PHASE III TRIAL FO SIROLIMUS IN LYMPHANGIOLEIOMYLMATOSIS

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DESCRIPTION (provided by applicant): LAM is a rare, fatal lung disease that affects only women, caused by mutations in tuberous sclerosis genes. Functional deficiencies of the encoded products, tuberin or hamartin, result in dysregulated signaling through the Akt pathway which controls cell growth, movement and survival. The lung becomes infiltrated with smooth muscle cells, most likely from a remote source, which promote destruction of alveolar walls and cyst formation through an unknown mechanism. Patients with LAM may also develop lymphangitic spread through axial lymph nodes. Sirolimus is a specific inhibitor of Akt signaling that acts at the same point in the pathway as the tuberin/hamartin complex. Preclinical evidence from tuberous sclerosis (TSC) animal models reveals that sirolimus shrinks kidney tumors and hepatic tumors, and a pilot study of 11 patients with LAM in Cincinnati suggested that sirolimus can shrink renal tumors and improve lung function in patients with LAM. The MILES (Multicenter International Lymphangioleiomyomatosis Efficacy and Safety) trial will test the safety and efficacy of sirolimus (Rapamycin) in patients with LAM. Two hundred and forty patients will be randomized to placebo or sirolimus groups in a double-blind fashion, treated for one year and followed off of drug or placebo for one additional year. The primary outcome will be change in forced expiratory volume in one second (FEV1) slope over twelve months. The analysis will be based on an 'intention to treat' design. Interim analyses will occur when 100 patients reach the one year point. The final analysis to assess the durability of response will occur at 24 months. Secondary outcome measures will include forced vital capacity, residual volume, diffusing capacity, six minute walk, cyst volume percent based on volumetric CT, all-cause mortality and questionnaire-based assessments of dyspnea, fatigue and depression. The LAM Foundation will assist with patient recruitment and education. The trial will be conducted using the infrastructure provided by the Rare Lung Disease Consortium, an NIH supported network of 12 institutions which perform cooperative trials and studies in LAM, pulmonary alveolar proteinosis, alpha one antitrypsin deficiency and pediatric interstitial lung disease. Patient safety will be monitored by an NIH Data Safety Monitoring Board (DSMB). The MILES trial is designed as a pivotal study to determine if sirolimus is effective in stabilizing or improving lung function in patients with LAM.