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Multicenter International LAM Efficacy of Sirolimus (MILES) Trial
Francis X. McCormack, M.D., Yoshikazu Inoue, M.D., Ph.D., Joel Moss, M.D., Ph. D., Lianne G. Singer, M.D., Charlie Strange, M.D., Koh Nakata, M.D., Ph.D., Alan F. Barker, M.D., Jeffrey T. Chapman, M.D., Mark L. Brantly, M.D., James M. Stocks, M.D., Kevin K. Brown, M.D., Joseph P. Lynch, 3rd, M.D., Hilary J. Goldberg, M.D., Lisa R. Young, M.D., Brent W. Kinder, M.D., Gregory P. Downey, M.D., Eugene J. Sullivan, M.D., Thomas V. Colby, M.D., Roy T. McKay, Ph.D, Marsha M. Cohen, M.D., Leslie Korbee, B.S., Angelo M. Taveira-DaSilva, M.D., Ph.D., Hye-Seung Lee, Ph.D., Jeffrey P. Krischer, Ph. D, and Bruce C. Trapnell, M.D., for the NIH Rare Lung Diseases Consortium and the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) Trial
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• Patent– “Use of VEGF-D as a diagnostic test in LAM”
• royalties directed to The LAM Foundation
• Pharmaceutical contributions to trials– CAST
• Wyeth = drug – MILES
• Wyeth (Pfizer) = drug + $200,000 for cost of trial conduct– TRAIL
• Novartis = drug + placebo– RAD001x2201
• Novartis = cost of trial conduct
Disclosure statement
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Rationale
• TSC1 and TSC2 gene mutations cause LAM (Carsillo & Henske; PNAS, 2000)
• TSC proteins regulate signaling through the mTOR pathway (Ito & Rubin; Cell, 1999)
• The lung lesions in LAM exhibit mTOR activation (Goncharova & Krymskaya; JBC, 2002)
• Constitutive mTOR activation that occurs in LAM cells is inhibited by sirolimus (rapamycin) (Goncharova & Krymskaya; JBC, 2002)
• Sirolimus results in regression and apoptosis of renal tumors in TSC rodent models (Kennerson & Yeung; Cancer Re,s 2002).
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In CAST patients with TSC or LAM, angiomyolipomas shrunk by 50% and lung function improved by 7-13%
NEJM 2008:358, 140-51 Lung Function by spirometry
Kidney tumor size by MRI
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The MILES TrialMulticenter International LAM Efficacy of Sirolimus Trial
• Hypothesis– Treatment of LAM patients with sirolimus for one year
will lead to an improvement in FEV1.
NCT00414648
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The MILES TrialMulticenter International LAM Efficacy of Sirolimus Trial
• Supported by the Office of Rare Disease Research Rare Lung Disease Consortium
• Regulatory oversight-National Center for Research Resources
• LAM Foundation assisted with recruitment and study logistics
• PI-Frank McCormack, M.D.• Primary site-Univ. of Cincinnati/Cincinnati Children’s• 12 other sites-9 domestic, 2 Japan, 1 Canada• Enrollment-Opened 12/06, Closed 8/09• Target-60 patients per armNCT00414648
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7
The MILES TrialDesign:
A Phase III Treatment, Randomized (1:1), Double-Blind, Placebo Control, Intention to Treat, Safety/Efficacy Study
Subjects:Adult subjects (18+ years old) with LAM
Primary Aim:To determine the safety and efficacy of sirolimus in subjects with LAM
DurationTwo years-1 year treatment period, 1 year observation off
treatment
Primary Endpoint:Difference between the placebo and sirolimus groups in the rate of change (slope) in forced expiratory volume in 1 second
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Statistics
• Conducted according to the “Intention to Treat” Principle
• Linear mixed effects model– Primary outcome method– Used to evaluate between group and within group
differences in FEV1 slope – Slope calculated from baseline, 3,6,9 and 12 month
data– Data from every patient that took drug included,
missing data not imputed
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MILES Timeline
2005 2006 2007 2008 2009 2010 2011
FDAIND
Cincinnati open
MUSCopen
Other sitesOpen
DSMBRevisions
EnrollmentCloses
Last Visit
InterimAnalysis
2004
Protocol drafting
MILESFinal
AnalysisNCT00414648
MILESPublished
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MILES eligibility
• Inclusion– Compatible CT +
• Biopsy or• Angiomyolipoma, tuberous sclerosis or chylothorax or• VEGFD ≥ 800 pg/ml (added in 2009)*
– Post bronchodilator FEV1 ≤ 70% predicted• Exclusion– Active on transplant list– Large pleural effusion– On other investigational agents
NCT00414648 *Young & McCormack Chest 2010
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111 Patients consented
89 Patients randomized
43 Assigned to Placebo 46 Assigned to Sirolimus
22 ineligible• 18 FEV1 >70%
• 3 LAM diagnosis unclear• 1 Pleural effusion
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MILES Trial SitesRare Lung Disease Consortium
OsakaNiigata
Toronto
Niigata
Data center
Osaka
2
7
1019
5
2
4
1
5
19
5
7
3
NCT00414648
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MILES subjectsQualifying Inclusion Criteria
Inclusion CriteriaAll patients
(n = 89)Placebo Group
(n = 43)Sirolimus Group
(n = 46) P Value Biopsy, n (%) 54 (61%) 25 (58%) 29 (63%) 0.887¶
Clinical context, n (%) 23 (26%) 12 (28%) 11 (24%)
VEGF-D, n (%) 12 (13%) 6 (14%) 6 (13%)
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MILES subjectsDemographics
CharacteristicAll patients
(n = 89)Placebo Group
(n = 43)Sirolimus Group
(n = 46) P ValueAge (years)
Mean ± S.D. 45.4 ± 10.6 45.9 ± 10.3 45.0 ± 10.9 0.736
Race
Caucasian, n (%) 59 (66) 30 (71) 29 (63) 0.581
Asian, n (%) 27 (30) 12 (28) 15 (33)
Other, n (%) 3 (3) 1 (2) 2 (4)
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MILES subjectsClinical Features
CharacteristicAll patients
(n = 89)Placebo Group
(n = 43)Sirolimus Group
(n = 46) P ValueHistorical Features Tuberous sclerosis complex, n (%) 8 (9) 4 (9) 4 (9) 1.000 Post-menopause, n (%) 30 (34) 16 (37) 14 (30) 0.499 History of angiomyolipoma, n (%) 44 (49) 22 (51) 22 (48) 0.753 History of pneumothorax, n (%) 53 (60) 29 (67) 24 (52) 0.143Oxygen therapy requirement Continuous use, n (%) 28 (32) 14 (33) 14 (30) 0.829
Intermittent use, n (%) 52 (58) 23 (54) 29 (63) 0.361
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MILESBaseline Pulmonary Function
(% predicted)
CharacteristicAll patients
(n = 89)Placebo Group
(n = 43)Sirolimus Group
(n = 46) P ValueFEV1 48.54 ± 13.77 47.73 ± 14.37 49.29 ± 13.31 0.771
FVC 79.71 ± 16.60 80.77 ± 17.62 78.73 ± 15.70 0.546
TLC 105.21 ± 25.63 106.70 ± 29.45 103.83 ± 21.71 0.607
FRC 112.49 ± 31.32 116.61 ± 38.29 108.67 ± 22.97 0.429
RV 141.42 ± 59.22 147.48 ± 69.25 135.78 ± 48.15 0.802
DLC0 43.43 ±18.97 43.77 ±20.56 43.12 ±17.66 0.699
MILES subjects had moderately severe obstructive lung disease with air trapping and a reduced diffusing capacity for carbon monoxide
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3 mo 6 mo 9 mo 12 mo 18 mo 24 moBaseline
TREATMENT PERIOD-sirolimus vs. placebo OBSERVATION PERIOD-no treatment
3 wk
PFTs
ResearchSample
QOL
6MWD
visits
Visit calendar
Sirolimuslevel
HRCT
Randomize
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Study article
• Patients were randomized to sirolimus 2 mg or an identical appearing placebo in a 1:1 ratio
• Sirolimus levels obtained at every visit after baseline and the dose was adjusted by medical monitor at the Data Center to maintain the serum level between 5-15 mg/ml
• Concomitant sham dose adjustments were made in the placebo group to maintain the blind
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111 Patients consented
89 Patients randomized
43 Assigned to Placebo 46 Assigned to Sirolimus1 Withdrew2 PFT unable
3 Withdrew
3 Withdrew2 PFT unable
2 Withdrew1 PFT unable
3 Withdrew
3 PFT unable
40 with 3 mo data available
42 with 6 mo data available
39 with 9 mo data available
34 with 12 mo data available
43 with 3 mo data available
41 with 6 mo data available
38 with 9 mo data available
41 with 12 mo data available
22 ineligible• 18 FEV1 >70%
• 3 LAM diagnosis unclear• 1 Pleural effusion
TREATMENT
OBSERVATION
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Interim analysisFebruary 2010
• Stopping rule for efficacy was met (investigators later learned)
• DSMB recommended continuing trial until all treatment period data was collected
• DSMB endorsed an investigator-initiated plan to truncate the observation period, owing to termination of the funding period
• All MILES investigators and patients remained blinded to the treatment assignment until the final analysis was complete
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2 Withdrew12 Early
termination
3 Withdrew6 Early
termination
6 Withdrew13 Early
termination1 PFT unable
1 Withdrew6 Early
termination1 PFT unable
OBSERVATION
22 with 18 mo data available
13 with 24 mo data available
21 with 18 mo data available
14 with 24 mo data available
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MILES enrollment and attrition• Target 120• Total consented 111• Total enrolled 89
– Attrition• Treatment period
– Withdrawal 13– Death (house fire) 1
• Observation period– Withdrawal 12– Early termination 37– Death (stroke) 1
• Completed 12 months 75• Completed 24 months 27
NCT00414648
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Individual FEV1 curves from 89 patients
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The primary endpoint was met.FEV1 fell over the course of 1 yr on placebo and stabilized on sirolimus
*p<0.0001
FEV1 slope was -12±2 ml/mo. (placebo) vs. 1±2 ml/mo. (sirolimus)
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FEV1 stabilized on sirolimus while treatment continued and declined in parallel with the placebo
group when drug was stopped
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At the end of the treatment period, FEV1 stabilized or improved for 46% of patients on sirolimus vs.
12% on placebo
*p<0.001
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Over the treatment period, the mean change in FEV1 was -134 ml in the placebo group and +19 ml on sirolimus; the between group difference
was 153 ml
153 ml
*p<0.001
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Clinical relevance of an FEV1 difference of 153 ml?
• More than 10% of baseline FEV1 (1370 ml)• It compares favorably with the minimal clinically
important difference (MCID) in FEV1 of 100-140 ml estimate for COPD1 which:– can be perceived by patients– is typical for bronchodilator response– correlates with relapse after exacerbation
• Stabilization may delay transplantation and associated risks
1Donohoue JF COPD 2005
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Secondary endpoints which were significantly different between the groups
• Forced vital capacity (FVC)• Functional residual capacity (FRC)• Quality of life visual analog scale (EuroQOL VAS)• Functional performance inventory (FPI)
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MILESIndividual FVC curves for 89 subjects
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MILESFVC slope increased on sirolimus
*P<0.0001FVC slope was -11±2 ml/mo. (placebo) vs. 8±3 ml/mo. (sirolimus)
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MILESFVC fell in patients on placebo and improved on sirolimus
p<0.001
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At the end of the treatment period, FVC was at or above baseline for 54% of patients on sirolimus, compared to 23 %
on placebo
<-15%
-15% to -10%
-10% to -5%
-5% to 0
0 to 5%
5% to 10%
10% to 15%
≥15%
25% 20% 15% 10% 5% 0% 5% 10% 15% 20% 25%
Placebo Sirolimus
Frequency (%)
FVC
%ch
ange
from
bas
elin
e to
1ye
ar
p<0.001
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Over the treatment period, the mean change in FVC was -129 ml in the placebo group and +97 ml on
sirolimus; the between-group difference was 226 ml
226 ml
*
*p=0.001
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How clinically important is a 226 ml change in FVC?
• 8% of the baseline FVC• Close to the estimated Minimum Clinically
Important Difference for Scleroderma of 250 ml
Khanna D. Clin Exper Rheumatol 2010
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The increase in FVC on sirolimus was accompanied by an increase in the slope for FRC (and similar, though
not significant, trends in RV and TLC) suggesting relief from restriction as a mechanism of increased airflow
*p=0.049
RV FRC TLC*
placebosirolimus
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Sirolimus resulted in an increase in the slope of the Functional Performance Inventory and Quality of Life visual analogue scale score
*p=0.03
*
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Sirolimus resulted in an increase in the slope of the Functional Performance Inventory score
*
*p=0.03
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Serum VEGF-D was stable in the placebo group and declined on sirolimus
*P<0.001 at 12 months
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In fact, VEGF-D levels tended to increase when the drug was withdrawn
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Secondary endpoints which were not different between the groups
• 6 minute walk test distance (6MWD)• Diffusing capacity for carbon monoxide (DLCO)• Total lung capacity (TLC)• Residual volume (RV)• St. George Respiratory Questionnaire (SGRQ)• SF-36 (SF-36)• General Well Being Questionnaire (GWB)
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Associated with increased rate of lung function decline in the placebo group?
• Yes– Higher baseline FVC (above the median (2.79L))– Premenopausal status
• No– History of AML– Need for supplemental oxygen– History of pneumothorax– Baseline FEV1
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Associated with treatment response?
• Yes– Higher baseline FVC (above the median (2.79L))– Premenopausal status– Higher baseline VEGF-D
• No– History of an AML– Need for supplemental oxygen– History of a pneumothorax– Baseline FEV1
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Serum VEGF-D appears promising as a biomarker of disease severity, and perhaps
disease progression and treatment response, but MILES analysis confounded by:
• the use of VEGF-D as both an eligibility criterion and an outcome
• The high termination and withdrawal rate in the observation year
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Adverse events
• Most common– Mouth ulcers– Diarrhea– Nausea– Elevated cholesterol– Acne-like rash– Lower extremity swelling
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Adverse event categories
Adverse Events Serious Adverse EventsTreatment† Observation† Treatment† Observation†
Placebo Sirolimus Placebo Sirolimus Placebo Sirolimus Placebo Sirolimus
Blood/Bone Marrow 4 12 1 0 0 1 0 0
Cardiac Arrhythmia 0 2 0 2
Cardiac General 12 15 3 2 0 5 0 0
Constitutional Symptoms 35 46 7 7
Death not related to event 0 0 1 0 0 0 1 0
Dermatology/Skin 41 106 8 11
Gastrointestinal 181 275 12 20 1 3 0 0
Hemorrhage/Bleeding 14 17 3 1 0 0 1‡ 0
Infection 74 78 20 24 3 2 1 0
Lymphatic 8 15 6 0
Metabolic 26 56 1 6 0 1 0 0
Musculoskeletal 21 35 2 4 0 1 0 1
Ocular/Visual 3 8 1 2
Pain 115 130 9 13 1 7 0 0
Pulmonary/Upper Resp 121 97 17 32 13 2 0 0
Renal/Genitourinary 8 11 0 2
Total # adverse events 718 959 99 135 18 23 5 1
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Treatment period Observation period
placebo sirolimus placebo sirolimus
Serious 8 0 0 0
Not serious 2 2 0 3
Total # ptx 10 2 0 3
MILESPneumothorax
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Treatment period Observation period
placebo sirolimus placebo sirolimus
Definitely not related 1 11 2 1
Probably not related 8 7 0 0
Possibly related 5 3 3 0
Probably related 4 2 0 0
Total # serious adverse events
18 23 5 1
MILESRelatedness of serious adverse events
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Conclusions
• Sirolimus stabilized FEV1 and improved FVC• Sirolimus improved quality of life and measures of
functional performance• Sirolimus did not improve measures of exercise
tolerance (6MWD) or gas exchange (DLCO)• Side effects were more common in the sirolimus
group but serious events were balanced between groups and the safety profile was acceptable
• Benefit persisted only while drug continued
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Compared to subjects in the LAM Registry, lung function impairment was more severe in MILES
subjects
MILESn = 89
LAM Registryn = 230
FEV1 48.5 70.3
FVC 79.7 87.5
TLC 105.2 95.8
FRC 112.5 109.9
RV 141.4 125.4
DLC0 43.4 67.6
Ryu et al. AJRCCM 173:105, 2006
% predicted
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Next questions to be answered with sirolimus/everolimus
• How much?– Could a lower dose produce similar benefit?
• How early?– Does sirolimus prevent progression if given early?
• How long?– Is benefit sustained beyond one year if drug continues?
• Who to treat?– Are there markers that predict who will progress and respond?
• How risky?– Short term and long term risk/benefit needs to be defined, especially
with longer courses of drug.
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National Institutes of Health Rare Lung Diseases ConsortiumSponsor: Office of Rare Disease Research, Director: Steve Groft, PharmD
Administered by: National Center for Research Resources, Director: Barbara Alving MD, Elaine Collier MD, Carl Hunt MDData Management and Monitoring Center: University of South Florida, Director: Jeffrey Krischer, Ph.D.
Rare Lung Diseases Consortium LeadershipDirector: Bruce Trapnell, M.D.
Co-director: Frank McCormack, M.D.DSMB Chair: Robert Senior, M.D., Jay Ryu MD, Kevin Flaherty MD, JP Clancy MD
Translational Research Trials Office, Cincinnati Children's Hospital Medical CenterMedical Director: Timothy P. Cripe, M.D., Ph.D.
Clinical Research Manager: Sheri Uber
MILES LeadershipMILES Principal Investigator: Frank McCormack, M.D.
MILES Core Pathologist: Thomas Colby, M.D.MILES Core Radiologists: Cristopher Meyer, M.D. and Alan Brody, M.D.
MILES Pulmonary Function Core Director: Roy McKay, Ph.D.MILES Biomarker Core Director: Lisa Young, M.D.
MILES QOL Core Director: Marsha M. Cohen, M.D.MILES Statistician: Hye-Seung Lee, Ph.D.
MILES Project Manager: Leslie Korbee, B.S.MILES Lead Research Nurse: Susan McMahan, R.N.
Thanks
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SITESBrigham and Women's Hospital-H. Goldberg (PI), F. Jacobson, E. Peters, I. RosasCleveland Clinic Foundation-J. Chapman (PI), D. Culver, D. Faile, M. MezianeMedical University of South Carolina-C. Strange (PI), A Gitter, J. Ravenel, S. SahnNational Heart, Lung, and Blood Institute- J. Moss (PI), A. Taveira-DaSilva, M. Vaughan, P. Barnes, S.
El-Chemaly, O. Hathaway, M. Haughey, C. Love, J. StarlingNational Jewish Medical and Research Center-K. Brown (PI), G. Cosgrove, G. Downey, S. Frankel, J.
Swigris, D. Kervitsky, M. Morrison, E. Perez, J. SchroederNational Hospital Organization Kinki-Chou Chest Medical Center-Y. Inoue (PI), M. Akira, M.
Kitaichi, T. Arai, C. Sugimoto, K. Hirohata, Y. Okumizu, Y. Inoue, K. Kumagai, A. Kikuyama, A. Ohya, K. Tachibana, K. Komatsu, Y. Sato, H. Moriguchi, S. Hayashi, M. Sakatani
Niigata University Medical & Dental Hospital-K. Nakata (PI), H. Nakayama, M. Sasagawa, A. Sato, T. Takada, R. Tazawa, M. Terada, C. Kaneko
Oregon Health and Science University-A. Barker (PI), J. Gold, K. Kennie, S. Nonas, S. Primack University of California Los Angeles- J. Lynch (PI), E. Callahan, M. Fishbein, S. Golleher, P.
Lopez, R. SaggarUniversity of Cincinnati/Cincinnati Children's Hospital Medical Center-F. McCormack (PI) & B.
Trapnell (PI), J. Bailey, W. Blower, A. Brody, J. Dahlquist, R. Dosani, M. Hodgson, P. Kaiser, B. Kinder, L. Korbee, M. Kuhlmann, D. Lagory, R. McKay, S. McMahan, C. Meyer, T. Roads, M. Stamper, E. Turner, S. Uber, L. Young, W. Zhang
University of Florida-M. Brantly (PI), L. Gilbert, P. Schreck, A. LeongUniversity of Texas Health Science Ctr- Tyler-J. Stocks(PI), T. Allen, L. Couch, J. Hoeft, J.
Padinjarayweetil, V. Taskar.University Health Network/University of Toronto-L. Singer (PI) & G. Downey (PI), M. Sichitu, J.
Thenganatt
Thanks
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MILES Funding (~$7.25 million)
• NCRR/NIH RLDC $3,000,000• FDA $1,200,000• Wyeth/Pfizer (inc. drug) $1,200,000• The LAM Foundation $500,000• CIHR (Canada) $200,000• Japanese Ministry Health $200,000• Tuberous Sclerosis Assoc. $200,000• Cincinnati Children’s $100,000• Adler Foundation $50,000
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∆FEV1 vs. ∆VEGF-D
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Mean change