Title: The Multicenter International LAM Efficacy of Sirolimus Trial MILES Trial
1- 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
2Treatments for LAM in 2008
3Compared 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
4State of the science for lung fibrosis compared
to LAM
5Finding 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.
6Examples of diseases that can be controlled and
sometimes cured because clinical trials were done
properly
- AIDS
- Leukemias
- Lymphomas
- Breast cancer
7Clinical trials
- Clinical trials often pose risk
8Renal AMLs shrunk by 50 on sirolimus, but tended
to return to baseline off drug
Bissler et. al NEJM 2008 358 140-51
9FEV1 and FVC increased on sirolimus, and then
resumed decline when the drug was stopped
FVC, CAST
FEV1, CAST
FVC, NIH Registry
N 11
FEV1, NIH registry
Bissler et. al NEJM 2008 358 140-51
10Parameters 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
11Adverse 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
12What 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
13Why 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 LAM-like features - Sirolimus has been tested in LAM patients in a
pilot study, called the Cincinnati Angiomyolipoma
Sirolimus Trial (CAST)
14Theory 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
15Major objective of the MILES Trial
- To determine if sirolimus has a beneficial effect
on lung function
16Who 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
17Geographic Distribution of Sites in The MILES
Trial
Toronto
Osaka
Osaka
Osaka
Niigata
18MILES 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
19Am 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
20Am 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
21Am 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
22Am I eligible for MILES
- Other exclusions
- Recent cancer (except skin or cervix)
- Angina or prior heart attack
- Recent surgery
- Ongoing infection, including Hep C
23Who 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.
24The 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
25MILESWhy 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
26How many patients will be enrolled in the MILES
trial
- 120 total
- 60 in the placebo arm
- 60 in the sirolimus arm
27MILESTime 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.
28MILESWhat 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
29MILESWhat 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.
30MILES Schedule of Events
31Sirolimus 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
32MILES
- 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
33The 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
34The 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.
35If 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.
36If 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
37What trials other trials are currently enrolling?
- UK doxycycline trial
- Multicenter Angiomyolipoma RAD Trial
38What other trials are being discussed
- Lipitor (Atorvastatin)
- Lymphangiogenesis inhibitors (anti-VEGF-D)
- Selective estrogen antagonists (SERMS)
39How 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 milestrial_at_cchmc.org
- Call or write to your local MILES team
40Site physician investigators
- Cincinnati Frank McCormack, MD
- Portland Alan Barker, MD
- NIH Joel Moss, MD, PhD
- Cleveland Clinic Jeffrey Chapman, MD
- Gainesville Mark Brantly, MD, PhD
- Charleston Charlie Strange, MD
- Denver Kevin Brown, MD
- Tyler James Stocks, MD
- UCLA Joseph Lynch, MD
- Osaka/Niigata Yoshikazu Inoue/Koh Nakata
- Toronto Lianne Singer MD
- Boston Hilary GoldbergMD
41How 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
42Cincinnati team
- Project manager
- - Leslie Korbee
- Trialwide coordinator
- Susan McMahan
- Trialwide monitors
- Elva Turner
- Rubina Dosani
43Site phone numbers and emails
Frank.McCormack_at_uc.edu 513-558-4831
- Cincinnati MILEStrial_at_cchmc.org 513-636-6272
- Portland barkera_at_ohsu.edu 503-494-7680
- NIH mhaughey_at_nhlbi.nih.gov 301-644-5864
- Cleveland Clin failed_at_ccf.org 216-444-9975
- Gainesville pschreck_at_ufl.edu 352-294-0512
- Charleston gitterac_at_musc.edu 843-792-3161
- Denver morrisonm_at_njc.org 303-398-1912
- Tyler jan.hoeft_at_uthct.edu 903-877-5518
- UCLA sgolleher_at_mednet.ucla.edu 310-794-7093
- Osaka/Niigata giichi_at_kch.hosp.go.jp 81-72-252-302
1 - Toronto lianne.singer_at_toronto.edu 416-340-4591
- Boston hjgoldberg_at_partners.org.
617-732-7420