NCT00130117

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.

Trial Health

87
On Track

Trial Health Score

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

Enrollment
20

participants targeted

Target at below P25 for phase_2

Timeline
Completed

Started Apr 2010

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

August 11, 2005

Completed
4 days until next milestone

First Posted

Study publicly available on registry

August 15, 2005

Completed
4.6 years until next milestone

Study Start

First participant enrolled

April 1, 2010

Completed
1.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 1, 2011

Completed
5.3 years until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2016

Completed
6 months until next milestone

Results Posted

Study results publicly available

May 17, 2017

Completed
Last Updated

May 17, 2017

Status Verified

April 1, 2017

Enrollment Period

1.3 years

First QC Date

August 11, 2005

Results QC Date

December 24, 2015

Last Update Submit

April 13, 2017

Conditions

Amenorrhea

Keywords

leptinhypothalamic amenorrheaexercise-induced amenorrheaneuroendocrine functionbone metabolism

Outcome Measures

Primary Outcomes (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 Outcomes (8)

  • Bone Markers - Ctx and Sclerostin

    36 weeks

  • Body Composition BMI

    36 weeks

  • Total Body BMD

    36 weeks

  • Body Fat

    36 weeks

  • Total Body BMD

    9 months

  • +3 more secondary outcomes

Study Arms (2)

r-metHuLeptin

EXPERIMENTAL

r-metHuLeptin administered subcutaneously.

Drug: r-metHuLeptinDrug: Oral Contraceptive Pills (OCPs)

Oral Contraceptive Pills (OCPs)

PLACEBO COMPARATOR

PLACEBO

Drug: Oral Contraceptive Pills (OCPs)Other: Placebo

Interventions

r-metHuLeptinDRUG

Starting dose: 0.08mg/kg once daily Subcutaneous injection.

Also known as: metreleptin
r-metHuLeptin
Oral Contraceptive Pills (OCPs)DRUG

Sprintec taken orally once daily.

Also known as: OCPs
Oral Contraceptive Pills (OCPs)r-metHuLeptin
PlaceboOTHER

placebo (no active medication)

Oral Contraceptive Pills (OCPs)

Eligibility Criteria

Age18 Years - 35 Years
Sexfemale
Healthy VolunteersYes
Age GroupsAdult (18-64)

You may qualify if:

  • 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)
  • 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

You may not qualify if:

  • 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
  • +21 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Beth Israel Deaconess Medical Center General Clinical Research Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (11)

  • 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. doi: 10.1056/NEJMoa040388.

    PMID: 15342807BACKGROUND

  • 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.

    PMID: 21791620BACKGROUND

  • 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. Metabolism. 2011 Sep;60(9):1211-21. doi: 10.1016/j.metabol.2011.05.016. Epub 2011 Jul 7.

    PMID: 21741057RESULT

  • 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.1015674108. Epub 2011 Apr 4.

    PMID: 21464293RESULT

  • Chrysafi P, Perakakis N, Farr OM, Stefanakis K, Peradze N, Sala-Vila A, Mantzoros CS. Leptin alters energy intake and fat mass but not energy expenditure in lean subjects. Nat Commun. 2020 Oct 13;11(1):5145. doi: 10.1038/s41467-020-18885-9.

    PMID: 33051459DERIVED

  • Bouzoni E, Perakakis N, Mantzoros CS. Circulating profile of Activin-Follistatin-Inhibin Axis in women with hypothalamic amenorrhea in response to leptin treatment. Metabolism. 2020 Dec;113:154392. doi: 10.1016/j.metabol.2020.154392. Epub 2020 Oct 10.

    PMID: 33045195DERIVED

  • Foo JP, Polyzos SA, Anastasilakis AD, Chou S, Mantzoros CS. The effect of leptin replacement on parathyroid hormone, RANKL-osteoprotegerin axis, and Wnt inhibitors in young women with hypothalamic amenorrhea. J Clin Endocrinol Metab. 2014 Nov;99(11):E2252-8. doi: 10.1210/jc.2014-2491. Epub 2014 Aug 22.

    PMID: 25148234DERIVED

  • Hwang JJ, Thakkar B, Chamberland JP, Mantzoros CS. Circulating fetuin-A levels are not affected by short and long-term energy deprivation and/or by leptin administration. Metabolism. 2014 Jun;63(6):754-9. doi: 10.1016/j.metabol.2014.02.006. Epub 2014 Feb 17.

    PMID: 24703486DERIVED

  • Matarese G, La Rocca C, Moon HS, Huh JY, Brinkoetter MT, Chou S, Perna F, Greco D, Kilim HP, Gao C, Arampatzi K, Wang Z, Mantzoros CS. Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):E818-27. doi: 10.1073/pnas.1214554110. Epub 2013 Feb 4.

    PMID: 23382191DERIVED

  • Aronis KN, Diakopoulos KN, Fiorenza CG, Chamberland JP, Mantzoros CS. Leptin administered in physiological or pharmacological doses does not regulate circulating angiogenesis factors in humans. Diabetologia. 2011 Sep;54(9):2358-67. doi: 10.1007/s00125-011-2201-x. Epub 2011 Jun 10.

    PMID: 21660636DERIVED

  • Alonso-Alonso M, Ziemke F, Magkos F, Barrios FA, Brinkoetter M, Boyd I, Rifkin-Graboi A, Yannakoulia M, Rojas R, Pascual-Leone A, Mantzoros CS. Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding. Am J Clin Nutr. 2011 Aug;94(2):377-84. doi: 10.3945/ajcn.110.010736. Epub 2011 May 18.

    PMID: 21593494DERIVED

Related Links

MeSH Terms

Conditions

Amenorrhea

Interventions

recombinant methionyl human leptinmetreleptin

Condition Hierarchy (Ancestors)

Menstruation DisturbancesPathologic ProcessesPathological Conditions, Signs and Symptoms

Limitations and Caveats

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

Results Point of Contact

Title
Christos Mantzoros
Organization
BIDMC
cmantzor@bidmc.harvard.edu
6176678630

Study Officials

  • Christos S Mantzoros, MD, ScD

    Beth Israel Deaconess Medical Center, Harvard Medical School

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
No
Restrictive Agreement
No

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, CARE PROVIDER
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Professor of Medicine

Study Record Dates

First Submitted

August 11, 2005

First Posted

August 15, 2005

Study Start

April 1, 2010

Primary Completion

August 1, 2011

Study Completion

December 1, 2016

Last Updated

May 17, 2017

Results First Posted

May 17, 2017

Record last verified: 2017-04

Data Sharing

IPD Sharing
Will not share

Locations

US(1)