Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial

Inclusion Criteria

• Female, age 18 or over
• Signed and dated informed consent
• Diagnosis of LAM as determined by compatible lung CT and one of the following
• biopsy (lung, abdominal mass, lymph node or kidney) or cytology from thoracic or abdominal sources revealing LAM, or
• tuberous sclerosis, angiomyolipomata (diagnosed by CT, MRI by the site radiologist or biopsy) or chylous pleural effusion (verified by tap), or
• VEGF-D level ≥ 800 pg/ml.
• Post-bronchodilator forced expiratory volume in one second of > 70%
• Presence of markers of non-trivial burden of LAM or likely progression based on one of the following:
• pretrial FEV 1 rate of decline of >60cc/yr, comparing enrollment FEV1 to any prior measurement in the past 3 years, or
• baseline supplemental oxygen requirement with exercise, or
• pre-menopausal and one of the following (if post-menopausal, must have a VEGF-D level ≥ 600 pg/ml and one of the following) baseline diffusing capacity for carbon monoxide ≤80% predicted, a) baseline residual volume ≥120% predicted, b) baseline desaturation by 4% or more on six minute walk testing on room air c) more than 20 cysts on the carinal cut of the CT

Exclusion Criteria

• Existing or imminent (within 12-18 months) clinical indication for treatment with mTOR inhibitors, based on judgment of site investigator
• DLCO <60% predicted
• Resting room air saturation <90%
• Exercise induced desaturation nadir on room air < 85%
• History of myocardial infarction, angina or stroke related to atherosclerosis
• Pregnant, breast feeding, or plan to become pregnant in the next 2.5 years
• Inadequate contraception
• Significant hematologic, renal, metabolic or hepatic abnormality (i.e. transaminase levels > three times the UL of normal range, HCT < 30%, platelets < 80,000/mm3, adjusted absolute neutrophil count < 1,000/ mm3, total WBC < 3,000/ mm3), creatinine >2.5 mg/dl, uncontrolled hyperlipidemia
• Acute or chronic infection, such as (nontuberculous mucobacteria or active hepatitis B or C infections)
• Recent surgery (involving entry into a body cavity or requiring 3 or more sutures) within three weeks of initiation of study drug
• Use of sirolimus, everolimus or investigational treatment for LAM within the 30 days prior to randomization
• Previous lung transplantation or active on transplant list
• Inability to attend scheduled clinic visits, or perform pulmonary function testing
• Pleural effusion or chylous ascites sufficient to affect pulmonary function based on the opinion of the Site Investigator
• Acute pneumothorax within the past month
• History of malignancy in the past two years, other than squamous or basal cell skin cancer.
• Use of estrogen containing medications within the 30 days prior to randomization.
• Known allergy to sirolimus