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New Organizational New Organizational Models for Optimal Models for Optimal Cell Processing and Cell Processing and
ApplicationApplicationRobert D. SimariRobert D. Simari
Chair, Cardiovascular ResearchProfessor of Medicine
Madrid 2009
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NHLBI Working Group onTranslation of Cardiovascular Cell
Based Therapies2005
…the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites)…
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What is an NIH Clinical Trial Research Network ?
• Provides opportunities for collaborative Phase 1-2 studies.
• Success in pulmonary medicine.
• Extends single center results (NIH or industry based)
• Builds infrastucture to do so.
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Clinical Center Selection
• Expertise in cell therapy– Preclinical studies– Early clinical trials
• Ability to recruit subjects in studies of acute and chronic LV dysfunction.
• Willingness to prioritize network studies.
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NHLBI Cardiovascular Cell Therapy Research Network Organization
Data Coordinating Data Coordinating CenterCenterTSPHTSPH
NHLBINHLBINHLBINHLBI
Tex HITex HIWillersonWillerson
Tex HITex HIWillersonWillerson
U FlaU FlaPepinePepineU FlaU Fla
PepinePepineCleveland ClinicCleveland Clinic
EllisEllisCleveland ClinicCleveland Clinic
EllisEllisVanderbiltVanderbilt
ZhaoZhaoVanderbiltVanderbilt
ZhaoZhaoU MnU MnHenryHenryU MnU MnHenryHenry
Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing Cell processingCell processingCell processingCell processing
PRCPRCPRCPRC DSMBDSMBDSMBDSMBSteering CommitteeSteering CommitteeSteering CommitteeSteering Committee
Skills Skills Development Development
CoreCore
Skills Skills Development Development
CoreCore
Skills Skills Development Development
CoreCore
Skills Skills Development Development
CoreCore
NetworkChair
NetworkChair
Sonia SkarlatosSonia Skarlatos
Lem Moye’Lem Moye’
Robert SimariRobert Simari
7 Clinical Satellites
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Clinical Centers1 - Cleveland ClinicCleveland, Ohio2 - Texas Heart Institute3 - University of Florida at GainesvilleGainesville, Florida4 - Minneapolis Heart Institute Minneapolis, Minnesota5 - Vanderbilt University Medical CenterNashville, Tennessee
4, 8
1, 10 6
5, 13
3, 9, 11, 122, 7, 14
Administration6 – Study Sponsor, NHLBIBethesda, Maryland7 - Data Coordinating CenterHouston, Texas14 – Cell Processing Quality Control LabHouston, Texas
CCTRN Network
Core Labs8 - Bio-RepositoryMinneapolis, Minnesota9 - Bio-RepositoryGainesville, Florida10 – Echo Core LabCleveland, Ohio11 – MRI Core LabGainesville, Florida12 – MV02 Core Lab Gainesville, Florida13 - SPECT Core LabNashville, Tennessee
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January 2007
• Met to select clinical trials to pursue
• Criteria – ability to obtain an IND for trial– Likely performed/completed early phase 1– Without need for more preclinical studies– Demonstrate need for network
resources/sites
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January 2007
• Acute MI– MHI pilot study (Traverse/Henry)– Broad European experience
• Chronic LV dysfunction– Based on THI experience (Perin/Willerson)
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Cardiovascular Cell Therapy Research Network (CCTRN)
Regulatory hurdles• CCTRN
– Protocol development committee– Steering committee
• NHLBI– Protocol Review Committee (Dzau)– DSMB (March)
• FDA – IND
• Sites– IRB– IBC
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Cardiovascular Cell Therapy Research Network (CCTRN)
• BMCs in Acute anterior MI– TIME
• Timing of delivery (d3 vs d7)• Fixed dose, isolation, delivery
– Late TIME• Timing 2-3 weeks
• BMCs in chronic ischemic LV dysfunction
• Biorepository
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Cardiovascular Cell Therapy Research Network (CCTRN)
Challenges
• Who holds the IND (regulatory responsibility)? New or amended?
• Cell preparation-central vs local? And how?• Very high, high or moderate risk population? • Biorepository and cell evaluation-central vs
local?• ? Placebo and if so blinding?• Global, regional or clinical endpoints?
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Acute MI studies
• 2000+ pt studied worldwide
• Safety parameters well established
• Phase 1 human trial ongoing at MHI (Traverse)-now completed
• Basis for IND
• Many important unanswered questions
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TIME and Late TIME Study Rationale
• Changing myocardial milieu following AMI may impact on cell delivery retention.
• Prior studies had not randomized to different times.
• Cell dose varied greatly within and between studies.
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TIME dependence of delivery
Schachinger Circ 2008
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PILOT TRIAL - Administration of BMCsFollowing Acute Myocardial Infarction at
Minneapolis Heart Institute
• IND: September 2005• 40 patients with acute anterior MI’s who received PTCA / Stenting of LAD ( 30% < EF <50% ).• Randomized ( 3:1 Active Treatment vs Placebo).• 100 million BMMC (intracoronary infusion).• Serial Cardiac MRI at Baseline, 3, 6, 12 months.• Potential for cross-over at 6 months
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PILOT TRIAL - Administration of BMCsFollowing Acute Myocardial Infarction at
Minneapolis Heart Institute
• 40 Patients (31M 9 F), 8 NIDDM, Age= 54yrs• 7 IABP, 2 hypothermia• 37/40 received DES• Transplant Day =5±2 days• Average Ischemic Time = 6:30 hrs• Peak CK = 3308, CKMB = 244• Baseline LVEF (ECHO 1 day p MI) = 37±12% • Baseline LVEF (cMRI, 4 days p MI) = 49±9%• All Patients had severe MVO on cMRI.• CD34+ count was 2%, Viability > 96%Results at AHA ‘09
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TIME Study• Large first Ant MI (EF<45%)
• Randomized – cells (2) vs placebo (1)– 3 days vs 7 days
• 150 million BMMNCs
• Stop flow delivery
• 120 pts
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Late TIME Study
• Large first Ant MI (EF<45%)• Randomized
– cells (2) vs placebo (1)– 14-21 days
• 150 million BMMNCs• Stop flow delivery• 86 pts
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TIME and Late TIME Study Endpoints
• Regional and global LV function (cMR)– Core evaluation
• Clinical endpoints
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Sepax System for BMMNC
Manual
Sepax
G Force
G Force
G Force
Plasma (yellow)
MNC
Ficoll (blue)
RBCs (red)
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Blinding procedure
Autologous blood as blinding agent
100ul50ul 250ul 500ul
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• Nonrandomized, open label 14 tx, 7 control
• BMNNCs (2M cells x 15 injection sites) via NOGA
• Safe• At 4 months
– Increased EF– Decreased ESV
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FOCUS-HF
• Two center US study (THI, MHI)
• Perin, Willerson, Henry
• Randomized delivery of 30M BMMNCs using NOGA
• To be presented at AHA 2009
• Basis for new IND
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FOCUS rationale-endpoints
• Severe ischemic LV dysfunction
• Increased dose (100M cells) in multi-center study.
• Placebo controlled
• Combined Endpoints = SPECT, Echo (LVV), MVO2 (all core assessed)
• 86 pts
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Cardiovascular Cell Therapy Research Network (CCTRN)
• Cells are processed locally using standardized devices.
• Release criteria are local.
• Blood and BM is shipped to central biorepository– Univ Minnesota (Taylor)– Univ Florida (Cogle)
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CCTRN Biorepository
The specific aim of the Biorepository is to examine the relationship between cell therapy clinical outcomes and cell characteristics such as phenotype and function. As a core laboratory, the Biorepository will:
•provide storage of critical biomaterials from patients enrolled in CCTRN trials; (BM, PB cells, serum)•provide long-term integrity (up to 10 years) of these specimens •provide phenotypic and functional analyses of BM and PB cells on freshly available samples.
Central, rigorous, robust and available
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CCTRN Biorepository Investigating the active agent
Defining mechanisms of cell based repair
Bone marrow harvestedBlood drawnfor PC and cytokinemeasurements
Shipments DateEntered into Web Interface
Web InterfaceSends an e-mailto Coordinatorand Technicianto expect shippedsamples
Confidential and Privileged
CCTRN Biorepository
University of Minnesota
“Biorepository”
FACS
Cytokines
Arrival Logged in Web Interface
Samples arePrepared
Functional Measurements
Results Enteredinto Web Interface
Real time status and trackingReport generation
Blinded data analysisEasy data sharing
Regulatory compliance Reduced work load
When a patient enters a clinical trial
Stem cells
Inflammation
Effect
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Functional assays
ViabilityCell Count
PB
BM
CFU-Endo
ECFC
EndoMSC
Migration
SDF-1
Rheology
iNO
Courtesy of Cogle, UFla
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CCTRN Biorepository
DiseaseProduct phenotype
and function
PB phenotype and function
Product delivery
Patient outcome
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Cardiovascular Cell Therapy Research Network (CCTRN)
Ongoing Challenges
• Declining severity of acute MI in the U.S.• Focus on the very sick (yet first MI) has
generated recruitment challenges.• Rapidly changing scientific landscape of stem
cells.
We should complete all 3 studies in late 2010/early 2011
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NHLBI Working Group onTranslation of Cardiovascular Cell
Based Therapies2005
…the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites) with an integrated preclinical investigative component.
…the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites)
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NHLBI Progenitor Cell Biology Consortium
NHLBI funded- preclinical network to be funded in 2009
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CCTRN Key Personnel Clinical CentersCleveland ClinicStephen Ellis – PI, Marc Penn – Co-PILinda Clarke – Study CoordinatorTexas Heart InstituteJames Willerson – PI, Emerson Perin – Co-PILynette Westbrook, Casey Kappenman, Fred Baimbridge, James Chen – Study CoordinatorsUniversity of FloridaCarl Pepine – PI, Barry Byrne – Co-PIEileen Handberg, Tempa Curry – Study CoordinatorsMinneapolis Heart Institute Tim Henry – PI, D Taylor, Jay Traverse – Co-PIRachel Olson, Beth Jorgenson – Study CoordinatorsVanderbilt UniversityDavid Zhao – PI, Antonis Hatzopoulos – Co-PIJudy Francescon, Sherry Bowman – Study Coordinators
AdministrationProject Office, NHLBISonia Skarlatos – Project OfficerDavid Gordon – Deputy Project OfficerWendy Taddei-Peters – Clinical Trials Specialist
Data Coordinating CenterLem Moyé – Coordinating Center PILinda Piller – Safety OfficerShelly Sayre, Rachel Vojvodic, Judy Bettencourt – Project Managers
Cell Processing Quality Control LabAdrian Gee – DirectorSara Richman – Senior QA Analyst
Core LabsBio-RepositoryDoris Taylor – Director
Bio-RepositoryChris Cogle – Director
Echo Core LabJames Thomas – Director
MRI Core LabJohn Forder – Director
MV02 Core Lab Daniel Martin – Director
SPECT Core LabMarvin Kronenberg – Director