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.

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

Adverse event data was collected over a 2 year period (12 month treatment period and 12 month observation period).

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.

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