Transcript The MILES Trial

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
•
•
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•
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
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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)
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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?
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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
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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
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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
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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
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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