Multicenter Randomized Controlled Trial of Cardiac Contractility Modulation in Patients with Advanced Heart Failure

William T. Abraham MD, Koonlawee Nademanee MD,Kent Volosin MD, Steve Krueger MD, Suresh Neelagaru MD,

Nirav Raval MD, Owen Obel MD, Stanley Weiner MD, Mark Wish MD,Peter Carson MD, Kenneth Ellenbogen MD, Robert Bourge MD,

Mike Parides MD, Richard P Chiacchierini PhD, Rochelle Goldsmith PhD,Sidney Goldstein MD and Alan Kadish MD on Behalf of the FIX-HF-5

Investigators and Coordinators*

*Dr. Abraham and other members of this group have received consulting fees and/or research grants from Impulse Dynamics

Cardiac Contractility Modulation (CCM)Background

• Preclinical and prior clinical studies have demonstrated that CCM:• Increases cardiac contractility• Reduces myocardial work• Produces LV reverse remodeling• Induces molecular changes (in genes,

proteins and phosphorylation) indicative of improved calcium handling and contractile function

The Concept Behind Cardiac Contractility Modulation (CCM)

Detect localactivation

Apply electric signal during absolute refractory period

Delay

Durat

ion

Amplitude

CCM

MuscleForce

Optimizer III™ System

FIX-HF-5 Trial

• Multi-center, unblinded, randomized, parallel- controlled clinical trial• 50 participating centers (all US)• 6-month efficacy endpoint• 1-year safety endpoint

• First US randomization occurred on April 8, 2005 and the last on June 12, 2007

• Last follow-up completed June 2008

FIX-HF-5: Study Schematic

Informed Consent

Baseline Testing

Eligibility Determination

Group 1 Group 2

12 MonthsCCM 5 hr/day

12 MonthsMedical Control

Device Implantation

2 week Run-In

Study visits at: Baseline, 12Wk, 24Wk and 50Wk

FIX-HF-5: Study Endpoints• Primary Safety Endpoint: Composite of all-cause mortality

and all-cause hospitalization assessed by non-inferiority analysis (active versus control group with 12.5% allowable delta)

• Primary Efficacy Endpoint: Anaerobic Threshold (AT) assessed by responders analysis (≥20% increase in AT = responder)

• Secondary Efficacy Endpoints:• Peak VO2

• Minnesota Living with Heart Failure Questionnaire

• Other Efficacy Endpoints• NYHA Functional Class Ranking• 6-Minute Hall Walk Distance

• Subgroup Analyses• Ischemic vs nonischemic• EF above or below the median• NYHA Class III vs IV

Metabolic Exercise Testing and Core Lab• Single core laboratory where a detailed procedure was

followed for objective determination of AT (using the V-slope method) by two independent readers blinded to treatment group

• On-site training on standardized procedures for conducting metabolic exercise tests and electronic data transfer to the core laboratory

• Site revalidation every 6 months• Rapid feedback on test quality from the core laboratory

(on the day the tests were performed)• Despite these efforts, it was anticipated that substantial

number of tests would be classified as indeterminate, either because of poor test quality, inability of subjects to reach AT, or because of poor subject compliance

12Wkn=204

Informed Consentn=774

345 Withdrew orIneligible

Randomizedn=428

1 Death

Treatmentn=215

Controln=213

24Wkn=201

50Wkn=189

8 W/D1 Death

3 W/D

6 W/D6 Deaths

NotImplanted

n=7Successful

Implantn=203

FailedImplant

n=2

12Wkn=2

24Wkn=2

50Wkn=2

5 W/D

12Wkn=199

24Wkn=195

50Wkn=189

2 W/D4 Deaths

1 W/D3 Deaths

3 W/D3 Deaths

12Wkn=2

24Wkn=2

50Wkn=2

Death Prior to Implant

n=3

Primary Efficacy

Primary Safety

FIX-HF-5: Baseline CharacteristicsControl (n=213) Treatment (n=215)

Mean (SD) or n (%) Mean (SD) or n (%)

Age (yrs) 58.55 (12.23) 58.09 (12.79) 0.51091

Male 151 (70.9%) 158 (73.5%) 0.59012

Ethnicity

White 142 (66.7%) 154 (71.6%) 0.50263

Black 45 (21.1%) 36 (16.7%)

Other 26 (12.2%) 25 (11.7%)

Weight (kg) 93.30 (22.16) 91.17 (23.27) 0.16321

BMI (kg/m2) 30.95 (6.53) 30.44 (7.04) 0.21791

Resting HR (bpm) 73.74 (12.19) 73.98 (13.13) 0.96811

SBP (mmHg) 115.61 (17.61) 116.65 (19.48) 0.86951

CHF Etiology

Ischemic 142 (66.7%) 139 (64.7%) 0.64653

Idiopathic 48 (22.5%) 58 (27.0%)

Other 23 (10.8%) 18 (8.3%)

NYHA

Class I 0 (0%) 0 (0%) 0.17203

Class II 1 (0.47%) 0 (0%)

Class III 183 (85.92%) 196 (91.16%)

Class IV 29 (13.62%) 19 (8.84%)

 Variable P-value

FIX-HF-5: Baseline CharacteristicsContinued

Control (n=213) Treatment (n=215)Mean (SD) or n (%) Mean (SD) or n (%)

QRS Duration (ms) 101.51 (12.81) 101.63 (15.30) 0.59684

PVCs/24hr (Holter) 1365.1 (2000.9) 1323.3 (1930.6) 0.51131

LVEF (%) 26.09 (6.54) 25.74 (6.60) 0.56411

LVEDD (mm) 63.01 (8.56) 62.41 (9.22) 0.77151

MLWHFQ 57.38 (22.62) 60.49 (23.00) 0.11091

6MW (meters) 323.99 (92.44) 326.38 (82.10) 0.59711

Duration (minutes) 11.50 (3.46) 11.34 (3.20) 0.48141

Peak SBP (mmHg) 138.8 (24.6) 139.7 (27.1) 0.97141

Peak HR (bpm) 121.2 (20.5) 122.1 (20.2) 0.52231

Peak RER 1.13 (0.09) 1.14 (0.10) 0.51891

Peak VO2 (ml/kg/min) 14.71 (2.92) 14.74 (3.06) 0.85751

AT (ml/kg/min) 10.97 (2.18) 10.95 (2.24) 0.97194

P-value

CPX (core lab)

 Variable

FIX-HF-5: Baseline Medications*

Medication

Control n/N (%)

Optimizer n/N (%) P-Value

ACE inhibitor (ACEi) 148/213 (69.48) 153/215 (71.16) 0.7512 Angiotensin receptor blocker (ARB) 51/213 (23.94) 52/215 (24.19) 1.0000

ACEi or ARB 195/213 (91.55) 195/215 (90.70) 0.8654

Beta Blocker 198/213 (92.96) 202/215 (93.95) 0.7005

Loop Diuretic 194/213 (91.08) 198/215 (92.09) 0.7307 Second Diuretic 12/210 (5.71) 19/212 (8.96) 0.2629

Aldosterone Inhibitor 102/213 (47.89) 95/215 (44.19) 0.4973

Hydralazine 15/213 (7.04) 12/215 (5.58) 0.5574

Nitrates 75/213 (35.21) 73/215 (33.95) 0.8391

Calcium Channel Blocker 9/213 (4.23) 18/215 (8.37) 0.1103

Anti -arrhythmic 28/213 (13.15) 37/215 (17.21) 0.2816

*95% of all subjects also had an implantable cardioverter defibrillator

Primary Safety EndpointAll-Cause Mortality Plus All-Cause Hospitalizations

• Control Group:• 103 events in 213 subjects = 48%

• CCM Group:• 112 events in 215 subjects = 52%

• Statistical tests confirm that the safety endpoint was met:• Blackwelder: p=0.034 (p<0.05=noninferior)• Log-Rank test: p=0.22 (p>0.05=noninferior)

Primary Efficacy EndpointAnaerobic Threshold Responder Analysis

• Completors analysis:• Control: 18/154 (11.7%)• Treatment: 28/159 (17.6%)• Difference: 5.9% (P = 0.093)

• Intention-to-Treat analysis*:• Control: 28/213 (13.2%)• Treatment: 38/215 (17.7%)• Difference: 4.5% (P = 0.314)

*27% missing data requiring imputation per analysis plan

Primary Efficacy EndpointAnaerobic Threshold Comparison of Mean Change

p=ns

Control Treatment Difference

-0.3

-0.2

-0.1

0.0

0.1

A

na

ero

bic

Th

res

ho

ld(m

l/kg

/min

)

Secondary Efficacy EndpointPeak VO2 Comparison of Mean Change

Treatment Difference

-0.75

-0.50

-0.25

0.00

0.25

0.50

0.75

P

eak

VO

2

(ml/k

g/m

in)

Control

p=0.024

Secondary Efficacy EndpointQuality of Life Comparison of Mean Change

Control Treatment Difference

-20

-15

-10

-5

0

M

LW

HF

Q

p<0.0001

Other Efficacy EndpointChange in NYHA Functional Class

Control Treatment Difference0

10

20

30

40

50

NY

HA

( %

Pat

ien

ts w

ith

≥ 1

P

oin

t R

edu

ctio

n)

p=0.0026

Other Efficacy Endpoint6-Minute Hall Walk Distance Comparison of

Mean Change

Control Treatment Difference0

10

20

30S

ix M

inu

te W

alk

(m)

p=0.108

SUBGROUP ANALYSES*

N∆VAT

(ml/kg/min) pEF<25 205 -0.59 0.09EF≥25 223 0.53 0.15NYHA III 380 0.13 0.55NYHA IV 48 -1.21 0.10NYHA III + EF≥25 200 0.69 0.04NYHA IV + EF<25 25 -1.17 0.19

*Hypothesis Generating

Subgroup Analysis: Baseline EF ≥ 25 and NYHA III

Responders Analysis

ParameterControl(n=84)

Treatment(n=101)

Treatment-Control P*

VAT (ml/kg/min) 4/69(5.8%) 17/83(20.5%) 14.7% 0.0073VAT (ml/kg/min) (ITT) 9/97 (9.4%) 23/109 (21.5%) 12.1 0.023Peak VO2 (ml/kg/min) 3/76(3.95%) 18/94(19.15%) 15.2% 0.002MLWHFQ 35/84(41.7%) 60/101(59.4%) 17.7% 0.0119NYHA Class 19/82(23.2%) 43/97(44.3%) 21.1% 0.00236MW (meters) 20/79 (25.3) 36/97 (37.1) 11.8% 0.065ITT, intention to treat population*P values by one-sided Fisher's exact test

Subgroup Analysis: Baseline EF ≥ 25 and NYHA III

Comparison of Changes in Mean Values

ParameterControl(n=84)

Treatment(n=101)

Treatment-Control P*

VAT ml/kg/min) -0.54±1.83 0.10±2.36 0.64 0.024Peak VO2 -0.97±2.31 0.34±3.11 1.31 0.001MLWHFQ -6.0±21.9 -16.8±20.2 -10.8 0.0003NYHA Class -0.17±0.64 -0.46±0.61 -0.29 0.00116MW 0.8 (82.6) 21.5 (77.5) 20.7 0.0445

*P values by one-sided equal varance Student's t-test

Potential Study Limitations

• Choice of anaerobic threshold as a primary endpoint

• Missing VAT data despite rigorous approach to metabolic exercise testing

• Use of responders analyses

• Un-implanted control group (no blinding)

FIX-HF-5: Summary• CCM failed to improve the anaerobic

threshold, pre-specified as the primary endpoint of the trial

• In the overall population, CCM significantly improved

• Peak VO2• Quality of Life (MLWHFQ score)• NYHA

• In a subgroup comprising ~50% of study population (EF≥25, NYHA III), CCM significantly improved

• Peak VO2• AT• MLWHFQ• NYHA

Study Oversight Committees

• Executive Steering Committee• William Abraham, Alan Kadish, Kenneth Ellenbogen,

Robert Bourge, Koonlawee Nademanee, Michael Parides

• Data Safety Monitoring Board• Sidney Goldstein, Steven Gottlieb, Andrea Natale,

David Callans, David Naftel

• Events Adjudication Committee• Peter Carson, Inder Anand, Christopher O’Conner

Study Principal Investigators

Suresh Neelagaru, Amarillo, TX Seth Worley, Lancaster, PAAndrew Merliss, Lincoln, NE Roy John, Burlington, MAStanislav Weiner, Tyler, TX David Smull, Winston-Salem, NCJose Joglar, Dallas, TX Raffaele Corbisiero, Trenton, NJNirav Raval, Atlanta, GA Steven Greenberg, Roslyn, NYKoonlawee Nadamanee, Inglewood, CA Mari Rosa Costanzo, Naperville, ILMasood Akhtar, Milwaukee, WI Thomas Mattioni, Scottsdale, AZKent Volosin, Philadelphia, PA Steven Hao, Larkspur, CAFreddy Abi-Samra, New Orleans, LA Mark Wathen, Nashville, TNMarc Wish, Fairfax, VA David Hayes, Rochester, MNImran Niazi, Milwaukee, WI Andrew Cohen, Aurora, COGervasio Lamas, Miami, FL Bengt Herweg, Tampa, FLJavier Sanchez, Austin, TX Harold Goldberg, Spokane, WAEli Gang, Beverly Hills, CA Jill Kalman, New York, NYDavis Baran, Newark, NJ Gregory Jones, Kingsport, TNRandy Lieberman, Detroit, MI Nancy Sweitzer, Madison, WIAlan Bank, St. Paul, MN Mark Wood, Richmond, VAJeffrey Goldberger, Chicago, IL Jonathan Steinberg, New York, NYAllan Murphy, Newport, VA Jose Tallaj, Birmingham, ALJonathan Langberg, Atlanta, GA Alan Heywood, Bellevue, WACharles Love, Columbus, OH Barbara Czerska, Detroit, MIFrank McGrew III, Germantown, TN Gregory Buser, Larkspur, CAHue-The Shih, Houston, TX Steven Klein, Greensboro, NC