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Trial of Aromatase Inhibition in Lymphangioleiomyomatosis (TRAIL)

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: NCT01353209
Recruitment Status : Completed
First Posted : May 12, 2011
Last Update Posted : August 26, 2015
United States Department of Defense
Information provided by (Responsible Party):
Francis McCormack, University of Cincinnati

Brief Summary:
The hypothesis in this study is that estrogen suppression by an aromatase inhibitor in postmenopausal women with Lymphangioleiomyomatosis (LAM) will prevent or delay progression of lung disease and result in a decrease in the rate of decline in FEV1

Condition or disease Intervention/treatment Phase
Lymphangioleiomyomatosis Drug: Letrozole Drug: Placebo Phase 2

Detailed Description:

Lymphangioleiomyomatosis, or LAM, is an uncommon, progressive, cystic lung disease that predominantly affects young women. Pulmonary parenchymal changes consistent with LAM are found in about one third of women with tuberous sclerosis complex (TSC), an autosomal dominant tumor suppressor syndrome. LAM also occurs in a sporadic form that is not associated with germ line mutations in TSC genes. Recent evidence that recurrent LAM after lung transplantation results from seeding of the graft from a remote source and suggests a metastatic mechanism for the disease.

Since LAM occurs almost exclusively in women, and exposure to estrogen either exogenously or during pregnancy can exacerbate LAM, estrogen suppression might be expected to prevent or delay progression of disease. In preclinical studies, estrogen induces the growth of TSC2-deficient cells and tumor cells derived from LAM patients. In a xenograft model of lymphangioleiomyomatosis presented by Dr. Yu at the 2008 LAM Research Meeting, estrogen promoted the pulmonary metastases of tuberin-deficient ELT3 cells (TSC2-deficient rat uterine leiomyoma cells) in female ovariectomized CB-17-scid mice, while the estrogen inhibitor fulvestrant completely blocked estrogen-promoted pulmonary metastases. This work was recently published.

Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis)(14). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)diben-zonitrile.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Study Start Date : May 2011
Actual Primary Completion Date : September 2014
Actual Study Completion Date : September 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Letrozole

Arm Intervention/treatment
Experimental: Letrozole Drug: Letrozole
2.5 mg daily for twelve months
Other Name: Femara

Placebo Comparator: Placebo Drug: Placebo
sugar pill given daily for twelve months

Primary Outcome Measures :
  1. The effect on Forced Expiratory Volume in one second [ Time Frame: twelve months ]

Secondary Outcome Measures :
  1. Other measures of pulmonary function [ Time Frame: twelve months ]

  2. Quality of life measures [ Time Frame: twelve months ]
    Quality of Life, dyspnea and fatigue, functional performance

  3. Serum VEGF-D [ Time Frame: twelve months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • All patients at least must have a diagnosis of pulmonary lymphangioleiomyomatosis as defined by one of the following:

    • CT chest compatible with LAM and a biopsy or cytology consistent withLAM.
    • CT chest consistent with LAM in the setting of tuberous sclerosis, renal angiomyolipomata, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen , or serum VEGF-D > 800 pg/uL.
  • All patients must have a post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted
  • All patients must be postmenopausal females as defined by one of the following:

    • Prior bilateral oophorectomy or bilateral ovarian irradiation.
    • If age greater than 55 years, no menstrual period for 12 months or longer.
    • If age 55 years or younger, must have an estradiol level in the postmenopausal range in the absence of current use of progestational agents.
    • If still premenopausal, may enter if rendered medically postmenopausal on clinical grounds with the use of gonadotropin releasing hormone (e.g. leuprolide), as long as serum estradiol, FSH, and LH are in the postmenopausal range
  • Patients with osteopenia or osteoporosis must be receiving appropriate treatment for their osteoporosis or osteopenia at entry into this study.
  • Patients must have adequate hematologic and hepatic function as defined by the following at the time of randomization.:

    • Neutrophils > 1500/mm3 and platelets > 100,000/mm3
    • Bilirubin < 1.25 X upper limit of normal
    • SGPT (ALT) and SGOT (AST) < 2.5 X upper limit of normal

Exclusion Criteria:

  • Known allergy to letrozole
  • Inability to comply with pulmonary function tests or follow up visits.
  • Treatment with investigational agents within 30 days
  • Hormonal therapy (e.g. estrogen, progestin, LHRH agonists or antagonists, estrogen receptor blockers, estrogen receptor down regulators, aromatase inhibitors) within 30 days month of registration
  • Medical or psychiatric conditions that would interfere with the ability to provide informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01353209

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United States, California
Stanford University Medical Center
Stanford, California, United States, 94305
United States, Florida
Mayo Clinic
Jacksonville, Florida, United States, 32224
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Illinois
Loyola University Medical Center
Maywood, Illinois, United States, 60153
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States, 45267
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Washington
Minor and James
Seattle, Washington, United States, 98122
Sponsors and Collaborators
University of Cincinnati
United States Department of Defense
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Principal Investigator: Francis X McCormack, MD University of Cincinnati
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Francis McCormack, Pulmonary Director, University of Cincinnati
ClinicalTrials.gov Identifier: NCT01353209    
Other Study ID Numbers: 5708
First Posted: May 12, 2011    Key Record Dates
Last Update Posted: August 26, 2015
Last Verified: August 2015
Additional relevant MeSH terms:
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Lymphatic Vessel Tumors
Neoplasms by Histologic Type
Perivascular Epithelioid Cell Neoplasms
Neoplasms, Connective and Soft Tissue
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs