Getting to answers with clinical trials: Being bold

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1 Getting to answers with clinical trials: Being bold Prof. Thomas Zeller Department Angiology University Heart-Center Freiburg - Bad Krozingen Bad Krozingen, Germany

2 Thomas Zeller, MD Faculty Disclosure For the 12 months preceding this presentation, I disclose the following types of financial relationships: Honoraria received from: Abbott Vascular, Angioslide, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Cordis Corp., Covidien, Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme, VIVA Physicians Consulted for: Abbott Vascular, Bard Peripheral Vascular, Boston Scientific Corp., Cook Medical, Gore & Associates, Medtronic, Spectranetics, ReCor Research, clinical trial, or drug study funds received from: 480 biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Cordis Corp., Covidien, Gore & Associates, Abbott Vascular -DEV Technologies, Inc., Medtronic, Spectranetics, Terumo, TriReme, Volcano

3 Landscape of PAD treatment Treatments for PAD are growing and changing PTA and Bare Metal Stents are used most often Leave nothing behind can include multiple strategies Atherectomy PTA DCB Each RCT is unique RCT are not equal to the Registry Registries are often not as rigorous as RCTs Core lab DSMB/CEC Patient population Data are needed to determine the best path forward

4 BMS, DES, DCB, Atherectomy

5 Drug Eluting Stents - Peripheral SFA BTK Zilver PTX Cook Medical Eluvia DES Boston Scientific Promus Element Plus BTK Boston Scientific Xience Prime BTK Abbott Vascular Product Image CE Mark/US Approval CE US CE US CE US CE US No Stent Platform Zilver Flex Innova Promus Premier Not indicated for BTK in US Material Nitinol Nitinol Platinum Chromium Alloy Cobalt Chromium No Polymer None Biostable Fluorinated Polymer Matrix Biostable Fluorinated Polymer Matrix Biostable Fluorinated Polymer Matrix Drug Paclitaxel Paclitaxel Everolimus Everolimus Deployment Self-expandable Self-expandable Balloon Expandable Balloon Expandable Sizes Diameter Length Diameter Length Diameter Length Diameter Length 6-8mm mm 6-7mm mm mm 12-38mm 2.5-4mm 28-38mm Cook Medical (2014). Zilver PTX Drug-Eluting Peripheral Stent Instructions for Use

6 Drug-Coated Balloons - Peripheral IN.PACT Admiral Medtronic Lutonix TM Bard Stellarex Spectranetics Ranger Boston Scientific Product Image Paclitaxel Dose 3.5 µg/mm 2 2 µg/mm 2 2 μg/mm 2 2 µg/mm 2 Coating Technology FreePac hydrophilic coating (excipient: urea) Proprietary hydrophilic nonpolymeric carrier EnduraCoat coating (excipient: Poly-ethylene Glycol) TransPax coating (excipient: Citrate ester) Guidewire Compatibility Matrix OTW OTW OTW 0.14/0.18 SFA: 4-7 mm; mm BTK: Recalled SFA: 4-6 mm; mm SFA: 4-6 mm; mm SFA: 4-8 mm; mm BTK: 2-4 mm; up to 150 mm CE Mark FDA Approval

7 Atherectomy Devices Jetstream Atherectomy System (Boston Scientific) Diamondback 360, Stealth 360 Atherectomy System (Cardiovascular Systems, Inc) SilverHawk, TurboHawk Plaque Excision System (Covidien) Turbo-Elite Laser Atherectomy Catheter (Spectranetics) Product Image Front-Cutting ( ) Differential Cutting NA Active Aspiration Concentric Lumens Lesion Morphology: Calcium 2,3 4 (large vessel only) 1 ( ) 1 Soft/Fibrotic Plaque Thrombus 1 contraindicated 1 1 In-stent restenosis 6 ( ), not approved 7 1. Instructions for Use/product website. 2. Zeller T, et al. J Endovasc Ther. 2009;16(6): Maehara A, et al. EuroIntervention ;11(1): Shammas N, et al. J Endovascular Ther, 2012; 19: McKinsey JF, et al. JACC Cardiovasc Interv ;7(8): Shammas NW, et al. J Endovasc Ther ;23(2): Dippel EJ,et al. JACC Cardiovasc Interv ;8(1 Pt A):

8 Outcomes for BMS, DES, DCB studies Device Rutherford Class, % Lesion Length Patency, % Wire interwoven Nitinol stents Drugeluting stents II III IV mm Year 1 Year 2 Year 3 Year 4 Year NA NA NA NA Covered stent 59, Drug-coated balloons NA NA Lutonix NA NA NA In.PACT NA NA NA Shishebor M, Jaff M. Circulation 2016.

9 Outcomes for Atherectomy studies Device Name* Diamondback 360 Excimer Laser Jetstream Mechanism of Action Orbital Photoablative Rotational / Aspirational Study No. of Patients/Lesions CALCIUM /64 Procedural Success Rate 93.1% in OA with PTA vs 82.4% in PTA alone Procedural Complication Rate Bailout stenting 6.9% vs 14.3% in PTA alone OASIS / % 2.5% COMPLIANCE /65 CONFIRM series 83 3,135/4,766 LACI /155 EXCITE ISR TRUE Residual stenosis 30% w/o stenting: 86.8% in OA vs 18.5% in PTA OA decreased preprocedural stenosis from an avg of 88% to 35% Procedural success (<50% residual stenosis) in 85% of the limbs 93.5% in ELA + PTA vs 82.7% in PTA alone Stenting in 5.3% in the OA vs 77.8% Stenting in <5.7% Procedural complication in 12% of the limbs Bailout stenting of 4.1% in ELA+PTA vs 11.1% in PTA alone Increase in mean luminal volume of 64.3 mm 3 0% Silverhawk/Turboh awk Excisional / Directional DEFINITIVE LE / % Bailout stenting 3.2% Shishebor M, Jaff M. Circulation 2016.

10 Peripheral Intervention Historical Patient Populations Simple Complex A * B C D POBA DCB Longer, more calcium Stents (Bare, Covered, DES) Surgery * Transatlantic Inter-Society Consensus (TASC ) II Lesion Classification (Type A, B, C, D ) for Peripheral Arterial Disease

11 Adjunctive treatment? DCB+Atherectomy: Clinical Evidence DEFINITIVE AR: directional atherectomy + DCB vs DCB alone Adjunctive atherectomy may improve procedural and clinical outcomes following DCB treatment of the SFA and/or popliteal artery, particularly for longer or severely calcified lesions Procedural Results Duplex Ultrasound Patency at 12-months DCB Ath + DCB Technical Success* 64.2% 89.6% 100% 80% 60% 86% 97% 63% 70% 90% 93% Bail-out Stent 3.7% 0% Flow-limiting Dissection 19% 2% 40% 20% 0% n=31 n=23 n=8 n=27 n=54 n=48 Lesions >10 cm Severely Calcified All patients Zeller, VIVA *Technical success: Defined as 30% residual stenosis following the protocol-defined treatment at the target lesion as determined by the Angiographic Core Laboratory. DCB, drug-coated balloon; DUS, duplex ultrasound; SFA, superficial femoral artery DCB DCB + Ather

12 Below the knee DCB vs PTA Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: results from the IN.PACT DEEP randomized trial Multicenter RCT 358 CLI patients Randomized DEB vs PTA 2:1 Primary endpoints Clinically driven lesion TLR Late lumen loss 6 months composite mortality, major amp, CD-TLR InPact Deep RCT DEB PTA Clinically Driven TLR 9.2% 13.1% Late Lumen Loss 0.61 ± ± 0.78 Major Amputation 8.8% 3.6% (P=0.08) Primary Safety (mortality, major amputation, CD TLR) 17.7% 15.8% Zeller T, J Am Coll Cardiol 2014

13 Below the knee DES vs PTA/BMS Systematic Review of infrapopliteal DES: A meta-analysis of randomized controlled trials 3 RCTs with 501 patients Achilles: DES vs PTA in CLI & IC, n=200 Destiny: DES vs BMS in CLI, n=140 Yukon-BTX: DES vs BMS in CLI & IC, n=161 Relatively short and focal infrapopliteal lesions InfraPop: Meta-Analysis of RCT Results at 1 year DES PTA/BMS P= Primary Patency 80.0% 58.8% < Rutherford class improvement 79.0% 69.6% Wound healing 76.8% 59.7% 0.04 TLR 9.9% 22.0% Event-free survival 72.2% 57.3% < Survival 85.5% 86.6% 0.75 Amputation 6.4% 10.8% 0.11 Katsanos K et al, Cardiovasc Intervent Radiol 2013

14 Below the knee DES vs PTA/BMS PADI CLI: PTA±BMS vs DES for infrapopliteal lesions Multi-center randomized two-arm study 136 patients with 144 limbs CLI, Rutherford 4-6 De novo stenoses or occlusions below knee joint Vessel diameter 2-6 mm, length 90 mm PTA±BMS or paclitaxel-des (Taxus Liberté) Heparin, Aspirin, Clopidogrel Overhagen et al. Circ Cardiovasc Interv 2016

15 Putting it all together

16 Clinical results of Drug-Eluting Technologies Network meta-analysis of RCTs of endovascular treatment POBA vs. DCB vs. DES vs. BMS vs. Covered stents Results: Baseline risk adjusted random effects mixed treatment comparison TLR lowest with paclitaxel-coated balloon and paclitaxel-eluting stent Vascular restenosis lowest with paclitaxel-eluting stent and paclitaxelcoated balloon Katsanos K: J Vasc Surg 2014;59;

17 Gaps in the data? DCB in Complex Lesions DCB vs DES Atherectomy + DCB DCB vs DCB DES vs DES Primary patency or TLR? Relavance? BTK? We need more data

18 Clinical Study Data Important Characteristics and Outcomes Clinical Characteristics Demographics (age, sex, socioeconomic class) Diabetes mellitus Angiographic Characteristics Lesion location, length Calcification Outcomes Patency (primary, assisted primary, secondary) Clinically driven target lesion revascularization Chronic kidney disease Number of runoff 6-minue walk test Rutherford class Stenosis versus occlusion Quality-of-life metrics Ankle brachial index De novo versus restenosis Amputation free survival Toe brachial index Comorbid coronary, cerebrovascular conditions Wound location, size, and depth Soft tissue/bone infection Major adverse limb events Time to wound healing Time to ambulation Hospital length of stay Readmission Total medical expense Shishebor M, Jaff M. Circulation 2016.

19 Clinical Studies Meaningful Endpoints Randomized Controlled Trials Real world studies Late Lumen Loss Important to: Primary Patency Important to: Freedom from TLR Important to: Patient Outcomes Important to: Physicians Regulatory agencies Physicians Regulatory agencies Physicians Patients Payers Regulatory agencies??? Physicians Patients Payers Regulatory agencies

20 Being Bold, BSC approach to finding the answers

21 Boston Scientific Drug Elution Clinical Program MAJESTIC (DES) Prospective, multicenter, single-arm, open label n= 57 (2yr follow-up complete) IMPERIAL (DES) Prospective, multicenter, RCT 2:1 (Eluvia : Zilver PTX) n = 485 (Enrolling) EMINENT (DES/BMS) Prospective, multicenter, RCT 2:1 (Eluvia : BMS) n = 750 (Enrolling) REGAL (DES) Prospective, multicenter, single-arm, open label n = 500 (Enrolling) Ranger FIM (DCB) Prospective, multicenter, randomized n = 105 Ranger II (DCB) Prospective, multicenter, RCT 3:1 (Ranger : POBA) n = 376 Ranger China Prospective, multicenter, single-arm n = 123 (DCB)

22 Boston Scientific Global Pivotal Study IMPERIAL Trial Clinical Study Overview: IMPERIAL Title Primary Investigators Objective Study Design A randomized trial comparing the ELUVIA drug-eluting stent versus Zilver PTX stent for treatment of superficial femoral and/or proximal popliteal arteries Global: William A. Gray, MD European: Prof. Dr. med Stefan Müller-Hülsbeck To evaluate the safety and effectiveness of the ELUVIA Drug-Eluting Vascular Stent System (ELUVIA Stent) for treating Superficial Femoral Artery (SFA) and/or Proximal Popliteal Artery (PPA) lesions up to 140 mm in length. The trial consists of the following: A prospective, multicenter, 2:1 randomized (ELUVIA vs Zilver PTX), controlled, singleblind, non-inferiority trial (RCT) A concurrent, non-blinded, single-arm, pharmacokinetic(pk) sub-study A concurrent, non-blinded, non-randomized, single arm Long Lesion sub-study (lesions 140mm-190mm in length treated with ELUVIA) Subjects 465 subjects treated with ELUVIA (N=310) or Zilver PTX (N=155) subjects treated with ELUVIA in the PK sub-study 50 subjects treated with ELUVIA in the Long Lesion sub-study Investigational Centers Up to 75 centers in US, Canada, New Zealand, Belgium, Germany, Austria, and Japan

23 Boston Scientific Global Pivotal Study IMPERIAL Trial Clinical Study Overview: IMPERIAL Primary Efficacy Endpoint Primary vessel patency as assessed by duplex ultrasound (DUS) at 12 months post-procedure and adjudicated by an independent core laboratory. Primary Safety Endpoint Major Adverse Event (MAE) rate defined as All cause death through 1 month Target limb major amputation through 12 months Target lesion revascularization (TLR) through 12 months Study Stents Zilver PTX Eluvia Medicinal Substance Paclitaxel Paclitaxel Coating Design No carrier PROMUS Polymer Drug/Total Dose Size Matrix 3µg/mm 2 8 x 120mm = 1112 µg 6-8mm mm 0.167µg/mm 2 7 x 150mm = 517 µg 6 & 7mm mm SEM Image 100x

24 Boston Scientific Global Pivotal Study RANGER II SFA Clinical Study Overview: RANGER II SFA Title Primary Investigators Objective Study Design Subjects Investigational Centers Primary Efficacy Endpoint Primary Safety Endpoint A 3:1 Randomized Trial Comparing the Boston Scientific RANGER Paclitaxel Coated Balloon vs Standard Balloon Angioplasty for the Treatment of Superficial Femoral Arteries (SFA) and Proximal Popliteal Arteries (PPA) Global: Prof. Thomas Zeller, MD - Germany National: Ravish Sachar, MD, FACC United States To evaluate the safety and effectiveness of the RANGER Paclitaxel Coated Balloon for treating lesions located in the SFA and PPA The trial consists of the following: Prospective, multicenter, single-blind, superiority, RCT 3:1 (RANGER DCB : Standard PTA) A concurrent, non-blinded, single-arm, pharmacokinetic(pk) sub-study 396 patients At least 376 patients into the randomized arm 12 to 20 subjects in the non-randomized PK Sub-study Up to 70 study centers in Canada, Europe (Austria, Belgium, Germany, Poland), Japan, New Zealand, and U.S. Primary Patency of lesion Determined by DUS and absence of clinically driven TLR Occurrence of MAEs All-cause death at 1 Month TLR at 12 Months Target limb major amputation at 12 Months

25 RANGER II SFA Study Flow Signed ICF & Baseline Testing NO Eligibility criteria met NO Do Not Enroll Guidewire crosses target lesion Successful pre-dilation Obtain randomization code (3:1) NO RANGER investigational balloon 282 3:1 94 Standard PTA commercial balloon Post-dilation per discretion Post-procedure & Pre-discharge Assessments Follow-up Evaluations Office : 1, 6, 12, 24, 36 Month FU Office / Phone: 48, 60 Month FU End of Study

26 Investigator Sponsored Research Drug Elution (DES and DCB) SPORTS Prospective, multicenter, RCT 1:1:1 N = 222 Hemodialysis AVF Rescue Prospective, multicenter, RCT 1:1 N = 200 SFA RCT Prospective, RCT 1:1 (Ranger : InPact) N = 150, study extended to 414 patients SFA Registry Prospective, multicenter, registry N = 180 BTK Angiographic Feasibility, observational, angio F/U N = 30 BTK Clinical Prospective, RCT 1:1 (Ranger vs PTA) N = 70 JET-PCB (IDE) Prospective, multicenter, RCT 2:1 (JS+Ranger : POBA+Ranger) N = 250 These investigator-sponsored studies are supported by grant funding from Boston Scientific. Boston Scientific is not responsible for the collection, analysis or reporting of these studies which remain the sole responsibility of the investigators. Information for the use in countries with applicable product registrations.

27 COMPARE I Pilot Investigator Sponsored Research Clinical Study Overview: COMPARE I Pilot Study Title Primary Investigator / Sponsor Objective Study Design Subjects Investigational Centers Primary Efficacy Endpoint Primary Safety Endpoint Prospective, Randomized, Multi-center Study for the Treatment of Subjects with Symptomatic Femoropopliteal Artery Disease with the Ranger Paclitaxel Coated PTA Balloon Catheter (study arm) vs. the IN.PACT Drug Eluting Balloon (control arm) Dierk Scheinert, MD Germany VascuScience GmbH Leipzig, Germany To compare two different Paclitaxel coated balloons in the treatment of high grade stenotic or occluded lesions in the SFA and/of PPA Prospective, multicenter, RCT 1:1 (Ranger DCB : InPact DCB) 150 patients 15 centers in Germany Patency rate after 1yr defined as absence of clinically driven TLR (due to symptoms and drop of ABI of 20% or > 0.15 when compared to post-procedure baseline) or restenosis with PVR > 2.4 evaluated by DUS Composite of freedom from device and procedure-related death through 12m post procedure as well as freedom from both target limb major amputation and clinically-driven TVR

28 COMPARE I Extenstion Investigator Sponsored Research Clinical Study Overview: COMPARE I Pilot Study Extension Title Prospective, Randomized, Multi-center Study for the Treatment of Subjects with Symptomatic Femoropopliteal Artery Disease with the Ranger Paclitaxel Coated PTA Balloon Catheter (study arm) vs. the IN.PACT Drug Eluting Balloon (control arm) Primary Investigator / Sponsor Objective Study Design Dierk Scheinert, MD Germany VascuScience GmbH Leipzig, Germany Subjects 150 patients 414 patients Investigational Centers Primary Efficacy Endpoint Primary Safety Endpoint To compare two different Paclitaxel coated balloons in the treatment of high grade stenotic or occluded lesions in the SFA and/of PPA Prospective, multicenter, RCT 1:1 (Ranger DCB : InPact DCB) 15 centers in Germany Patency rate after 1yr defined as absence of clinically driven TLR (due to symptoms and drop of ABI of 20% or > 0.15 when compared to post-procedure baseline) or restenosis with PVR > 2.4 evaluated by DUS Composite of freedom from device and procedure-related death through 12m post procedure as well as freedom from both target limb major amputation and clinically-driven TVR

29 SPORTS trial Investigator Sponsored Research Clinical Study Overview: JET-PCB Trial (Investigator sponsored IDE) Title Primary Investigator / Sponsor Objective Study Design Study Devices Subjects Investigational Centers Primary Endpoint Sequent Please Drug coated balloons versus primary stent application in long SFA lesions Prof. Dr. med. Gunnar Tepe - Germany InnoRa GmbH Berlin To show superiority in terms of diameter stenosis 12 months after intervention of long lesions with PES compared to NS (hypothesis 1a) and non-inferiority in terms of diameter stenosis 12 months after intervention of long lesions with PCB compared to NS (hypothesis 2a). A prospective, multicenter, open, RCT 1:1:1 PTA with PES PTA with PCB PTA with NS Hypothesis 1a = PES Eluvia ; PCB - SeQuent ; NS SMART, Zilver, Innova, Absolut, LIfeStent, Everflex 222 subjects (74 per treatment arm) 9 11 Centers in Germany and Austria Percent diameter stenosis (DS) at 12 M as assessed by quantitative angiography PES=paclitaxel-eluting stent; PCB=paclitaxel-coated balloon PTA=Percutaneous transcatheter angioplasty; NS=Nitinol Stent

30 JET-PCB study Investigator Sponsored Research Clinical Study Overview: JET-PCB Trial (Investigator sponsored IDE) Title Primary Investigator / Sponsor Objective Study Design Subjects Investigational Centers Primary Efficacy Endpoint Primary Safety Endpoint JETStream Atherectomy with Adjunctive Paclitaxel-Coated Balloon Angioplasty vs Plain Old Balloon Angioplasty followed by Paclitaxel-Coated Balloon in Treating Complex Denovo Femoropopliteal Arterial Disease Nicolas W. Shammas, MD Midwest Cardiovascular Research Foundation To evaluate the use of Jetstream Atherectomy (JS) followed by DCB in comparison to the use of plain old balloon angioplasty (POBA) followed by DCB alone in the treatment of complex lesions in femoropopliteal arteries (Rutherford Cat 2-4) Complex lesions are defined: Long lesions ( 10 cm) Moderately or highly calcified lesions Chronic total occlusions (irrespective of length) A prospective, multicenter, 2:1 randomized (JS ath+ranger DCB : POBA+DCB), 250 subjects (~167 DCB+JS vs 83 POBA+DCB) Up to 25 study sites in US TLR at 1 year, TLR defined as: Retreatment of the index lesion (extended 1 cm prox and dist to the lesion) at 1 year. For the primary endpoint, intra-procedural bail out stenting of the index lesion is considered meeting a TLR endpoint MAE at 30 days Unplanned amputation Total mortality TLR (includes bailout stenting)

31 Ranger DCB BTK Investigator Sponsored Research Ranger BTK A safety and efficacy study to evaluate Ranger drug-eluting balloon for below the knee angioplasty in patients with critical limb ischemia Below the Knee Studies - DCB CRURAL DEB Randomized trial comparing drug coated balloon vs plain balloon angioplasty in critical limb ischemia and treatment of long lesions in crural arteries PI Marc Sapoval PI Torbjorn Fransson Design Prospective, single centre, noncontrolled, open-label Design Centres France Centres Sweden Population 30 patients Population 70 patients Primary Efficacy Endpoint Primary Safety Endpoint Primary patency (no stenosis >50%) and Late Lumen Loss (LLL) of the Target Lesion measured by Quantitative Vascular Angiography (QVA) at 6 months adjudicated by independent core lab Composite of all death and major amputation at 6 and 12 months Primary Efficacy Endpoint Secondary Endpoints Prospective, single centre, randomized 12 month primary patency TLR, Event Free Survival, MRA analysis

32 Conclusions The amount of clinical data surrounding PAD therapies is rapidly increasing Boston Scientific has a broad portfolio of clinical studies with the goal of advancing the evidence for various PAD treatment technologies Large Head-to-head randomized trials Complex lesions being studied Adjunctive therapies being studied Inclusion of more endpoints including cost effectiveness The future is exciting in the landscape for endovascular treatment for PAD, specifically in regards to Drug Elution technologies

33 IMPORTANT INFORMATION: These materials are intended to describe common clinical considerations and procedural steps for the on-label use of referenced technologies as well as current standards of care for certain conditions. Of course, patients and their medical circumstances vary, so the clinical considerations and procedural steps described may not be appropriate for every patient or case. As always, decisions surrounding patient care depend on the physician s professional judgment in light of all available information for the case at hand. BSC does not promote or encourage the use of its devices outside their approved labeling. The presenter s experience with BSC products may not be interpreted or relied upon to support clinical claims about BSC devices or product comparison claims regarding BSC and competitive devices. The experiences of other users may vary. Results from case studies are not predictive of results in other cases. Results in other cases may vary.

34 Getting to answers with clinical trials: Being bold Prof. Thomas Zeller Department Angiology University Heart-Center Freiburg - Bad Krozingen Bad Krozingen, Germany