Update on New INTERMACS/NIH Initiatives

•PumpKIN (15 min) T. Baldwin

Sixth Annual Meeting, March 12, 2012

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Tim Baldwin, Ph.D.

Deputy Chief, Advanced Technologies and Surgery BranchBasic and Early Translational Research Program

Division of Cardiovascular SciencesNHLBI

6th Annual INTERMACS Meeting

NHLBI Pumps for Kids, Infants, and Neonates (PumpKIN) Program

Update

March 12th, 2012Crown Plaza Washington Airport, Arlington, VA

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PumpKIN Pre-Clinical ProgramFour-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 (<25 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 TimelinePumpKIN Program Timeline

2010 20122011 2013

Pre-IDE Submission

HUD Designation Requests

IDE Applications

IDE Approvals (Contingent on FDA Decision)

DCCC RFP

Pre-Clinical Awards

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pCAS Ension, Inc.

PI: Mark Gartner, Ph.D.

PediPL Univ. Maryland-Baltimore Med. Ctr.Thoratec

PI: Barley Griffith, M.D.

ProgramProgram

PediaFlow U. PittsburghChildren’s Hosp. of PittsburghCMUWorldHeart, Inc.LaunchPoint

PI: Harvey Borovetz, Ph.D.

Jarvik Pediatric 2000 VADJarvik Heart, Inc.

PI: Robert Jarvik, M.D.

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

Pediatric Cardiopulmonary Assist System (pCAS)

Advanced Compact ECMO (ACE) System

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Pediatric Pump-Lung (PediPL) DeviceAdvanced 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

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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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

(Independent Members)• Pedro del Nido, MD (Chair) Boston Children’s Hospital

• Kurt Dasse, PhD Pharos, LLC

• Deirdre Epstein, RN Washington University in St. Louis

• Rebecca Ichord, MD Children’s Hospital of Philadelphia

• Patricia Massicotte, MD University of Alberta, Stollery Children’s Hospital

• David Morales, MD Texas Children’s 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 Children’s Hospital of Philadelphia

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PumpKINProtocol Development Committee

(Contract Team Members)• Harvey Borovetz, PhD University of Pittsburgh

• Peter Wearden, MD, PhD Children’s Hosp. of Pittsburgh, U. of Pitt.

• Steven Webber, MD Children’s 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 (N=30)• Follow-up

– VADs: 12 months

– ACE Systems: 6 months

• Endpoints– Primary: Survival to TX, Recovery, Death– Safety: Frequency of SAE’s, device-related AE’s, infections, and bleeding– Secondary Endpoints: Neuro-development and QOL

• Hypothesis: Survival and rates of SAE’s equal to or better than historical or concurrent controls.

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PumpKIN Program TimelinePumpKIN Program Timeline

2010 20122011 2013

Pre-IDE Submission

HUD Designation Requests

IDE Applications

IDE Approvals (Contingent on FDA Decision)

DCCC RFP

Pre-Clinical Awards

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PumpKIN Program TimelinePumpKIN Program Timeline

Protocol DevelopmentClinical Site PrepTrainingIRB ApprovalsSite Subcontracts

Data AnalysesPublicationsHDE Applications

20162014 2015

2010 20122011 2013

Pre-IDE Submission

HUD Designation Requests

IDE Applications

IDE Approvals (Contingent on FDA Decision)

DCCC RFP 2017

DCCC Award

Clinical Trial

20132012

Pre-Clinical Awards

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NHLBI PumpKIN Team

Jonathan Kaltman, MDVictoria Pemberton, RNC, MSEllen Rosenberg, MHA, BSN

Mario Stylianou, PhD

Roxane BurkettScott Bredow

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Update on New INTERMACS/NIH Initiatives

•Revive-IT (15 min) Pagani

Sixth Annual Meeting, March 12, 2012

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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.

• ≈ 10–20% of patients are supported with IABP.

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Rationale for Studying LVAD Therapy in Less Advanced Heart Failure

• We’re 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 we’ve 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– 1:1 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 < 16 mmHg; CVP/ PCWP ratio < 0.65; RVSWI > 300 – Carotid duplex criteria

• Any carotid stenosis must be < 80%– Confirmed not a transplant candidate by transplant

committee at clinical siteIN

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Can We Find The Sweet Spot?

NYHA III

“Too Early” Profiles 1-3 “Too Late”

Death

Inotrope dependent? Hemodynamic criteria?

Non-inotrope dependent?

High mortality in control armHigh crossover to conventional DT“Not so early VAD vs. Conventional DT” or“Not so early VAD vs. Not so early VAD”Unlikely to show benefit!

Low crossover to conventional DTLow mortality in control arm“Too early VAD vs. Conventional DT”Unlikely to show benefit!

THE SWEET SPOT???

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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.

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