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The Multicenter International LAM Efficacy of Sirolimus Trial (MILES Trial) Frank McCormack, M.D. Scientific Director, The LAM Foundation Professor and Director, Division of Pulmonary, Critical Care and Sleep Medicine The University of Cincinnati Treatments for LAM in 2008 TREATMENT BENEFIT Progesterone unknown GnRh agonists (Lupron) Doxycycline unknown Removal of ovaries unknown unknown Compared to other diseases that scar the lung, LAM has several assets • We understand a lot about the cause of LAM • We have many ideas for drugs to test based on sound science • LAM science is moving as quickly as any in pulmonary medicine • We have a motivated, intelligent, organized patient population State of the science for lung fibrosis compared to LAM Cause known? Effective therapy? Lung Fibrosis no no Molecular Years from start of targets research to for trials? trials no over 30 LAM yes no many less than 10 Finding an effective treatment for LAM Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health. Examples of diseases that can be controlled and sometimes cured because clinical trials were done properly • • • • AIDS Leukemias Lymphomas Breast cancer Clinical trials • Clinical trials often pose risk Renal AMLs shrunk by 50% on sirolimus, but tended to return to baseline off drug Bissler et. al NEJM 2008: 358: 140-51 FEV1 and FVC increased on sirolimus, and then resumed decline when the drug was stopped FVC, CAST FEV1, CAST N = 11 FVC, NIH Registry FEV1, NIH registry Bissler et. al NEJM 2008: 358: 140-51 Parameters that did not change in CAST • Diffusing capacity for carbon monoxide • Total lung capacity • Six minute walk distance Bissler et. al NEJM 2008: 358: 140-51 Adverse events • There were six serious adverse events (I.e.with hospitalization) probably or possibly related to sirolimus – – – – – – Diarrhea Community acquired pneumonia Pyelonephritis Cellulitis Stomatitis Hemorrhage into AML • Aphthous ulcers in 17/23 patients • Hyperlipidemia in 13/23 patients Bissler et. al NEJM 2008: 358: 140-51 What is sirolimus? • Sirolimus (also known as rapamycin) is a drug that is FDA approved for kidney transplant patients. • Sirolimus suppresses the immune system, and helps to prevent rejection. • Sirolimus inhibits cell growth and has activity against some tumors Why was sirolimus chosen for the first LAM clinical trial? • Sirolimus has been tested in the lab against LAM-like cells and in experimental animals that have LAMlike features • Sirolimus has been tested in LAM patients in a pilot study, called the Cincinnati Angiomyolipoma Sirolimus Trial (CAST) Theory for use of sirolimus in LAM • Our theory is that sirolimus will restore orderly growth and movement to LAM cells, so that they stop multiplying, and invading and damaging the lung Major objective of the MILES Trial To determine if sirolimus has a beneficial effect on lung function Who is sponsoring the MILES Trial? • National Institutes of Health – NCRR (National Center for Research Resources) – NHLBI (National Heart Lung and Blood Institute) • • • • The LAM Foundation The Tuberous Sclerosis Alliance Wyeth Pharmaceuticals The Adler Foundation Geographic Distribution of Sites in The MILES Trial Toronto Tokyo, Japan Osaka Melbourne, Australia Niigata Osaka MILES Lead Personnel FDA IND Sponsor/Principal Investigator Frank McCormack, M.D. Co- Investigator Brent Kinder, M.D., Lisa Young, M.D. Project Manager/Regulatory: Leslie Korbee Senior Study Monitor: Elva Turner, CCRC Lead Study Coordinator: Susan McMahan, RN PFT Consultant: Roy McKay, PhD Radiology Consultant: Cris Meyer, M.D. Investigational Pharmacist: Denise LaGory, RPh Central Laboratory: Lori Davis Am I eligible for MILES? • You must be 18 or over and able to consent for yourself • You must have a definite diagnosis of LAM by: – CAT scan • and – either a biopsy or known tuberous sclerosis, angiomyolipoma or chylothorax or Serum VEGF-D greater than 800 pg/ml Am I eligible for MILES? • Lung function must be abnormal – FEV1 must be equal to or less than 70% of predicted (postbronchodilator) – for statistical power, there needs to be the capacity for ‘improvement’ on the drug Am I eligible for MILES? • You should not enroll in MILES if you are, or will soon be, active on a lung transplant list • You cannot enroll in MILES if you have a large collection of chyle in your chest or abdomen that may interfere with pulmonary function tests Am I eligible for MILES • Other exclusions – Recent cancer (except skin or cervix) – Angina or prior heart attack – Recent surgery – Ongoing infection, including Hep C Who is eligible for MILES? • Eligibility is determined from the history and tests performed on the first visit • Patients who are eligible and willing are assigned a treatment by randomization. The MILES Trial is: • Placebo-controlled – Some patients get sirolimus 2 milligrams and some patients get a placebo (sugar pill) • Randomized – The computer ‘flips a coin’ to determine who gets placebo or sirolimus • Double-blind – neither the doctor or the patient knows who is taking the drug or the placebo MILES Why does there have to be a placebo arm? • Without a placebo, it is very easy to be fooled. – pulmonary test results vary with how hard patients try – patients who are hopeful they are on an effective drug may try harder How many patients will be enrolled in the MILES trial • 120 total – 60 in the placebo arm – 60 in the sirolimus arm MILES Time in the trial • Each MILES subject spends two years on the study • The first year is on the drug or placebo and the second year is off treatment. MILES What will be expected of me? • • • • 8 visits over 2 years The first visit is two days long. All other visits are one day long. Pulmonary function tests, questionnaires and blood tests are done on all visits • Chest xrays are done at the beginning and the end • CAT scans of the chest are done at the beginning, middle and the end MILES What will be expected of me? • Sirolimus levels will be performed on all visits after the first one. Levels are not revealed to your study team. • Urine pregnancy tests are done at every visit and 3 months after the drug or placebo is stopped. MILES Schedule of Events Sirolimus Side Effects • • • • • • • Mouth ulcers High cholesterol Lung inflammation Low platelets Acne-like lesions Diarrhea High blood pressure • Protein in the urine • Suppression of the immune system • Swelling • Hypertension • Skin cancer • Latent malignancy • Death MILES • How is patient safety ensured? – Adverse events are reviewed by • • • • the principal investigator a study monitor a Data and Safety Monitoring Board the FDA • The patient can withdraw consent at any time • The investigator can remove the patient from the study at any time The interim analysis • When40- 50 patients (25 in each arm) reach the 1 year point, an analysis will be done. • If sirolimus is proven to be of benefit, all patients will cross into the sirolimus arm. • If sirolimus appears to impair lung function, or to cause harm, the study will be interrupted and the Data and Safety Monitoring Board will conduct a review The final analysis • The final analysis will occur when all patients complete their two years on study. • Since it may take a year or more to recruit all subjects, MILES will take at least 3 years to complete. If MILES shows that sirolimus has a positive effect on lung function, what is next? • Determine if sirolimus has a beneficial effect on exercise tolerance, survival and quality of life. • Determine the minimum effect dose • Determine if therapy should be one time, intermittent or continuous • Determine if combination therapies with other drugs may be even more effective. If MILES shows that sirolimus is not effective, what is next? • Sirolimus or another drug like it may be tested using other trial designs • Other drugs and targets may be explored – – – – – – – metalloproteinase inhibitors angiogenesis/lymphangiogenesis inhibitors statins selective estrogen antagonists aromatase inhibitors farnesyl transferase inhibitors tyrosine kinase inhibitors What trials other trials are currently enrolling? • UK doxycycline trial • Multicenter Angiomyolipoma RAD Trial What other trials are being discussed • Lipitor (Atorvastatin) • Lymphangiogenesis inhibitors (anti-VEGF-D) • Selective estrogen antagonists (SERMS) How can I learn more about MILES? • Review materials and register at www.rarediseasesnetwork.org • Go to the LAM Foundation Website www.thelamfoundation.org • Write an email to [email protected] • Call or write to your local MILES team Site physician investigators • • • • • • • • • • • • Cincinnati Portland NIH Cleveland Clinic Gainesville Charleston Denver Tyler UCLA Osaka/Niigata Toronto Boston Frank McCormack, MD Alan Barker, MD Joel Moss, MD, PhD Jeffrey Chapman, MD Mark Brantly, MD, PhD Charlie Strange, MD Kevin Brown, MD James Stocks, MD Joseph Lynch, MD Yoshikazu Inoue/Koh Nakata Lianne Singer MD Hilary GoldbergMD How to explore participation in MILES • Contact the research coordinator at your local site. • A consent form will be mailed to you to read before you visit the site. • The site investigator will explain the risks and benefits of the study to you. • To enroll, you must sign the consent in the presence of the site personnel Cincinnati team • Project manager - Leslie Korbee • Trialwide coordinator – Susan McMahan • Trialwide monitors – Elva Turner – Rubina Dosani Site phone numbers and emails [email protected] 513-558-4831 Cincinnati Portland NIH Cleveland Clin Gainesville Charleston Denver Tyler UCLA [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Osaka/Niigata [email protected] Toronto [email protected] Boston [email protected]. 513-636-6272 503-494-7680 301-644-5864 216-444-9975 352-294-0512 843-792-3161 303-398-1912 903-877-5518 310-794-7093 81-72-252-3021 416-340-4591 617-732-7420