Letrozole for Lymphangioleiomyomatosis (TRAIL)

Trial of Letrozole in Lymphangioleiomyomatosis

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

Study Overview

• Status: Completed
• Conditions: Lymphangioleiomyomatosis
• Intervention / Treatment: Drug: Letrozole; Drug: Placebo

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 germline 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 is exacerbated by pregnancy, menses and hormonal therapies suggest that estrogen suppression might be expected to prevent or delay progression of disease.

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 can therefore be achieved by specifically inhibiting the aromatase enzyme. Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) that has been shown to be effective in other neoplasms that affect women, such as breast cancer.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Washington
    • Seattle, Washington, United States, 98122
      • Minor and James

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Definite diagnosis of based on compatible chest CT and at least one of the following:

  1. biopsy or cytology consistent with LAM, or
  2. tuberous sclerosis, renal angiomyolipoma, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen, or
  3. serum VEGF-D ≥ 800 pg/uL.
• post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted

• female and postmenopausal status as defined by one of the following:

  1. prior bilateral oophorectomy or bilateral ovarian irradiation, or
  2. age greater than 55 years, and no menstrual period for 12 months or longer.

  3. age 18-55 years and 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.

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.
• abnormal 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) or SGOT (AST) >2.5 X upper limit of normal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Letrozole; Patients are placed on letrozole, 1 tablet (2.5 mg) daily for one year	Drug: Letrozole; 2.5 mg daily for twelve months; Other Names: Femara
Placebo Comparator: Placebo; Patients are placed on placebo, 1 tablet daily for one year	Drug: Placebo; placebo given daily for twelve months; Other Names: sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month	FEV1 values reported are in liters or milliliters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Higher FEV1 scores indicate better lung function.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-bronchodilator FVC	Post-bronchodilator FVC in milliliters	twelve months
St George Respiratory Questionnaire	Quality of Life scale for respiratory symptoms. This is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating worse quality of life.	twelve months
Serum VEGF-D	VEGF-D values represent serum VEGF-D levels in pg/ml. Higher levels of VEGF-D are associated with Lymphangioleiomyomatosis. A serum VEGF-D greater than 400 pg/ml is a diagnostic biomarker for LAM.	twelve months

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Francis X McCormack, MD, University of Cincinnati

Publications and helpful links

General Publications

• Lu C, Lee HS, Pappas GP, Dilling DF, Burger CD, Shifren A, Veeraraghavan S, Chapman JT, Parambil J, Ruoss SJ, Young LR, Hammes SR, Kopras EJ, Roads T, Krischer JP, McCormack FX; Trial of an Aromatase Inhibitor in Lymphangioleiomyomatosis Group. A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis. Ann Am Thorac Soc. 2017 Jun;14(6):919-928. doi: 10.1513/AnnalsATS.201610-824OC.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: May 11, 2011
• First Submitted That Met QC Criteria: May 11, 2011
• First Posted (Estimated): May 12, 2011

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Postmenopausal; Lymphangiomyomatosis
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphangiomyoma; Lymphatic Vessel Tumors; Perivascular Epithelioid Cell Neoplasms; Lymphangioleiomyomatosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: 5708

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified demographics and outcomes can be shared. Because LAM is a rare disease, demographics will be limited. A data transfer agreement will be implemented between the University of Cincinnati and the requesting entity.
• IPD Sharing Time Frame: immediately, indefinitely
• IPD Sharing Access Criteria: Email the PI: mccormfx@ucmail.uc.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes