Efficacy and Safety of Sirolimus in LAM

University of Cincinnati89 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Conditions

Lymphangioleiomyomatosis

Interventions

SirolimusDRUG

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

PlaceboDRUG

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

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 18 or older * Signed and dated informed consent * Diagnosis of LAM based on compatible chest CT scan and a) biopsy or cytology consistent with LAM, or b) presence of tuberous sclerosis, angiomyolipoma or chylous pleural effusion; or c) a VEGF-D level of at least 800 pg/ml * Forced expiratory volume in one second (FEV1) of 70% or less of predicted value after administration of a bronchodilator Exclusion Criteria: * Known allergy to sirolimus * History of heart attack, angina, or stroke due to clogging, narrowing, and hardening of the arteries and blood vessels * Significant hematologic or hepatic abnormality (transaminase levels greater than three times the upper limit of normal, HCT less than 30%, platelets less than 80,000/cubic mm, adjusted absolute neutrophil count less than 1,000/cubic mm, total white blood cell count less than 3,000/cubic mm) * Intercurrent infection at the time treatment with sirolimus begins * Any surgery involving entry into a body cavity or requiring three or more sutures within 8 weeks of initiation of study drug * Use of an investigational drug within the 30 days prior to random assignment * Uncontrolled hyperlipidemia * Previous lung transplant or currently on lung transplant list * Unable to attend scheduled study visits * Unable to perform pulmonary function tests * Creatinine levels greater than 2.5 mg/dl * Chylous ascites severe enough to affect diaphragmatic function * Pleural effusion severe enough to affect pulmonary function, as determined by the study physician * History of acute pneumothorax within the 2 months prior to study entry * History of malignancy within the 2 years prior to study entry (except for squamous or basal cell skin cancer) * Use of estrogen containing medication within the thirty days prior to randomization * Unable or unwilling to use adequate contraception * Pregnant, breastfeeding, or plans to become pregnant within the next 2 years

Locations (13)

University of California Los Angeles

Los Angeles, California, United States

National Jewish Medical and Research Center

Denver, Colorado, United States

University of Florida, Gainesville

Gainesville, Florida, United States

Outcomes

Primary Outcomes

Changes in Forced Expiratory Volume in One-second (FEV1) Slope in Milliliters Per 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. Normative ranges are determined in populations stratified by gender, height, age and race/ethnicity. Higher FEV1 values indicate better lung function.

Time frame: Baseline to Month 12

Secondary Outcomes

Percent of Participants With Serious Adverse Events

Time frame: Baseline to Month 12

Changes in FVC Slope in ml/Month

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.

Time frame: Baseline to Month 12

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

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.

Time frame: Baseline to Month 12

Rate of Change in Total Lung Volume in ml Per Month

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.

Data from ClinicalTrials.gov

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