Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial

The primary objective of the MILED trial is to determine if early, long term (2 yr), low dose
(fixed at 1 mg/day) treatment of patients with well-preserved lung function will prevent
disease progression to more advanced stages. Sixty patients with FEV1>70% predicted will be
enrolled and randomized to receive 1 mg/day sirolimus or placebo, and followed for a period
of 2 years with pulmonary function testing every 4 months. The primary endpoint will be the
between-group (placebo vs. sirolimus) difference in the rate of change in FEV1 (in liters)
over two years. Secondary endpoints will include severity grade adverse events, time to 200cc
or 10% FEV1 decline, forced vital capacity, lung volumes, diffusing capacity, serum VEGF-D,
and early airflow obstruction assessed using hyper-polarized gas MRI. The study will be
conducted through the Rare Lung Disease Clinic Network, a confederacy of clinics organized by
the LAM Foundation that is currently following over 1300 U.S. LAM patients and conducting the
Department of Defense sponsored Trial of an Aromatase Inhibitor in LAM (TRAIL) trial. The LAM
Foundation will assist with study recruitment and dissemination of results, and the
University of South Florida will function as the Data Coordinating Center. Successful
completion of this study will define the safety and efficacy of low dose sirolimus in
patients with normal lung function, and determine if sirolimus can be used to prevent disease
progression to symptomatic stages.

Inclusion Criteria:

1. Female, age 18 or over

2. Signed and dated informed consent

3. Diagnosis of LAM as determined by compatible lung CT and

1. biopsy (lung, abdominal mass, lymph node or kidney) or cytology from thoracic or
abdominal sources revealing LAM, or

2. tuberous sclerosis, angiomyolipomata (diagnosed by CT, MRI by the site
radiologist or biopsy) or chylous pleural effusion (verified by tap), or

3. VEGF-D level ≥ 800 pg/ml.

4. Post-bronchodilator forced expiratory volume in one second of > 70%

5. Presence of markers of non-trivial burden of LAM or likely progression based on:

1. pretrial FEV 1 rate of decline of >60cc/yr, comparing enrollment FEV1 to any
prior measurement in the past 3 years, or

2. baseline supplemental oxygen requirement with exercise, or

3. premenopausal status or VEGF-D ≥ 600 pg/ml and any one of the following: A)
baseline diffusing capacity for carbon monoxide ≤80% predicted, B) baseline
residual volume ≥120% predicted, C) baseline desaturation by 4% or more on six
minute walk testing on room air D) more than 20 cysts on the carinal cut of the
CT

Exclusion Criteria:

1. Existing or imminent (within 12-18 months) clinical indication for treatment with mTOR
inhibitors, based on judgment of site investigator

2. DLCO <60% predicted

3. Resting room air saturation <90%

4. Exercise induced desaturation nadir on room air < 85%

5. History of myocardial infarction, angina or stroke related to atherosclerosis

6. Pregnant, breast feeding, or plan to become pregnant in the next 2.5 years

7. Inadequate contraception

8. 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

9. Acute or chronic infection, such as (nontuberculous mucobacteria or active hepatitis B
or C infections)

10. Recent surgery (involving entry into a body cavity or requiring 3 or more sutures)
within three weeks of initiation of study drug

11. Use of sirolimus, everolimus or investigational treatment for LAM within the 30 days
prior to randomization

12. Previous lung transplantation or active on transplant list

13. Inability to attend scheduled clinic visits, or perform pulmonary function testing

14. Pleural effusion or chylous ascites sufficient to affect pulmonary function based on
the opinion of the Site Investigator

15. Acute pneumothorax within the past month

16. History of malignancy in the past two years, other than squamous or basal cell skin
cancer.

17. Use of estrogen containing medications within the 30 days prior to randomization.

18. Known allergy to sirolimus