COMPLETED	7	6
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	r-metHuLeptin	Placebo	Total
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)	Total of all reporting groups
Overall Participants	11	9	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	9 100%	20 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.6 (1.4)	25.4 (1.2)	26 (1.3)
Sex: Female, Male (Count of Participants)
Female	11 100%	9 100%	20 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	11 100%	9 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	the Difference Between the Placebo and Leptin Treated Groups in the Change in Bone Mineral Content(BMC) at the Anteroposterior (AP) Spine From Baseline to 36 Weeks
Time Frame	36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	7	6
Mean (Full Range) [g]	51.0	58.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	r-metHuLeptin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	r-metHuLeptin, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Bone Markers - Ctx and Sclerostin
Time Frame	36 weeks

Outcome Measure Data

Analysis Population Description

Only for subjects participating in both phase A and phase B (n=4), bone markers were assessed to see the change over 24 month period. All these patient got metreleptin treatment

Arm/Group Title	r-metHuLeptin
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.
Measure Participants	4
CTX	0.60
Sclerostin	0.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	r-metHuLeptin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	p value reflects treatment of leptin for "on-treatment", n=4
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Body Composition BMI
Time Frame	36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	7	6
Mean (Standard Error) [BMI-kg/m^2]	20.8 (0.6)	21.1 (0.6)

4. Secondary Outcome

Title	Total Body BMD
Time Frame	36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	7	6
Median (Inter-Quartile Range) [g/cm^2]	1.07	1.13

5. Secondary Outcome

Title	Body Fat
Time Frame	36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	7	6
Mean (Standard Error) [fat %]	23.9 (1.4)	20.8 (1.3)

6. Secondary Outcome

Title	Total Body BMD
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Oral Contraceptive Pills (OCPs)
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	PLACEBO Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	10	9
Median (Inter-Quartile Range) [g/cm2]	1.09	1.13

7. Secondary Outcome

Title	Lumbar BMD
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	10	9
Median (Inter-Quartile Range) [g/cm2]	0.92	0.97

8. Secondary Outcome

Title	Radial BMD
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	10	9
Median (Inter-Quartile Range) [g/cm2]	0.54	0.54

9. Secondary Outcome

Title	Hip BMD
Time Frame	9months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	r-metHuLeptin	Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.	placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
Measure Participants	10	9
Median (Inter-Quartile Range) [g/cm2]	0.89	0.88

Adverse Events

Adverse Event Reporting Description	11 participants started on the metreleptin arm , although only 7 finished the study. hence participants at risk are 11
Arm/Group Title	r-metHuLeptin		Placebo
Arm/Group Description	r-metHuLeptin administered subcutaneously. r-metHuLeptin: Starting dose: 0.08mg/kg once daily Subcutaneous injection. Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily.		placebo Oral Contraceptive Pills (OCPs): Sprintec taken orally once daily. Placebo: placebo (no active medication)
All Cause Mortality
	r-metHuLeptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	r-metHuLeptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	r-metHuLeptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/11 (18.2%)		0/6 (0%)
Skin and subcutaneous tissue disorders
local injection site reactions with erythematous rashes	2/11 (18.2%)	2	0/6 (0%)	0

Limitations/Caveats

Number of participants was small and, therefore, our observations need to be validated in studies with larger sample sizes.

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.