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Trial of Aromatase Inhibition in Lymphangioleiomyomatosis (TRAIL)

Primary Purpose

Lymphangioleiomyomatosis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Letrozole
Placebo
Sponsored by
University of Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphangioleiomyomatosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Stanford University Medical Center
  • Mayo Clinic
  • University of Miami
  • Emory University School of Medicine
  • Loyola University Medical Center
  • Washington University School of Medicine
  • University of Cincinnati
  • Cleveland Clinic
  • Minor and James

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Letrozole

Placebo

Arm Description

Outcomes

Primary Outcome Measures

The effect on Forced Expiratory Volume in one second

Secondary Outcome Measures

Other measures of pulmonary function
FVC, DLCO, TLC,RV, FRC, 6MWT
Quality of life measures
Quality of Life, dyspnea and fatigue, functional performance
Serum VEGF-D

Full Information

First Posted
May 11, 2011
Last Updated
August 24, 2015
Sponsor
University of Cincinnati
Collaborators
United States Department of Defense
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1. Study Identification

Unique Protocol Identification Number
NCT01353209
Brief Title
Trial of Aromatase Inhibition in Lymphangioleiomyomatosis
Acronym
TRAIL
Official Title
A TRIAL OF LETROZOLE IN PULMONARY LYMPHANGIOLEIOMYOMATOSIS
Study Type
Interventional

2. Study Status

Record Verification Date
August 2015
Overall Recruitment Status
Completed
Study Start Date
May 2011 (undefined)
Primary Completion Date
September 2014 (Actual)
Study Completion Date
September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cincinnati
Collaborators
United States Department of Defense

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphangioleiomyomatosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Letrozole
Arm Type
Experimental
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Letrozole
Other Intervention Name(s)
Femara
Intervention Description
2.5 mg daily for twelve months
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
sugar pill given daily for twelve months
Primary Outcome Measure Information:
Title
The effect on Forced Expiratory Volume in one second
Time Frame
twelve months
Secondary Outcome Measure Information:
Title
Other measures of pulmonary function
Description
FVC, DLCO, TLC,RV, FRC, 6MWT
Time Frame
twelve months
Title
Quality of life measures
Description
Quality of Life, dyspnea and fatigue, functional performance
Time Frame
twelve months
Title
Serum VEGF-D
Time Frame
twelve months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francis X McCormack, MD
Organizational Affiliation
University of Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University Medical Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Mayo Clinic
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Emory University School of Medicine
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Loyola University Medical Center
City
Maywood
State/Province
Illinois
ZIP/Postal Code
60153
Country
United States
Facility Name
Washington University School of Medicine
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Minor and James
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
28570161
Citation
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.
Results Reference
derived

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Trial of Aromatase Inhibition in Lymphangioleiomyomatosis

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