Update on New INTERMACS/NIH Initiatives

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Sixth Annual Meeting, March 12, 2012

• Update on New INTERMACS/NIH Initiatives
• PumpKIN (15 min) T. Baldwin

INTERMACS Annual Meeting March 2012
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6th Annual INTERMACS Meeting NHLBI Pumps for
Kids, Infants, and Neonates (PumpKIN) Program
Update March 12th, 2012 Crown Plaza Washington
Airport, Arlington, VA
Tim Baldwin, Ph.D. Deputy Chief, Advanced
Technologies and Surgery Branch Basic and Early
Translational Research Program Division of
Cardiovascular Sciences NHLBI
INTERMACS Annual Meeting March 2012
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PumpKIN Pre-Clinical Program

• Four-year contracts. Began in January, 2010
• Objective To obtain IDEs for circulatory assist
  devices for infants and/or small children
• Eligible Devices Circulatory support devices
  appropriate for small children (lt25 kg) with
  heart disease who experience cardiopulmonary
  failure and circulatory collapse.
• Work includes
• Pre-clinical testing and analysis
• Developing manufacturing documentation
• Regulatory, technical, and clinical support
• Submitting pre-IDE, request for HUD, IDE
  application
• Collaborating with DCCC and other contractors on
  Clinical Trial

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PumpKIN Program Timeline
Pre-IDE Submission
HUD Designation Requests
IDE Applications
IDE Approvals (Contingent on FDA Decision)
2010
2012
2011
2013
Pre-Clinical Awards
DCCC RFP
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Program

• PediPL
• Univ. Maryland-
• Baltimore Med. Ctr.
• Thoratec
• PI Barley Griffith, M.D.

• pCAS
• Ension, Inc.
• PI Mark Gartner, Ph.D.

• PediaFlow
• U. Pittsburgh
• Childrens Hosp. of Pittsburgh
• CMU
• WorldHeart, Inc.
• LaunchPoint
• PI Harvey Borovetz, Ph.D.

• Jarvik
• Pediatric 2000 VAD
• Jarvik Heart, Inc.
• PI Robert Jarvik, M.D.

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Pediatric Cardiopulmonary Assist System
(pCAS) Advanced Compact ECMO (ACE) System

• Small
• Low Priming Volume
• Transportable
• Integrated System
• Modular
• Improved Biocompatibility
• No Plasma Breakthrough

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Pediatric Pump-Lung (PediPL) Device
Advanced Compact ECMO (ACE) System

• Integrated System
• Mag-Lev Impeller
• Uniform Flow
• Low Priming Volume
• Simplified Circuit
• Compact Design
• Transportable
• Modular
• No Plasma Breakthrough

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PediPL Initial In-vivo Animal Study
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Explanted Devices
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PPL09 after 32 days
PPL08 after 30 days
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Jarvik 2000 Pediatric VAD

• Implantable
• No Pump Pocket
• Versatile Positioning
• Out-of-Hospital Use
• Long-Term Support
• Human-Engineered Controller

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INTERMACS Annual Meeting March 2012
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PediaFlow PF4 Pump

• Implantable
• No one way flow valves
• Virtually infinite operating life
• Exceptionally Small
• Exceptional biocompatibility
• Out-of-Hospital Use

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PediaFlow
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PumpKIN Data and Clinical Coordinating Center
(DCCC)

• Work includes
• Developing Clinical Protocol(s) Related Forms
• Developing Monitoring Procedures
• Providing Safety Oversight
• Coordinating Clinical Sites
• Implementing and Conducting Clinical Study
• Training Supporting Sites
• Analyzing and Disseminating Data
• Providing FDA Documentation for HDE Applications
• Collaboration with contractors and industry
  sponsors
• 66-month Contract
• Targeted to start April, 2012

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PumpKINProtocol Development Committee(Independen
t Members)

• Pedro del Nido, MD (Chair) Boston Childrens
  Hospital
• Kurt Dasse, PhD Pharos, LLC
• Deirdre Epstein, RN Washington University in St.
  Louis
• Rebecca Ichord, MD Childrens Hospital of
  Philadelphia
• Patricia Massicotte, MD University of Alberta,
  Stollery Childrens Hospital
• David Morales, MD Texas Childrens Hospital
• Robert Morrow, MD University of Arkansas for
  Medical Sciences
• David Naftel, PhD University of
  Alabama-Birmingham
• Richard Ohye, MD University of Michigan
• David Rosenthal, MD Stanford University
• Robert Shaddy, MD Childrens Hospital of
  Philadelphia

INTERMACS Annual Meeting March 2012
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PumpKINProtocol Development Committee(Contract
Team Members)

• Harvey Borovetz, PhD University of Pittsburgh
• Peter Wearden, MD, PhD Childrens Hosp. of
  Pittsburgh, U. of Pitt.
• Steven Webber, MD Childrens Hosp. of Pittsburgh,
  U. of Pitt.
• Robert Jarvik, MD Jarvik Heart, Inc.
• Bartley Griffith, MD University of
  Maryland-Baltimore Medical Center
• Barry Gellman, MS Thoratec, Inc.
• Mark Gartner, PhD Ension, Inc.
• Greg Johnson, PhD Ension, Inc.
• Joseph Tamblyn, CCP Ension, Inc.

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Proposed PumpKIN Trials

• Multi-Center Single-Arm Trials. One for each
  device
• Similar patient sample size used in Berlin Heart
  Trial (N30)
• Follow-up
• VADs 12 months
• ACE Systems 6 months
• Endpoints
• Primary Survival to TX, Recovery, Death
• Safety Frequency of SAEs, device-related AEs,
  infections, and bleeding
• Secondary Endpoints Neuro-development and QOL
• Hypothesis Survival and rates of SAEs equal to
  or better than historical or concurrent controls.

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PumpKIN Program Timeline
?
Pre-IDE Submission
?
HUD Designation Requests
IDE Applications
IDE Approvals (Contingent on FDA Decision)
2010
2012
2011
2013
Pre-Clinical Awards
?
DCCC RFP
INTERMACS Annual Meeting March 2012
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PumpKIN Program Timeline
?
Pre-IDE Submission
?
HUD Designation Requests
IDE Applications
IDE Approvals (Contingent on FDA Decision)
2010
2012
2011
2013
Pre-Clinical Awards
DCCC Award
2012
2013
2017
2016
2015
?
2014
DCCC RFP
Clinical Trial
INTERMACS Annual Meeting March 2012

• Protocol Development
• Clinical Site Prep
• Training
• IRB Approvals
• Site Subcontracts

• Data Analyses
• Publications
• HDE Applications

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NHLBI PumpKIN Team Jonathan Kaltman, MD Victoria
Pemberton, RNC, MS Ellen Rosenberg, MHA,
BSN Mario Stylianou, PhD Roxane Burkett Scott
Bredow
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Sixth Annual Meeting, March 12, 2012

• Update on New INTERMACS/NIH Initiatives
• Revive-IT (15 min) Pagani

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Pilot Trial

• Francis D. Pagani MD PhD
• Department of Cardiac Surgery
• University of Michigan

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Overview of Current Device Use for Destination
Therapy

• VAD therapy has been limited to late-stage heart
  failure (NYHA Class IV symptoms) because of the
  associated device risks.
• 70 of patients are on inotrope support at the
  time of VAD implantation.
• 1020 of patients are supported with IABP.

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Rationale for Studying LVAD Therapy in Less
Advanced Heart Failure

• Were neglecting a much larger group of patients
  who may benefit from DT
• Substantial improvements in patient outcomes
• Improved device technology
• Improved patient selection and management
• For MCS to have a real public health effect, we
  must determine how to preoperatively identify
  potential destination therapy patients who have
• poor prognosis with continued medical therapy
  alone
• good end organ function
• expected good survival with an implanted LVAD

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Hypotheses

• A substantial fraction of the ambulatory heart
  failure patients whom weve been thinking are
  too well for an LVAD for DT would likely
  experience a mortality benefit from an LVAD.
• We can identify these patients using existing
  heart failure and post-LVAD survival risk models.
• Risk modeling can provide the clinical equipoise
  needed to perform a randomized trial in less
  sick heart failure patients for destination
  therapy.
• The hypothesis proposed for the trial is that VAD
  therapy may improve both survival and quality of
  life in moderately advanced heart failure
  patients who are neither inotrope-dependent nor
  exercise-intolerant and have not yet developed
  serious consequences such as malnourishment,
  end-organ damage, and immobility.

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• Objective To explore the potential benefit of
  LVAD therapy in advanced HF patients who have
  significant functional impairment but have not
  yet developed serious consequences such as
  malnourishment, end-organ damage, and immobility.
• Hypothesis VAD therapy will improve functional
  status at 12 months post-randomization and
  all-cause mortality will be no worse than that in
  the optimal medical management (OMM) arm of the
  trial.

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• RFP announced July 2009
• Contract Awarded Jan 15, 2011
• Timeline
• 9 month planning
• 18 month patient recruitment (May 2012)
• 24 month patient follow-up
• 9 months closeout

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REVIVE-IT Study Organization

• PIs Keith Aaronson, Francis Pagani (Univ
  Michigan), Robert Kormos (Univ Pittsburgh)
• NHLBI COTR Timothy Baldwin
• Steering Committee Chair Douglas Mann (WUSL)
• DCCC Michigan Institute for Clinical Health
  Research (MICHR)
• Core Labs
• Exercise Donna Mancini Columbia Univ
• Biomarker Dennis McNamara Univ Pittsburgh
• QoL Kathleen Grady Northwestern Univ
• Neurocognition Ralph Petrucci Drexel Univ
• Echocardiography John Gorcsan Univ Pittsburgh
• Health Economics Henry Glick Univ Pennsylvania

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REVIVE-IT Study Organization

• Steering Committee
• Chair, PIs, DCCC, Clinical Sites, Study Cores,
  INTERMACS
• Gatekeepers (2)
• Donna Mancini Columbia Univ
• Allen Anderson Univ Chicago
• Clinical Sites (14)
• Abbott-Northwestern, U Alabama-Birmingham,
  Cleveland Clinic, Duke, Montifiore (NY), U
  Louisville, U Michigan, Northwestern, U
  Pennsylvania, U Pittsburgh, Columbia Univ,
  Washington Hospital Center, U Chicago, WUStL

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REVIVE-IT Study Design

• Pilot, open-label, RCT testing a strategy of
  earlier LVAD vs. OMM in pts not txp eligible
• 11 randomization, 50 patients per group
• OMM patients may receive LVAD if meet standard
  contemporary DT criteria
• Patients in either group may be transplanted if
  contraindications resolve
• Intention-to-treat analysis

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The HeartWare Ventricular Assist System
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REVIVE-IT Primary Study Endpoint

• The Primary Study Outcome for REVIVE-IT will be
  evaluated at 2 years and include the composite
  outcome of
• Survival
• Freedom from severely disabling stroke (defined
  as Modified Rankin Scale (MRS) 3)
• Improvement of functional capacity from
  prerandomization baseline (metric TBD)
• 6 Minute Walk Test distance by 75 meters
• Non-weight adjusted peak VO2 15

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REVIVE-IT Secondary Endpoints

• Functional capacity
• Health-related Quality of Life and Health Utility
• Neurocognition
• Heart failure-related adverse events
• Cost and cost-effectiveness
• LVAD associated adverse events (as defined by
  INTERMACS)
• Cross-over rates to LVAD in the OMM arm
• Cross-over rates to cardiac transplantation in
  the OMM and LVAD arms

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REVIVE-IT Screening Criteria

• Ambulatory, systolic heart failure 12 months
• NYHA III 3 months
• 1 hospitalization prior 6 months, none within
  prior 30 days
• Maximally tolerated doses of beta blocker, ACE
  inhibitor or ARB, spironolactone for 3 months
  with stable doses for 30 days
• No intravenous inotrope within the prior 3 months
• Left ventricular ejection fraction 35 by any
  imaging modality within the previous year

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REVIVE-IT Study Design (Proposed)

• Key Inclusion Criteria (all must be met)
• Peak VO2 35-55 of predicted (Wasserman)
• Peak VO2 14 (women), 16 (men)
• 6 minute walk test distance 350 m
• SHFM Score 1.5 (est. 1-year mortality 17)
• Estimated 1-year cohort mortality 25
• RHC criteria (w/o any intravenous inotrope)
• CVP lt 16 mmHg CVP/ PCWP ratio lt 0.65 RVSWI gt
  300
• Carotid duplex criteria
• Any carotid stenosis must be lt 80
• Confirmed not a transplant candidate by
  transplant committee at clinical site

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Can We Find The Sweet Spot?
Inotrope dependent?
Hemodynamic criteria?
Too Early
Profiles 1-3
Too Late
NYHA III

Death
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Summary

• Patient selection for VAD therapy has been
  limited to patients with significantly advanced
  heart failure with significant comorbidities.
• Outcomes are dependent on patient selection and
  device technology.
• The minimum level of symptoms and degree of heart
  failure that is necessary to obtain benefit from
  VAD therapy is not well defined.
• Ongoing improvements in VAD technology have
  improved outcomes.
• no trial to date investigating VAD therapy
  utilizing advanced technology against medical
  therapy
• Indication creep less advanced heart failure
  symptoms at implant.

INTERMACS Annual Meeting March 2012