Lymphangioleiomyomatosis
Conditions
Keywords
Lymphangiomyomatosis, Postmenopausal
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 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.
Interventions
DRUGLetrozole
2.5 mg daily for twelve months
DRUGPlacebo
placebo given daily for twelve months
Sponsors
United States Department of Defense
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month | 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-bronchodilator FVC | twelve months | Post-bronchodilator FVC in milliliters |
| St George Respiratory Questionnaire | twelve months | 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. |
| Serum VEGF-D | twelve months | 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. |
Countries
United States
Participant flow
Pre-assignment details
Patients were eligible for inclusion in the study if they were postmenopausal women with a definite diagnosis of pulmonary LAM and abnormal pulmonary function. Patients on sirolimus were required to wait three months before beginning this trial.
Participants by arm
| Arm | Count |
|---|---|
| Letrozole Letrozole: 2.5 mg daily for twelve months | 9 |
| Placebo Placebo: sugar pill given daily for twelve months | 8 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
Baseline characteristics
| Characteristic | Letrozole | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 15 Participants | 7 Participants |
| Age, Continuous | 57 years | 58 years | 59 years |
| LAM subtyped Sporadic LAM | 6 participants | 14 participants | 8 participants |
| LAM subtyped TSC LAM | 3 participants | 3 participants | 0 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 13 Participants | 6 Participants |
| Region of Enrollment United States | 9 participants | 17 participants | 8 participants |
| Sex: Female, Male Female | 9 Participants | 17 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Sirolimus status Not on sirolimus | 4 Participants | 7 Participants | 3 Participants |
| Sirolimus status On sirolimus | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 9 | 1 / 8 |
| serious Total, serious adverse events | 0 / 9 | 1 / 8 |
Outcome results
Primary
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.
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letrozole | Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month | 1.04 milliliters per month |
| Placebo | Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month | 1.66 milliliters per month |
p-value: 0.4Mixed Models Analysis
Secondary
Post-bronchodilator FVC
Post-bronchodilator FVC in milliliters
Time frame: twelve months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letrozole | Post-bronchodilator FVC | 2.58 milliliters per month |
| Placebo | Post-bronchodilator FVC | 2.46 milliliters per month |
p-value: 0.7Mixed Models Analysis
Secondary
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.
Time frame: twelve months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letrozole | Serum VEGF-D | 572 pg/ml |
| Placebo | Serum VEGF-D | 944 pg/ml |
p-value: 0.015Mixed Models Analysis
Secondary
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.
Time frame: twelve months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Letrozole | St George Respiratory Questionnaire | 38 score on a scale |
| Placebo | St George Respiratory Questionnaire | 62 score on a scale |
p-value: 0.8Regression, Linear
p-value: 0.8Regression, Linear