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Study Description

Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (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.

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Study Inclusion/Exclusion Criteria

Inclusion Criteria
a. Female, age 18 or over
b. Signed and dated informed consent
c. Diagnosis of LAM as determined by

  1. biopsy (lung, abdominal mass, lymph node or kidney or cytology from thoracic or abdominal sources revealing HMB45+ staining of spindled/epithelioid cells), and chest CT scan findings compatible with LAM; or
  2. compatible chest CT scan findings in the setting of tuberous sclerosis, angiomyolipomata (diagnosed by CT, MRI by the site radiologist or biopsy ) or chylous pleural effusion (verified by tap); or
  3. chest CT scan findings compatible with LAM (confirmed by the two MILES core radiologists) and a VEGF-D level ≥ 800pg/ml.
d. Post-bronchodilator forced expiratory volume in one second of ≤ 70% of predicted during baseline visit.

Exclusion Criteria
a. History of myocardial infarction, angina or stroke related to atherosclerosis
b. Pregnant, breast feeding, or plan to become pregnant within the next 2 years
c. Inadequate contraception
d. Significant hematologic or hepatic abnormality (i.e. transaminase levels > three times the upper limit of normal range, HCT < 30%, platelets < 80,000/cumm, adjusted absolute neutrophil count < 1,000/cumm, total WBC < 3,000/cumm)
e. Intercurrent infection at initiation of study drug
f. Recent surgery (involving entry into a body cavity or requiring 3 or more sutures) within eight weeks of initiation of study drug
g. Use of an investigational drug within 30 days prior to randomization
h. Uncontrolled hyperlipidemia
i. Previous lung transplantation or active on transplant list
j. Inability to attend scheduled clinic visits
k. Inability to give informed consent
l. Inability to perform pulmonary function testing
m. Creatinine> 2.5 mg/dl
n. Chylous ascites sufficient to affect diaphragmatic function based on the opinion of the site investigator
o. Pleural effusion sufficient to affect pulmonary function based on the opinion of the site investigator (generally > 500cc)
p. Acute pneumothorax within the past 8 weeks
q. History of malignancy in the past two years, other than squamous or basal cell skin cancer
r. Use of estrogen containing medications within the 30 days prior to randomization
s. Known allergy to sirolimus

Study History

Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women (1). LAM is associated with the neurocutaneous disorder, tuberous sclerosis complex (TSC), an autosomal dominant tumor suppressor syndrome which results in hamartomatous growths in multiple organs (2). LAM also occurs in a sporadic, non-heritable form (sporadic LAM or S-LAM) associated with somatic TSC mutations which affect only the lung, the kidney and the axial lymphatics. The most common presentation of LAM is progressive dyspnea on exertion. The disease course is punctuated by pneumothorax in about 70% of patients, and/or chylothorax in about 30% of patients. Lung function is lost at a rate 6-9 cc of FEV1 per month and 5 cc of FVC per month, due to diffuse infiltration of the pulmonary interstitium with atypical smooth muscle cells and cystic destruction of lung parenchyma (3, 4). The origin of the smooth muscle cells is unclear, but recurrence in transplanted lungs indicates that metastasis from remote sites represents at least one pathogenic mechanism (5-9). Renal angiomyolipomas, unusual hamartomas containing fat, smooth muscle and blood vessels, are present in about 70-80% of patients with TSC-associated LAM (TSC-LAM)(10) and 50% of S-LAM (11) and may constitute one source for LAM cells that populate the lung.

LAM is frequently fatal, although estimates based on data from recent studies suggest that median survival from the onset of symptoms is closer to 15 years than to 8 years as previously reported (12). There is no convincing evidence that current therapies for LAM, most targeted at antagonizing the level or action of estrogen, are effective. The need for effective alternatives to empiric therapy with progesterone and Lupron is self-evident to physicians caring for patients with LAM.

The number of patients who could benefit from an effective therapy for LAM and TSC is substantial. TSC-LAM is predicted to affect about 1 woman in 15,000. This estimate is based on the 1.5 million patient global prevalence of TSC, the equal gender distribution of TSC, and the 30-40% prevalence of cystic change in the lungs of women with TSC (13, 14). Sporadic LAM appears to affect approximately 1 to 3 per million women (3000-10000 total women world wide). Surprisingly, sporadic LAM patients are disproportionately represented in pulmonary clinics and in medical studies compared to TSC LAM patients. LAM advocacy organizations have registered patients numbering 550 in the U.S, 70 in the U.K., 150 in France, 22 in Italy, 120 in Japan, 44 in Germany, 44 in Australia and over 100 in Canada.

The primary objective of this trial is to determine if sirolimus has a beneficial effect on lung function in patients with LAM. Another objective of this study is to evaluate the safety of therapy with sirolimus for LAM.

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Study Attribution
  • Principal Investigator
    • Frank McCormack, MD. University of Cincinnati Medical Center, Cincinnati, OH, USA.
  • Funding Source
    • 1 U54 RR019498-01. National Institutes of Health, Bethesda, MD, USA.
    • Grant #FD-R-003362-01. FDA OrphanProduct Development (OOPD).
    • Wyeth Pharmaceuticals.
    • LAM Foundation Award.
    • Translational Research Initiative-Cincinnati Children's Hospital Medical Center.
    • Tuberous Sclerosis Alliance, Rothberg Courage Award.
    • Adler Foundation.