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

Duratio

n

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=7 SuccessfulImplantn=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) 0.51091Male 151 (70.9%) 158 (73.5%) 0.59012Ethnicity 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) 0.16321BMI (kg/m2) 30.95 (6.53) 30.44 (7.04) 0.21791Resting HR (bpm) 73.74 (12.19) 73.98 (13.13) 0.96811SBP (mmHg) 115.61 (17.61) 116.65 (19.48) 0.86951CHF 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) 0.59684PVCs/24hr (Holter) 1365.1 (2000.9) 1323.3 (1930.6) 0.51131LVEF (%) 26.09 (6.54) 25.74 (6.60) 0.56411LVEDD (mm) 63.01 (8.56) 62.41 (9.22) 0.77151MLWHFQ 57.38 (22.62) 60.49 (23.00) 0.110916MW (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

Ana

erob

ic T

hres

hold

(ml/k

g/m

in)

Secondary Efficacy EndpointPeak VO2 Comparison of Mean Change

Treatment Difference

-0.75

-0.50

-0.25

0.00

0.25

0.50

0.75

Pe

ak V

O2

(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

LWH

FQ

p<0.0001

Other Efficacy EndpointChange in NYHA Functional Class

Control Treatment Difference0

10

20

30

40

50

NYH

A

( % P

atie

nts

with

≥ 1

Po

int R

educ

tion )

p=0.0026

Other Efficacy Endpoint6-Minute Hall Walk Distance Comparison of

Mean Change

Control Treatment Difference0

10

20

30Si

x M

inut

e 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 AnalysisParameter

Control(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 InvestigatorsSuresh 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