ILLUMENATE European Randomized Clinical Trial: Prof. Dr. Marianne Brodmann 12-Month Final Results for the Stellarex DCB Division of Angiology, Medical University Graz, Austria On behalf of Dr. Henrik Schröder Jewish Hospital, Berlin, Germany
Disclosures • Consulting/Honoraria for – Medtronic – BARD – Spectranetics – Intact Vascular – Avinger – Soundbite Medical – Rexgenero – Biotronik – Bayer – Daiichi – Böhringer Ingelheim – Astra Zeneca
ILLUMENATE EU RCT Overview Stellarex DCB vs. PTA Prospective, randomized, multi-center, trial Patients will be followed for up to 5 years Rigorous data collection process, independent adjudication by: • Angiographic Core Laboratory1 • Duplex Ultrasound Core Laboratory2 • Clinical Events Committee • Data Safety Monitoring Board Monitoring with 100% source data verification 1.SynvaCore, Springfiedld, IL 2.VasCore, Boston, MA
ILLUMENATE EU RCT Investigators Dr. Henrik Schroeder :Jewish Hospital, Berlin National Principal Investigator Prof. Marianne Brodmann: LKH University Hospital Graz Dr. Beata Lux: St Joseph Hospital, Berlin Prof. Peter Reimer:Clinical Center, Karlsruhe Dr. Dirk-Roelfs Meyer: Lutheran Hospital Hubertus, Berlin Prof. Markus Duex: Hospital Nordwest GmbH, Frankfurt a. Main Dr. Karsten Krueger: Vivantes Humboldt Hospital, Berlin Dr. Goetz Voshage: Robert Koch Clinical Center, Gehrden Dr. Karsten Krueger: Vivantes Clinic Spandau, Berlin Prof. Giovanni Torsello: Saint Francis Hospital GmbH, Münster Dr. Volker Sesselmann: SHR Central Clinic, Suhl Prof. Gunnar Tepe: RoMed Hospital, Rosenheim Prof. Martin Zwaan: Ammerland-Clinic GmbH, Westerstede Prof. Claus Nolte-Ernsting: Lutheran Hospital, Mülheim Prof. Thomas Albrecht: Vivantes Clinic Neukölln, Berlin Prof. Christian Loewe: University Hospital, Vienna Prof. Roman Fischbach: Altona-Asklepios Clinic, Hamburg Dr. Martin Werner: Hanusch Hospital of WGKK Group, Vienna
Objective and Primary Endpoints ILLUMENATE EU RCT Objective: Demonstrate safety and efficacy of the Stellarex DCB vs. standard PTA for treatment of arterial disease in the SFA and/or popliteal arteries Primary Safety Endpoint: Freedom from device- and procedure- related death through 30 days and freedom from target limb major amputation and clinically-driven TLR through 12 months Primary Efficacy Endpoint: Primary patency at 12 months, defined as freedom from restenosis (determined by duplex ultrasound PSVR ≤ 2.5) and freedom from clinically-driven TLR at 12 months
Study Device: StellarexTM DCB (Spectranetics) CAUTION: Investigational device. Not for sale or distribution in the United States. EnduraCoatTM technology: • Low dose paclitaxel, 2 µg/mm2 • Excipient: Polyethylene Glycol (PEG) • Proprietary open-folded coating technology Balloon catheter features: • Catheter shaft designed for pushability • Low 0.039” tip entry profile • Flexible balloon and tip for tracking through tortuous anatomy
Key Eligibility Criteria ILLUMENATE EU RCT Inclusion Criteria • Rutherford class 2, 3 or 4 • Lesion(s) located in the SFA and/or popliteal • Has at least one patent run-off below-the-knee • 1 or 2 target lesion(s) with cumulative length 3-20 cm • Target vessel reference diameter 4-6 mm Exclusion Criteria • Acute or sub-acute thrombus in target vessel • Significant inflow disease • In-stent restenosis • Severe calcification that precludes adequate PTA treatment • Use of adjunctive therapies (i.e. atherectomy or cutting/scoring balloons)
ILLUMENATE EU RCT Trial Design Patient Eligible & Consented Pre-dilatation N=328 Stent required (N=33) (BMS + Stellarex) Stent not required (N=295) Randomization (3:1) Stellarex DCB (N=222) PTA (N=72) Provisional stenting as required Post-dilatation as required Provisional stenting as required Post-dilatation as required 1 patient treated w/ DCB, but not randomized is excluded from the analyses 12 Month Follow-up Compliance: 97% 12 Month Follow-up: Compliance:100%
Baseline Patient Characteristics ILLUMENATE EU RCT ITT data set Stellarex PTA p Age (years) 66.8 ± 9.2 (222) 69.0 ± 8.6 (72) 0.079 Male 72.1% (160/222) 68.1% (49/72) 0.514 Rutherford Clinical Category 0.525 2 15.4% (34/221) 21.1% (15/71) 3 82.8% (183/221) 77.5% (55/71) 4 1.8% (4/221) 1.4% (1/71) Diabetes 37.4% (83/222) 36.1% (26/72) 0.846 Hypertension 77.9% (173/222) 83.3% (60/72) 0.326 Hyperlipidemia 61.7% (137/222) 68.1% (49/72) 0.332 Smoking Status 0.188 Never Smoked 10.8% (24/222) 16.7% (12/72) Previous or Current 89.2% (198/222) 83.3% (60/72) ABI 0.72 ± 0.21 (212) 0.69 ± 0.26 (68) 0.250
Baseline Angiographic Data ILLUMENATE EU RCT ITT Data Set: Per Core Lab Stellarex PTA p Lesion Length (cm)1 7.2± 5.2 (250) 7.1 ± 5.3 (79) 0.878 Lesion Type De Novo Restenotic 92.1% (234/254) 7.9% (20/254) 89.9% (71/79) 10.1% (8/79) 0.529 Total Occlusion 19.2% (48/250) 19.0% (15/79) 0.967 Calcification None/Mild Moderate Severe 55.8% (140/251) 31.5% (79/251) 12.7% (32/251) 59.5% (47/79) 30.4% (24/79) 10.1% (8/79) 0.775 Diameter Stenosis (%) 78.7 ± 16.0 (250) 80.8 ± 15.7 (79) 0.297 Reference Vessel Diameter (mm) 5.02 ± 0.79 (250) 4.77 ± 0.69 (79) 0.012 # of Patent Run-off Vessels 0 1 2 3 8.5% (18/211) 19.0% (40/211) 32.2% (68/211) 40.3% (85/211) 5.9% (4/68) 13.2% (9/68) 45.6% (31/68) 35.3% (24/68) 0.229
Procedural Characteristics ILLUMENATE EU RCT ITT data set Stellarex PTA p Pre-dilatation Performed1 100% (254/254) 98.7% (78/79) 0.237 Post-DCB/PTA Dissection Grades Grade A-C Grade D-F 61.1% (151/247) 1.2% (3/247) 74.0% (57/77) 0.0% (0/77) 0.095 Flow-limiting Dissection 0.4% (1/247) 0.0% (0/77) 1.000 Bail-out Stent Placement1 15.4% (39/254) 11.4% (9/79) 0.381 Post-procedure Diameter Stenosis (%) 23.6 ± 11.4 (251) 23.1 ± 10.3 (78) 0.724 1. Site-reported data
Primary Safety Endpoint Met ILLUMENATE EU RCT As-Treated Data Set 1. Composite of freedom from device and procedure-related death through 30 days & freedom from target limb major amputation & CD-TLR through 395 days. Per subject, as adjudicated by the CEC. 2. Numbers are % (n/N) [Events]- Denominator includes subjects with an event or those without an event having follow-up on or past the opening of the visit window. 3. Non-inferiority was evaluated from the 95% confidence limits based on the exact Farrington-Manning Score statistic. The non – inferiority margin of 5% was met. As pre-specified, superiority was subsequently assessed and achieved as the lower 95% confidence bound was greater than 0%. Superiority Endpoint Achieved Primary Safety Endpoint1,2 Stellarex PTA Difference [95% CI] Superiority Endpoint3 As-Treated Data Set 94.1% (193/205) [90.0, 96.9] 83.3% (50/60) [71.5, 91.7] 10.8% [0.9%, 23.0%] Met ITT Data Set (Secondary Analysis) 94.1% (193/205) [90.0, 96.9] 83.3% (50/60) [71.5, 91.7] 10.8% [0.9%, 23.0%] Met
Key Safety Outcomes ILLUMENATE EU RCT As-Treated Data Set Stellarex PTA P2 12-Month MAEs1 6.8% (14/207) [20] 18.0% (11/61) [12] 0.008 Cardiovascular Death 1.0% (2/206) [3] 1.6% (1/61) [1] 0.542 Target Limb Amputation 0.5% (1/204) [1]3 0.0% (0/60) [0] >0.999 Clinically-Driven TLR 5.9% (12/205) [16] 16.7% (10/60) [11] 0.014 12-Month All-Cause Mortality 1.4% (3/207) 1.6% (1/61) >0.999 1. Numbers are % (n/N) [Events]- Denominator includes subjects with an event or those without an event having follow-up on or past the opening of the visit window. 2. Descriptive, post-hoc analyses; Hypothesis testing was not pre-specified. P-values presented are not adjusted for multiple testing. 3. Minor amputation (toe) on day 354, not device- or procedure-related per CEC
Primary Efficacy Endpoint Met ILLUMENATE EU RCT Stellarex PTA Difference [95% CI] P-value Primary Patency at 12 months1 ITT Data Set 83.9% (188/224) [78.5, 88.5] 60.6% (40/66) [47.8, 72.4] 23.3% [10.6%, 36.1%] P<0.001 As-Treated Data Set 83.9% (188/224) [78.5, 88.5] 61.5% (40/65) [48.6, 73.3] 22.4% [9.6%, 35.2%] P<0.001 2. The patency rate in the DCB arm exceeded that observed in the PTA arm and with the two-sided chi-square test p-value less than 0.05, superiority of the primary efficacy endpoint is claimed at the 1-sided alpha level 0.025. 1. Primary patency is defined as freedom from restenosis (determined by duplex ultrasound PSVR ≤ 2.5) and freedom from clinically-driven TLR at 12 months (through day 395). Superiority Endpoint Achieved
Primary Patency at 12 Months: 89.0% ILLUMENATE EU RCT ITT Data Set P<0.001 by log-rank test 65.0% @ day 365 Primary patency is defined as freedom from restenosis (determined by duplex ultrasound PSVR threshold of 2.5) and freedom from clinically-driven TLR at 12 months. Assessed per lesion. KM estimates reported at day 395 to capture all patients and events within the full (and legitimate) 335-395 follow-up window. Rates from the middle of the protocol visit window (365 days) reported for consistency and comparative purposes with other trials. 83.4% @ day 395 89.0% @ day 365 61.2% @ day 395
CD-TLR1 Free at 12 Months: 94.8% ILLUMENATE EU RCT ITT3 Data Set 1. Clinically-driven TLR defined as reintervention due to PSVR≥2.5 (or >50% stenosis via angio) due to an increase in the RCC >1 category or deterioration in the ABI by >0.15 compared to maximum early post-procedural level. Per subject analysis. 2. Descriptive, post-hoc analyses; Hypothesis testing was not pre-specified. Log-rank p-value is post-hoc. 3. As-treated data set is considered the primary data set for the endpoint 85.3% @ day 365 P=0.010 by log-rank test2 83.1% @ day 395 94.8% @ day 365 94.1% @ day 395
Key Secondary Endpoints ILLUMENATE EU RCT ITT Data Set Percent of Subjects with Improvements at 12 Months vs. Baseline Similar outcomes at 12 months, with almost 3x greater rate of reintervention in the PTA arm.1 1. CD-TLR rate in the Stellarex arm = 5.9% vs. 16.7% in the PTA arm 2. Data derived from 6 minute walk test outcomes and treadmill test outcomes combined
89.0% 89.5% 86.5% ILLUMENATE EU RCT N=222 ILLUMENATE FIH N=50 ILLUMENATE Global Interim Data N=220 Consistent Patency Rates Observed across 3 separate studies with Stellarex Kaplan-Meier estimates at day 365 shown 1. H. Schroeder et al. Catheter Cardiovasc Interv. 86:278-286 (2015). 2. P. Krishnan oral presentation. NCVH, New Orleans, June 2016. CAUTION: Stellarex is an Investigational Device 2 1
89.0% 65.0% 89.8% 66.8% 73.5% 56.8% Stellarex 2 µg/mm PTA IN.PACT Admiral 3.5 µg/mm PTA Lutonix 2 µg/mm PTA Data in Context with Core Lab* Adjudicated 12-Month Patency Rates ILLUMENATE EU-RCT IN.PACT SFA1 LEVANT 2 2 1. Tepe G. Oral presentation . Charing Cross. April 5–8, 2014. London, UK, 2014. 2. Rosenfield K, et al. NEJM 2015;373:145-53. Data overview for informational purposes only and not for head-to head comparison. *VasCore (Boston, MA); PSVR: 2.5, KM estimates at day 365 (360 for IN.PACT SFA) CAUTION: Stellarex is an Investigational Device 2 2 2
5.9% 16.7% 2.4% 20.6% 12.3% 16.8% Stellarex 2µg/mm PTA IN.PACT Admiral 3.5 µg/mm PTA Lutonix 2µg/mm PTA Data in Context: Clinically-Driven TLR at 12 Months ILLUMENATE EU-RCT IN.PACT SFA1 LEVANT 22 1. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation. 2015;131(5):495-502 2. Rosenfield K, Jaff MR, White CJ et al. NEJM 2015;373:145-53. Data overview for informational purposes only and not for head-to head comparison CAUTION: Stellarex is an Investigational Device 2 2 2 * * * only includes data through day 360, other studies report data through full follow-up window (day 395)
Conclusions • This robust randomized study confirms First-in- Human study results • Primary safety and efficacy endpoints met and superiority was demonstrated • Stellarex is a low-dose DCB with consistently positive results – Primary Patency= 89.0% at day 365 – Freedom from CD-TLR= 94.8% at day 365 • ILLUMENATE Pivotal Data will be released Fall 2016
