Study of Leptin for the Treatment of Hypothalamic Amenorrhea

Amenorrhea Clinical Trial

Official title:

Randomized, Double-blind, Placebo-controlled Trial of Human Recombinant Leptin (r-metHuLeptin) for the Treatment of Hypothalamic (Exercise-Induced) Amenorrhea

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00130117
• Other study ID #: 2004P-000123
• Status: Active, not recruiting
• Phase: Phase 2
• First received: August 11, 2005
• Last updated: January 12, 2015
• Start date: April 2010
• Est. completion date: December 2015

Study information

• Verified date: January 2015
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 57
• Est. completion date: December 2015
• Est. primary completion date: August 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 35 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Amenorrhea

Intervention

Drug:
• r-metHuLeptin
Starting dose: 0.08mg/kg once daily Subcutaneous injection.
• Oral Contraceptive Pills (OCPs)
Sprintec taken orally once daily.

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center General Clinical Research Center	Boston	Massachusetts

Sponsors (4)

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

Country where clinical trial is conducted

United States, 

References & Publications (4)

Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, Mantzoros CS. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6585-90. doi: 10.1073/pnas.1015 — View Citation

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. — View Citation

Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, Arampatzi KM, Gao C, Koniaris A, Mantzoros CS. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metaboli — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the difference between the placebo and leptin treated groups in the change in bone mineral density (BMD) at the anteroposterior (AP) spine from baseline to 36 weeks		36 weeks	Yes
Secondary	hormone levels and bone markers		36 weeks	Yes
Secondary	immune function		36 weeks	Yes
Secondary	body composition (weight and body fat)		36 weeks	No
Secondary	total, radial, hip bone density		36 weeks	Yes
Secondary	resting metabolic rate		36 weeks	No
Secondary	overall sense of well-being, appetite and food intake		36 weeks	No

External Links

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