The REMEDEE Study: A Randomized Comparison of a Combination

Sirolimus Eluting EPC Capture Stent with a Paclitaxel Eluting Stent

Michael Haude, MD

On behalf of the REMEDEE Investigators

TCT 2011 Late Breaking Clinical Trial

November 11, 2011

Disclosure Statement of Financial Interest

• Grant/Research Support

• Consulting Fees/Honoraria

• Orbus Neich• Biotronik• Abbott Vascular• Medtronic• Volcano

Within the past 12 months, I , Michael Haude, MD, or my spouse/ Within the past 12 months, I , Michael Haude, MD, or my spouse/ partner have had a financial interest/arrangement or affiliation with the partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.organization(s) listed below.

Affiliation/Financial Relationship Company

Combo Dual Therapy Stent

Design features:

• Abluminal biodegradable polymer matrix

• Sirolimus elution

• Genous technology for accelerated endothelial coverage

316L Stainless Steel Stent Strut

Cross-section

Lumen Side

Vessel Side

Outer Immobilized Anti-CD34 Antibody Treatment

Abluminal Sirolimus Release

Matrix

100 μm

3-5 μm

Antibody Monolayer;

nanometers thick

In vitro elution of Combo and CYPHER® (% of total drug eluted over time)

0

20

40

60

80

100

0 0.25 1 3 7 14 28 35

Time (days)

% Elution over time

Combo

Cypher

Combo StentSirolimus Drug Elution

• Drug – Sirolimus

• Polymer - biodegradable Surmodics SynBiosys™ proprietary blend of urethane-linked block co-polymers of lactide, glycolide, and ε-caprolactone; degradation time <90 days

• Drug content is 5 µg/mm stent length, approximately half the dose of CYPHER™ but with a similar release profile

Granada et al., Circ Cardiovasc Intervent. 2010; 3:257-266

REMEDEE Study Design

Objective:

• To demonstrate non-inferiority of the Combo Stent compared to the TAXUS Liberté ® stent for the primary endpoint of 9-month angiographic in-stent late lumen loss

Major Inclusion Criteria:

• Single de-novo lesions in native coronary arteries

• Lesion length < 20 mm

• 2.5 mm to 3.5 mm in diameter

Major Exclusion Criteria:

• Acute Myocardial Infarction

• Ostial lesions

• Unprotected left main with > 50% stenosis

REMEDEE Study Overview

Single De Novo Native Coronary Artery LesionsReference Vessel Diameter: 2.5-3.5 mm

Lesion Length: < 20 mm

COMBOTM

Dual Therapy Stent(n=124)

TAXUS Liberté®

PES(n=59)

30 Day 9 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr30 Day 9 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr

Clinical / MACE

Angio - 109 Combo: 52 Taxus LibertéIVUS Sub-group - 35 Combo: 15 Taxus Liberté

2:1 Randomization

Principal Investigators..…………..…..Principal Investigators..…………..….. Alexandre Abizaid, MD, PhDAlexandre Abizaid, MD, PhDMichael Haude, MDMichael Haude, MDIan Meredith, MBBS, PhDIan Meredith, MBBS, PhDStephan Windecker, MDStephan Windecker, MD

CRO……………………………..…………CRO……………………………..…………-organization & managementorganization & management-QCA / IVUS Core LabQCA / IVUS Core Lab-Statistical analysisStatistical analysis-CEC/DSMB coordinationCEC/DSMB coordination

Cardiovascular Research FoundationCardiovascular Research Foundation Roxana Mehran, MD, CSO Clinical Trial CenterRoxana Mehran, MD, CSO Clinical Trial Center Helen Parise, ScD, Director BiometricsHelen Parise, ScD, Director Biometrics Ecaterina Cristeria, MD, Director Angio Core LabEcaterina Cristeria, MD, Director Angio Core Lab Akiko Maehara, MD, Director Intravascular ImagingAkiko Maehara, MD, Director Intravascular Imaging Madan Mohan, MD, Clinical Trial Safety ManagerMadan Mohan, MD, Clinical Trial Safety Manager LaTosha Eligon, Program ManagerLaTosha Eligon, Program Manager

Executive Committee…....………………Executive Committee…....……………… Alexandre Abizaid, MD, PhDAlexandre Abizaid, MD, PhDMichael Haude, MDMichael Haude, MDRoxana Mehran, MDRoxana Mehran, MDIan Meredith, MBBS, PhDIan Meredith, MBBS, PhDStephen Rowland, PhDStephen Rowland, PhDStephan Windecker, MDStephan Windecker, MD

REMEDEETrial Management

Participating Investigative Sites

• Michael Haude, Lukaskrankenhaus Neuss, Neuss, Germany (32)

• Stephen W.L. Lee, Queen Mary Hospital, Hong Kong (31)

• Sigmund Silber, Cardiology Practice & Hospital, Munich, Germany (14)

• Stephen Worthley, Royal Adelaide Hospital, Adelaide, SA, Australia (14)

• Sandra Erbs, Herzzentrum Leipzig, Leipzig, Germany (13)

• Stefan Verheye, Algemeen Ziekenhuis Middelheim, Antwerp, Belgium (13)

• Mohd Ali Rosli, Institut Jantung Negara, Kuala Lumpur, Malaysia (12)

• Roberto Botelho, Instituto de Cardiologia de Triangulo Mineiro, Uberlandia, Brazil (11)

• Ian Meredith, Monash Medical Center, Melbourne, Victoria, Australia (9)

• Kiu Hian Sim, Sarawak General Hospital, Kota Samarahan, Sarawak, Malaysia (7)

• Pieter Stella, UMC Utrecht, Utrecht, The Netherlands (6)

• Huay-Cheem Tan, National University Hospital, Singapore (5)

• Robert Whitbourn, St. Vincent's Hospital, Melbourne, Victoria, Australia (5)

• Alexandre Abizaid, Institute Dante Pazzanese, Ibirapuera, Sao Paulo, Brazil (4)

• Sukumaran Thambar, John Hunter Hospital, Newcastle, NSW, Australia (4)

• Tian Hai Koh, Singapore General Hospital, Singapore (2)

• Peter den Heijer, Amphia Ziekenhuis, Breda, The Netherlands (1)

REMEDEE: Key Endpoints

Primary endpoint:

• Angiographic 9-month in-stent late lumen loss

Secondary endpoints:

• All-cause and cardiac mortality, MI, MACE

• Stent thrombosis (ARC definition, definite and probable)

• Clinically (ischemia)-driven TLR, TVR, TLF, TVF

• Device, lesion, procedure success

• In-stent / in-segment binary restenosis, MLD, proximal & distal late lumen

• NIH volume and % in-stent volume obstruction at 9 months by IVUS

• Change in human anti-murine antibody (HAMA) levels (30d & 9mo)

Statistical RationaleHypothesis

•Non-inferiority; Angiographic In-Stent Late Loss

•H0: µCombo ≥ µTAXUS + Δ

•Ha: µCombo < µTAXUS + Δ

Assumptions:

•µTAXUS = 0.40 mm; SD = 0.53 mm

•µCombo = 0.30 mm; SD = 0.53 mm

•Non-inferiority Margin, Δ = 0.20 mm

•One sided α=0.025; 90% Power

•Randomization 2:1

Sample Size (20% margin for loss to angiographic FU):

120 Combo: 60 Taxus Liberté

+ 0.53

+ 0.53

Baseline Patient Characteristics

Combo(N=124)

TAXUS(N=59)

p-value

Age (mean ± SD, yrs) 64.2 ± 9.5 64.0 ± 10.5 0.92

Male 71.8% 71.2% 0.93

Smoking /tobacco usage 57.3% 47.5% 0.21

Diabetes mellitus 33.1% 37.3% 0.57

Insulin dependent 7.3% 11.9% 0.30

History of hypertension 80.6% 76.3% 0.50

History of hyperlipidemia 82.3% 72.9% 0.14

Left ventricular ejection fraction (%)

mean ± SD 63.9 ± 11.9 63.3 ± 11.6 0.77

Previous Congestive Heart Failure 13.7% 10.2% 0.50

Previous MI 25.0% 27.1% 0.76

Previous PCI 23.4% 20.3% 0.64

Previous CABG 3.2% 3.4% 1.00

History of renal insufficiency 6.5% 1.7% 0.28

Pre-procedure Cardiac Status

Combo(N=124)

TAXUS(N=59)

p-value

Baseline, pre-procedure

Angina status:

Silent ischemia 10.5% 10.2% 0.95

Stable angina 73.4% 72.9% 0.94

CCS I 10.5% 16.9% 0.22

CCS II 48.4% 49.2% 0.92

CCS III 12.1% 6.8% 0.27

CCS IV 2.4% 0.0% 0.55

Unstable angina 16.1% 16.9% 0.89

Braunwald I 4.8% 3.4% 1.00

Braunwald II 6.5% 3.4% 0.50

Braunwald III 4.8% 10.2% 0.21

Device & Procedure CharacteristicsCombo(N=124)

TAXUS(N=59)

p-value

Number of Lesions Treated per Patient; mean ± SD

1.1 ± 0.3 1.1 ± 0.4 0.36

Target lesion type – de novo 100.0% 100.0% N/A

Location of target lesion

RCA 25.0% 16.9% 0.22

LCX 31.5% 28.8% 0.72

LAD 43.5% 54.2% 0.18

Lesion Location

Ostial 0.8% 1.7% 0.54 Proximal 35.5% 39.0% 0.65 Mid 54.0% 47.5% 0.41 Distal 9.7% 11.9% 0.65Number of study stents deployed per patient; mean ± SD

1.1 ± 0.3 1.0 ± 0.2 0.42

(min, max) (0, 3) (1, 2) N/A

Baseline Lesion CharacteristicsCombo(N=124)

TAXUS(N=59)

p-value

Lesion Length (mm)

mean ± SD 13.69 ± 5.07 14.64 ± 4.41 0.22 (min, max) (5.08, 45.57) (5.25, 24.83) N/A

Eccentric 3.2% 8.5% 0.15

Angulation > 45o 9.7% 6.8% 0.52

Thrombus 0.0% 0.0% N/A

Tortuosity None 96.0% 96.6% 1.00 Moderate 3.2% 3.4% 1.00 Severe 0.8% 0.0% 1.00

Calcification

None or Mild 78.2% 86.4% 0.19 Moderate 21.0% 13.6% 0.23 Severe 0.8% 0.0% 1.00

TIMI Score

TIMI 0 0.0% 0.0% N/A TIMI 1 0.8% 1.7% 0.54 TIMI 2 4.0% 3.4% 1.00 TIMI 3 95.2% 94.9% 1.00

Acute Success

Combo(N=124)

TAXUS(N=59)

p-value

Device Success1 99.2% 100.0% 1.00

Lesion Success2 100.0% 100.0% N/A

Procedure Success (Protocol Def.)3 96.8% 98.3% 1.00

Procedure Success (ARC)4 91.9% 94.9% 0.55

1 – attainment of a final in-stent residual diameter stenosis of <50% (by QCA), using the assigned device only and without device malfunction 2 – attainment of <50% residual stenosis using any percutaneous method3 – achievement of a final in-stent residual diameter stenosis of <50% (by QCA), using the assigned device, without the occurrence of cardiac death, Q wave or non-Q wave MI adjudicated using protocol definition, or repeat revascularization of the target lesion during the hospital stay4 – achievement of a final in-stent residual diameter stenosis of <50% (by QCA), using the assigned device, without the occurrence of cardiac death, Q wave or non-Q wave MI adjudicated using Academic Research Consortium (ARC) definition, or repeat revascularization of the target lesion during the hospital stay

Angiographic In-Stent Late Lumen LossStatistical Analysis

Combo(N=124)

TAXUS(N=59)

Margin of Non-Inf, Δ

(mm)

Non-inferiority

p-value

Difference[95% CI]

Superiorityp-value

In-stent Late Lumen Loss at 9 months (mm)

N 109 52

mean ± SD 0.39 ± 0.45 0.44 ± 0.56 0.2 0.0012-0.05

[-0.21,0.11]0.5514

(min, max) (-0.34, 2.63) (-0.40, 1.97) N/A N/A

 

Full analysis set: ITT patients with qualifying 9-month angiographic follow-up included in the analyses.

Late loss estimated by Angiographic Core Lab for patients with available 9-month qualifying angiogram.

Non-inferiority Testing for AngiographicIn-stent Late Lumen Loss

In-stent Late Lumen Loss at 9 MonthsCumulative Frequency Distribution

2.52.01.51.00.50.0-0.5

100

80

60

40

20

0

In Stent Late Loss @ 9 mo [mm]

Perc

ent

ComboTaxus

LLL (mean ± SD) Combo: 0.39 ± 0.45mm Taxus: 0.44 ± 0.56mm

Cumulative Frequency Distribution PlotsBaseline MLD, Post-Stent MLD, In Lesion MLD

3.53.02.52.01.51.00.50.0

100

80

60

40

20

0

MLD [mm]

Perc

ent

Baseline MLD ComboBaseline MLD TaxusFinal MLD ComboFinal MLD TaxusIn Lesion MLD @ 9 mo ComboIn Lesion MLD @ 9 mo Taxus

9-Month Binary Angiographic Restenosis and In-Segment Late Loss

Combo(N=124)

TAXUS(N=59)

p-value

Restenosis (%)

In-stent 5.5% 9.6% 0.34

In-segment 8.3% 13.5% 0.30

Minimum Lumen Diameter (MLD) (mm)

In-stent, mean ± SD 2.31 ± 0.58 2.30 ± 0.56 0.86

In-segment, mean ± SD 2.09 ± 0.56 1.97 ± 0.57 0.19

In-stent late lumen loss (mm)

mean ± SD 0.39 ± 0.45 0.44 ± 0.56 0.55

In-segment late lumen loss (mm)

mean ± SD 0.27±0.46 0.41±0.54 0.08

Proximal In-segment, mean ± SD 0.19 ± 0.44 0.29 ± 0.53 0.24

Distal In-Segment, mean ± SD 0.09 ± 0.30 0.13 ± 0.30 0.45

Neointimal Hyperplasia Volume andIn-stent Volume Obstruction (IVUS)

Combo(N=35)

TAXUS(N=15)

p-value

IVUS endpoints

Neointimal hyperplasia volume (mm3)

mean ± SD 21.53 ± 21.71 25.95 ± 18.65 0.50

Relative difference of NIH Volume (17% less NIH volume)

In-stent volume obstruction (%)

mean ± SD 15.24 ± 14.22 14.59 ± 8.38 0.84

30 Day Secondary Effectivenessand Safety Endpoints

Combo(N=124)

TAXUS(N=59)

p-value

30 day follow up

Death 0.0% 0.0% N/A

Cardiac death 0.0% 0.0% N/A

Myocardial infarction (Protocol def.) 2.4% 1.7% 0.75 Q-Wave 0.0% 0.0% N/A

non Q-Wave 2.4% 1.7% 0.75

Clinically-driven TLR 0.0% 0.0% N/A

MACE (Protocol def.) 2.4% 1.7% 0.75

Stent thrombosis (ARC def.) 0.0% 0.0% N/A

Clinically-driven TVR 0.0% 0.0% N/A

Clinically-driven TVF (Protocol def.) 2.4% 1.7% 0.75

Clinically-driven TLF (Protocol def.) 2.4% 1.7% 0.75

9-Month Secondary Effectivenessand Safety Endpoints

Combo(N=124)

TAXUS(N=59)

p-value

Measures at 9 months

Death 1.0% 0.0% 0.49

Cardiac death 0.0% 0.0% N/A

Myocardial infarction (Protocol def.) 2.4% 1.7% 0.75

Q-Wave 0.0% 0.0% N/A

non Q-Wave 2.4% 1.7% 0.75

Clinically-driven TLR 5.2% 9.5% 0.35

MACE (Protocol def.) 8.7% 11.0% 0.69

Stent thrombosis (ARC def.) 0.0% 0.0% N/A

Clinically-driven TVR 7.0% 9.5% 0.65

Clinically-driven TVF (Protocol def.) 10.4% 11.0% 0.97

Clinically-driven TLF (Protocol def.) 8.7% 11.0% 0.69

To 9-Months + 30 Days: Protocol clinical assessment 270±30 days

Conclusions

In this First-In-Man study, the COMBO Dual Therapy Stent

effectively controls neointimal proliferation:

• 0.39 mm average angiographic in-stent late loss at 9

months with the Combo stent is non-inferior to the Taxus

Liberté stent

• In-stent and In-segment Late Loss, and Binary Restenosis

Rates are accordingly low and comparable to the Taxus

Liberté stent

• Overall low rate of clinical events in both groups, including

no stent thrombosis

• Combo shown to be effective & safe