Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lung Diseases

Lymphangioleiomyomatosis

Respiratory Tract Diseases

Lymphangiomyoma

Neoplasms by Histologic Type

Perivascular Epithelioid Cell Neoplasms

Neoplasms, Connective and Soft Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Gerald Beck

To establish a registry of individuals with LAM by forming a consortium of six clinical centers and referring physicians who treat LAM patients.

BACKGROUND:

LAM is a rare multi-system disease that can affect the lungs of young women, is of uncertain cause, is usually progressive, and can cause debilitating lung disease which may be corrected with lung transplantation. Several hundred women with the disease have been identified, largely through a LAM Foundation in Cincinnati, Ohio.

DESIGN NARRATIVE:

The Data and Coordinating Center is located at the Cleveland Clinic Foundation. The registry has six major clinical centers: Cleveland Clinic Foundation, Mayo Clinic-Rochester, National Heart, Lung, and Blood Institute, National Jewish Medical and Research Center, New England Medical Center, and Stanford University Medical Center. Data and lung tissue collected by the registry will be used to characterize the clinical features and natural history of the disease and to determine the efficacy of lung transplantation in this disorder. Eligible patients are to be seen yearly for up to 4 years at the Clinical Centers or, in some cases, by individual referring physicians. Tissue collected by the LAM Registry will be stored at a central NHLBI repository. Outcome events include measures of pulmonary function (eg, spirometry and, when available, lung volumes and diffusing capacity), arterial blood gases or oximetry, walking and resting oxygen titration, cardiopulmonary stress testing, cause-specific mortality, functional status, and clinical events associated with lung transplantation.

The Office of Research on Women's Health provided funding in FY 1997 in the amount of $100,000.

The study completion date listed in this record was obtained from the "End Date" entered in the Protocol Registration and Results System (PRS) record.

Lymphangioleiomyomatosis (LAM) Registry

National Heart, Lung, and Blood Institute (NHLBI)

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Sirolimus

Temsirolimus

MTOR Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

Participants receive sirolimus daily for 1 year and are followed with serial pulmonary function tests, 6-minute walk tests, and symptom and QOL questionnaires over a 2-year period.

Participants receive placebo daily for 1 year and followed with serial pulmonary function tests, 6-minute walk tests, and symptom and QOL questionnaires over a 2-year period.

A sirolimus dose of 2 tablets (1 mg/tablet) per day for 1 year.

A placebo dose of 2 tablets per day for 1 year.

Placebo

Francis X McCormack, MD

Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that is caused by genetic mutations. It results in the uncontrolled growth of an unusual type of smooth muscle cell in the lung. These cells invade lung tissue, including the airways, blood vessels, and lymph vessels, and restrict the flow of air, blood, and lymph, respectively. Respiratory failure, lung collapse (pneumothorax), and pleural effusions (chylothorax) are hallmarks of the disease. This study will evaluate the safety and effectiveness of sirolimus, an inhibitor of the mTOR pathway, in stabilizing or improving lung function in people with LAM.

LAM is an uncommon, progressive, cystic lung disease that predominantly affects young women. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes, which regulate cellular pathways that control nutrient sensing, cell size, cell migration, and cell proliferation. Individuals with LAM often experience pneumothorax and chylothorax, as well progressive loss of lung function. Sirolimus is drug that was approved for the prevention of kidney transplant rejection. It directly affects the cellular pathway that causes LAM. This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with LAM.

Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and month 24; and a volumetric computed tomography scan will occur at baseline, month 12, and month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.

Unlabeled sirolimus tablets were provided by Pfizer. Identical appearing placebo tablets were obtained from a commercial source. Sirolimus levels were reported only to the medical monitor. To maintain the blind, when dose adjustments were made in the sirolimus group, a sham adjustment was also made in the placebo group

Efficacy and Safety of Sirolimus in LAM

Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus Trial

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. Normative ranges are determined in populations stratified by gender, height, age and race/ethnicity. Higher FEV1 values indicate better lung function.

FVC values are reported in liters or milliliters. Normative ranges are determined in populations that are stratified by gender, height, age and race/ethnicity. There are no minimum or maximum values as it is a physiologic measure of lung function and varies from individual to individual. Higher FVC scores indicate better lung function.

Diffusing capacity for carbon monoxide is abbreviated DLCO. DLCO is measured in liters and 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. A lower DLCO means that there is lower lung function.

There are two methods for measurement of total lung volume, nitrogen or helium wash out (total lung capacity or TLC), or plethysmography (Total gas volume or TGV). TLC or TGV is measured in milliliters or liters. Normative ranges for TLC or TGV are stratified by age, height, and sex in population based studies of normal subjects.. There are no definite minimum and maximum values of lung volume as it is a physiological measure of lung function and varies from individual to individual. A low TGV or TLC is suggestive of a restrictive lung disease, and a high TGV or TLC is consistent with obstructive lung disease with hyperinflation.

Number of meters walked in six minutes. There is no minimum or maximum number of feet walked as this varies from individual to individual. A higher number of feet walked indicates better exercise tolerance

Serum VEGF-D is a protein produced by LAM cells that serves as a biomarker of mTOR activation and sirolimus response. Mean serum levels of VEGF-D in normal subjects are around 350 pg/ml. Higher levels of serum VEGF-D are correlated with greater degrees of mTOR activation, and a fall in VEGF-D levels suggest suppression of the mTOR axis.

Office of Rare Diseases (ORD)

FDA Office of Orphan Products Development

National Center for Research Resources (NCRR)

University of Cincinnati

Professor

Participants will receive sirolimus daily for 1 year followed with serial pulmonary functional tests and 6-minute walk tests over a 2-year period. Note: study truncated to 1 year with daily sirolimus in 2010. Second year of follow up eliminated after August 31, 2010.

Sirolimus Treatment Arm

Participants will receive placebo sirolimus daily for 1 year followed with serial pulmonary functional tests and 6-minute walk tests over a 2-year period. Note: study truncated to 1 year with daily placebo sirolimus in 2010. Second year of follow up eliminated after August 31, 2010.

Placebo Treatment Arm

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

The observation period of the trial was truncated for some subjects, driven by funding limitations, need for timely reporting and drug expiration factors. Please see supplement to McCormack FX, et al. Efficacy and safety of sirolimus in LAM. N Engl J Med. 2011, 28;364:1595-606. PMID: 21410393 for more detail.

Francis X. McCormack, MD

sirolimus treatment arm FEV1 at 12 months.

Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per Month

Participants received sirolimus daily for 1 year and were followed with serial pulmonary function tests and 6-minute walk tests over a 2-year period.

Sirolimus: Initial sirolimus dose of 2 mg was given in the form of 2 tablets (1 mg/tablet) per day for 1 year, and was titrate to maintain a serum level of 5-10 ng/ml.

Active Agent (Sirolimus)

Participants receive placebo daily for 1 year and were followed with serial pulmonary function tests and 6-minute walk tests over a 2-year period.

Placebo sirolimus: Placebo was administered as 2 tablets per day for 1 year, and was sham adjusted in some subjects to maintain the blind.

Placebo Arm

Percent of Participants With Serious Adverse Events

Participants received sirolimus daily for 1 year and were followed with serial pulmonary function tests and 6-minute walk tests over a 2-year period.

Participants received placebo daily for 1 year followed with serial pulmonary function tests and 6-minute walk tests over a 2-year period.

Changes in FVC Slope in ml/Month

Rate of Change in Diffusing Capacity for Carbon Monoxide (DLCO) in ml/Min/mmHg

Rate of Change in Total Lung Volume in ml Per Month

Participants received sirolimus daily for 1 year followed with serial pulmonary function tests and 6-minute walk tests over a 2-year period.

Rate of Change in Six Minute Walk Distance in Meters/Month

Participants received placebo daily for 1 year and were followed with serial pulmonary function tests and 6-minute walk tests over a 2-year period.

Rate of Change in Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels in pg/ml Per Month

Overall Study

Letrozole

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Patients are placed on letrozole, 1 tablet (2.5 mg) daily for one year

Patients are placed on placebo, 1 tablet daily for one year

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

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.

Letrozole for Lymphangioleiomyomatosis

Trial of Letrozole in Lymphangioleiomyomatosis

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.

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.

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.

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.

United States Department of Defense

Professor and Director, Pulmonary, Critical Care and Sleep Medicine

Adverse effects were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.

Letrozole: 2.5 mg daily for twelve months

Placebo: sugar pill given daily for twelve months

Age, Continuous

United States

Region of Enrollment

Sporadic LAM

TSC LAM

LAM subtyped

On sirolimus

Not on sirolimus

Sirolimus status

Under enrollment. Post menopause not originally assessed by estradiol levels. Small sample sizes led to some imbalances in baseline parameters, such as VEGF-D levels and bronchodilator responsiveness, which could have biased outcomes.

Susan McMahan, Clinical Research Manager

Rate of Change in Forced Expiratory Volume in 1 Second in ml/Month

Patients are placed on letrozole, 1 tablet (2.5 mg) daily for one year

Letrozole: 2.5 mg daily for twelve months

Patients are placed on placebo, 1 tablet daily for one year

Placebo: placebo given daily for twelve months

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lymphangioleiomyomatosis (LAM) Registry	NCT00005486	Lung Diseases Lymphangiomyoma...		- 100 Years	National Heart, Lung, and Blood Institute (NHLBI)
Lymphangioleiomyomatosis (LAM) Registry	NCT00005486	Lung Diseases Lymphangiomyoma...		- 100 Years	National Heart, Lung, and Blood Institute (NHLBI)
Efficacy and Safety of Sirolimus in LAM	NCT00414648	Lymphangioleiom...	Sirolimus Placebo	18 Years -	University of Cincinnati
Letrozole for Lymphangioleiomyomatosis	NCT01353209	Lymphangioleiom...	Letrozole Placebo	18 Years -	University of Cincinnati

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