Success Factors of DCB, Technical
and Clinical Considerations.
Enrico Maria Marone, MD Associated Professor of Vascular Surgery
University of Pavia - Italy
San Raffaele Scientific Institute – Milano, Italy
• I, Enrico Maria Marone have the following
conflict of interest in the context of the
subject of this presentation:
- Biotronik (consultant)
- Cordis (consultant)
- Terumo (consultant)
Passeo-18 Balloon Catheter
Ø (mm) 2.0, 2.5, 3.0, 4.0,
5.0 mm
L (mm) :40, 80, 120
Balloon Platform
Improves ease of handling
Protects the user and balloon from contact and damage
SafeGuard Insertion Aid
Drug: paclitaxel (3.0 μg/mm2)
Excipient: butyryl-tri-hexyl citrate (BTHC)
Process: Micro-pipetting
Coating Technology
Passeo-18 Lux combines proven
technologies for treating lower limb arteries
Design of SafeGuard Insertion Aid
Distal end Raised Portion Crimped End
SafeGuard Insertion Aid
It is pre-mounted on the balloon and does not require any
preparation prior to use
Improves ease of handling and protects coating and
physician during device preparation.
Protects the user and coating from contact and damage
Reduces drug loss due to friction with the introducer sheath
valve by up to 94%
94%
*Passeo-18 Lux 4/120/130 with Cordis Avanti Plus 4F, 11 cm, w & w/o SafeGuard insertion aid
SafeGuard Insertion Aid Ease and Safety of Handling
– Rapid drug transfer into vessel
– Sustained therapeutic effect in local tissue while
remaining non-toxic
– Homogeneous drug coating (longitudinal,
circumferential, thickness)
– Homogeneous drug concentration throughout the
coating
– Minimal drug loss during tracking and inflation
– Balance between coating adhesion and drug transfer
Baseline considerations for the development of Passeo-18 Lux
Paclitaxel blocks the cell cycle directly
Paclitaxel inhibits the cell cycle directly vs. Limus drugs which act indirectly
DCB‘s aim for a high-dose effect of Paclitaxel, causing cell‘s mitotic arrest
A low-dose effect is expected to sustain antiproliferation long term
Mode of action for Paclitaxel and Limus drugs
– The excipient is used to balance coating
adhesion and drug release properties
– The excipient aims to ensure a micro-
crystalline Paclitaxel structure and make the
compound more absorbable to the tissue
– The excipient is designed to improve
effectiveness and time of drug retention in
the arterial tissue
Excipients play a key role in DCB
technologies
0
1000
2000
3000
1 hr 24 hrs 72 hrs
ng/
mg
Tissue Concentration
0
1000
2000
3000
4000
5 min 30 min 1 hr 3 hrs 24hrs
ng/
mL
Blood Concentration
5 min 30 min 1 hr 3 hrs 24 hrs
3346.7 11.0 6.2 2.4 0.4
712.8 7.6 5.1 3.4 1.8
Non-atherosclerotic Rabbit Iliac Model – 28 days
PTX + Iopromide
PTX Only PTX + Iopromide (SeQuent)
Excipients improve tissue uptake of
Paclitaxel
PTX only
Source: Virmani, presented at Linc 2012
Excipient Butyryl-Trihexyl Citrate (BTHC)
Common uses of BTHC
Used in medical devices & cosmetics
Additive in blood bags to keep the crystalline structure of the plastic malleable
Safe: it is approved to be dissolved into the blood and used in the body
Metabolism Quickly metabolized by the body and excreted via urine,
bile and expired air¹
Degrades to citric acid and alcohol (n-hexanol¹)
BTHC is hydrophobic and less dissolvable in blood and
saline/water used during interventional procedures
compared to other common hydrophilic excipients
1 European Commission SCENIHR Report Feb 2008
Lux coating technology uses BTHC as excipient Biocompatible, safe and effective
Characteristics
BTHC improves coating integrity and
durability
Coating characteristics are
modified when surface is
wettened
Hydrophilic excipients are
more soluble and degrade
faster
Hydrophobic excipients
improve coating integrity
ensuring more drug is
available at the lesion site
Device Excipient Type Solubility*
Passeo-18 Lux Butyryl-trihexyl citrate (BTHC) Hydrophobic Very low
Lutonix Polysorbate/sorbitol Hydrophilic/
hydrophobic Fast dissolving
In.Pact Urea Hydrophilic Fast dissolving
*In water
**Data on file at BIOTRONIK (IIB Test)
50.0%
75.0%
100.0%
Passeo-18 Lux Lutonix 035
% o
f to
tal d
rug
load
Coating Integrity* After submerging and deployment of a 5x40mm
balloon in physiological solution at 37ºC
50.0%
75.0%
100.0%
Passeo-18 Lux In.Pact Admiral
% o
f to
tal d
rug
load
Coating Integrity* After submerging and deployment of a 5x40mm
balloon in physiological solution at 37ºC
Passeo-18 Lux delivers sufficient drug to
give long lasting therapeutic effect
A high tissue concentration is achieved after balloon inflation Drug concentration rapidly declines within 7d Therapeutic effect is sustained beyond 28d Prolonged presence of drug in vessel tissue is important for
clinical efficacy SFA Porcine model
Lux coating technology achieves uniform
drug distribution to the vessel wall
3D-surface plot of fluorescence intensity
Drug distribution in target arterial tissue in rabbit iliac model
PTX, DAPI, max intensity z-projection at 400x Whole sample scan of fluorescently labeled Paclitaxel in a rabbit iliac artery
PASSEO-18 LUX CLINICAL TRIAL
PROGRAM
Study Device(s) Indication Design Primary
Endpoint PI(s)
Passeo-18 Lux
vs. Passeo-18 SFA
EU Multicenter FIM RCT
(60 pts/5 sites) LLL @6m D. Scheinert
Passeo-18 Lux
vs. Passeo-18 BTK
EU Multicenter FIM RCT
(72 pts/6 sites)
MAE@1m
PP@6m T. Zeller
Passeo-18 Lux
Infrainguinal
Arteries
Global Multicenter All-comers
Registry
(min. 700 pts/55 sites)
MAE@6m
FTLR@12m G. Tepe
Passeo-18 Lux
+ Pulsar-18 SFA
EU Multicenter Single-arm trial
(120 pts/5 sites) PP@12m M. Bosiers
Passeo-18 Lux
vs. PTA
AV Fistula
Access
Canadian Multicenter RCT
(120 pts/4 sites) LLL@6m E. Terasse
Passeo-18 Lux
+ Pulsar-18 SFA
Australian Single-arm trial
(100 pts)
PP@12m
PP@24m P. Mwipatayi
Passeo-18 Lux In-stent
restenosis
Australian Retrospective
registries
(35* pts / 29° pts)
PP, FTLR, MAE
@6m
P. Myers*
D. Robertson°
*Investigator-Initiated Trials
*
*
*
*
BIOLUX P-I:
PASSEO-18 LUX DCB PROVEN IN THE SFA
60 patients
DCB Passeo-18 Lux
N=30
POBA Passeo-18
N=30
12 mo FUP N=25
12 mo FUP N=26
1:1
6 mo FUP LLL 0.51 ± 0.72 mm
BR 11.5%
6 mo FUP LLL 1.04 ± 1.00 mm
BR 34.6%
Study Design
DESIGN:
Prospective, multicenter, 1:1 randomized controlled trial for
treatment of femoro-popliteal arteries.
PRINCIPAL INVESTIGATOR:
Prof. D. Scheinert, Leipzig, Germany
PRIMARY ENDPOINT:
6 mo LLL in TL measured by QVA1
SECONDARY ENDPOINTS:
6 mo Binary Restenosis
6 mo and 12 mo TLR
6 mo and 12 mo change in mean ABI and RC
6 mo and 12 mo MAE2
BIOLUX P-I 12 Months Results: Scheinert D. presented at TCT 2013
p= 0.033* p= 0.048*
1 Assessed by an independent core laboratory using Quantitative
Vascular Angiography (QVA)
2MAE = procedure or device-related death or amputation, TL
thrombosis, clinically driven TLR
p* < 0.05 significant
6 MONTHS ANGIOGRAPHIC RESULTS EVALUATED BY AN INDEPENDENT CORE LABORATORY
Variable DCB
N=30
POBA
N=30 p-value*
Reference Vessel Diameter [mm] 4.4 ± 0.8 4.8 ± 0.9 0.144
In Segment DS [%] 36.5 ± 18.5 47.5 ± 20.8 0.048*
In Segment Late Loss [mm] 0.5 ± 0.7 1.0 ± 1.0 0.033*
In Segment Binary Restenosis 3 11.5% 9 34.6% 0.048*
Thrombus 0 0% 1 3.8% 1.000
p* < 0.05 significant
12 MONTHS CLINICAL OUTCOMES ADJUDICATED BY AN INDEPENDENT CLINICAL EVENTS COMMITTEE
Ankle Brachial Index
DCB
N=25
POBA
N=26 p-Value*
Kaplan-Meier Estimates
Freedom from clinically driven TLR (As-Treated Population) 84.0% 47.1% 0.020*
Freedom from amputation 96.2% 96.0% 0.954
Freedom from Target Lesion Thrombosis 100.0% 100.0% 1.000
Freedom from procedure or device related death 100.0% 100.0% 1.000
Major Adverse Event Rate
(hierachical, adjudicated by an independent Clinical Events
Committee)
80.8% 58.8% 0.140
Improvement in Rutherford Classification 17 72.0% 15 65.2% -
BIOLUX P-I 12 Months Results: Zeller T. presented at EuroPCR 2013
p* < 0.05 significant
CLINICAL CONCLUSIONS
In the ‘as treated’ population at 12 months, Passeo-18 Lux demonstrated significant improvement in freedom from TLR of 84.0% vs. 47.1% in the POBA group.
More patients improved in Rutherford Classification in the DCB group than in the control group with 72.0% vs. 65.2%.
Passeo-18 Lux demonstrated a significant reduction in late luminal loss and binary restenosis at 6 months compared to the control PTA balloon
Late loss was 0.51 ± 0.72 mm and 1.04 ± 1.00 mm in the
Passeo-18 Lux and Control group respectively (p= 0.033*)
Binary restenosis was 11.5% in the study group vs. 34.6% in the control group (p= 0.048*)
p* < 0.05 significant
BIOLUX P-II STUDY
PASSEO-18 LUX IN BTK ARTERIES
72 patients with symptomatic PAOD or CLI (Rutherford 2-5)
DCB Passeo-18 Lux
N=36
POBA Passeo-18
N=36
FUP N=30 Withdrawals N=3
Early Termination N= 3 (Death N= 2,
Amputation N= 1)
6-mo FUP
FUP N=33 Withdrawals N=0
Early Termination N= 3 (Death N= 1,
Amputation N= 2)
1:1
1 MAE = all cause death, major amputation of target extremity, TLR ,
TVR, target lesion thrombosis, adjudicated by an independent
Clinical Events Committee
2 Assessed by an independent core laboratory via Quantitative
Vascular Angiography (QVA) 12 mo Clinical FUP
FUP N=35 Withdrawals N=1
Early Termination N=0 (Death N= 0, Amputation
N= 0)
FUP N=35 Withdrawals N=0
Early Termination N= 1 (Death N= 0,
Amputation N= 1)
30 days FUP
DESIGN:
Prospective, international, multicenter, 1:1 RCT
DCB vs. POBA, for the treatment of stenosis and
occlusion of the infrapopliteal arteries.
PRINCIPAL INVESTIGATOR:
Prof. T. Zeller, Bad Krozingen (DE)
PRIMARY ENDPOINT:
30 Days Major Adverse Event1 (MAE) rate
6-month patency in target lesion measured by
Quantitative Vascular Angiography (QVA).
SECONDARY ENDPOINTS:
Device, technical and procedural success.
TLR at 6 and 12 mo.
Change in ABI and Rutherford Class at 1, 6, 12 mo.
BIOLUX P-II: Brodmann M. presented at LINC 2014
Evaluated by an
independent core
laboratory
DCB
N=50
POBA
N=54
p-value*
Lesion location
Anterior Tibial Artery 24 48.0% 25 46.3%
0.693
Posterior Tibial Artery 11 22.0% 12 22.2%
Peroneal Artery 7 14.0% 11 20.4%
Tibioperoneal Trunk 5 10.0% 2 3.7%
Other 3 6.0% 4 7.4%
Calcification
None 19 38.0% 31 57.4% 0.018*
Mild 6 12.0% 4 7.4% 0.501
Moderate 1 2.0% 0 0.0% 0.472
Moderately severe 3 6.0% 1 1.9% 0.338
Severe 5 10.0% 2 3.7% 0.243
N/A 16 32.0% 16 29.6%
DCB POBA
Mean # lesions
per patient 1.4 ± 0.6 1.5 ± 0.6
p=0.334
p=0.317
p=1.000
BIOLUX P-II: Brodmann M Presented at LINC 2014
p* < 0.05 significant
LESION/PROCEDURAL CHARACTERISTICS EVALUATED BY AN INDEPENDENT CORE LABORATORY
Death Major
Amputation TLR TVR
TL
Thrombosis
DCB (%) 0.0% 0.0% 0.0% 0.0% 0.0%
POBA (%)
[CI] 0.0%
2.8%
[0.4-18.1]
5.6%
[1.4-20.7]
5.6%
[1.4-20.7] 0.0%
p-value - 1.000 0.493 0.493 -
p* < 0.05 significant
BIOLUX P-II: Brodmann M Presented at LINC 2014
MAJOR ADVERSE EVENTS AT 30 DAYS ADJUDICATED BY AN INDEPENDENT CLINICAL EVENTS COMMITTEE
Time to Event (days)
POBA 8.3% [2.8 – 23.7]
DCB 0.0% [0.0 – 0.0] 0%
10%
20%
30%
40%
50%
0 30
MAE (%)
p-value : 0.239
(Fisher‘s exact)
p-value : 0.239 (Fisher‘s Exact)
BIOLUX P-II: Brodmann M Presented at LINC 2014
0.0%
20%
40%
60%
80%
100%
Time to Event (days)
0 30 60 90 120 150 180
POBA 75.9% [61.4 – 85.6]
DEB 82.4% [66.5 – 91.2]
p-value : 0.452
(Log Rank)
TL PRIMARY PATENCY AT 6 MONTHS EVALUATED BY AN INDEPENDENT CORE LABORATORY
p* < 0.05 significant
RUTHERFORD CHANGE SHOWS SIGNIFICANT
IMPROVEMENT IN CLASS 5 PATIENTS TREATED
WITH PASSEO-18 LUX
POBA at 6 M: Improvement: 47%
Worsening: 6%
DCB 6 MONTH FUP
BASELINE 0 1 2 3 4 5 NAV
0 - - - - - - -
1 - - - - - - -
2 - 1 - - - - -
3 3 - 1 1 - - 2
4 1 - - - 1 - -
5 8 - - 2 - 9 7
NAV
POBA 6 MONTH FUP
BASELINE 0 1 2 3 4 5 NAV
0 - - - - - - -
1 - - - - - - -
2 - 2 - - - 1 -
3 2 2 - 1 - - -
4 1 - - - - 1 -
5 8 - - - - 14 4
NAV
0 01
7
2
26
12
1 13
1
9
0
5
10
15
20
25
30
0 1 2 3 4 5
Base
6M FUP
0 0
3
5
2
26
11
4
01
0
16
0
5
10
15
20
25
30
0 1 2 3 4 5
Base
6M FUP
p=0.001*
p=0.001*
p* < 0.05 significant
p=0.046* p=0.046*
p=0.001*
DCB at 6 M: Improvement: 59%
Worsening: 0% p=0.002*
MAJOR AMPUTATIONS AT 12 MONTHS ADJUDICATED BY AN INDEPENDENT CLINICAL EVENTS COMMITTEE
POBA 5.7% [1.5 – 21.0]
DCB 3.3% [0.5 – 21.4] p-value : 0.655
(log-rank)
Time to Event (days)
0%
10%
20%
30%
40%
50%
0 30 180
p* < 0.05 significant
365
No additional amputations after 180 days
At 30 days clinical results show MAE composite of 0.0% for the Passeo 18
Lux vs. 8.3% compared to the control PTA balloon (p=0.239).
At 6 months angiographic follow-up, Passeo-18 Lux DEB demonstrated a
target lesion primary patency of 82.4% vs. 75.9% compared to the control
PTA balloon (p=0.452).
At 6 months, 59% of patients improved in Rutherford Classification in the
DEB group vs. 47% in the control group. No patients worsened in the DEB
group, vs. 6% in the POBA group.
Improvement of Rutherford Class 5 patients at 6 months was significant in
the DEB group (p=0.002*) compared to the POBA group.
The Passeo 18 LUX is safe – demonstrated in a low amputation rate and
no additional amputations beyond 180 days
CONCLUSIONS
p* < 0.05 significant
BIOLUX P-III: ‘REAL’ ALL-COMERS REGISTRY CLINICALTRIALS.GOV: NCT02276313
DESIGN: Prospective, international, multi-centre, open label, all-comers registry to expand and understand the safety and efficacy data on the Passeo-18 Lux DCB in a real world population of subjects with obstructive disease of the infrainguinal arteries.
PRINCIPAL INVESTIGATOR: Prof. G. Tepe, Klinikum Rosenheim, Germany PRIMARY ENDPOINTS: Clinical: Major Adverse Events (MAE) at 6 months Performance: Freedom from clinically-driven TLR at 12 months DEDICATED SUBGROUPS: Diabetes; Renal Insufficiency, TASC C&D lesions; Heavily calcified lesions; Rutherford 3+; 65 yrs+.
>700 subjects with de novo or restenotic
lesions in the infrainguinal arteries
55 sites world-wide
12 months: freedom from C-TLR,
primary patency, MAE, change in ABI,
RC, Amputation-free survival, QoL
6 months: MAE, change in ABI, RC,
Amputation-free survival, QoL
Passeo-18 Lux
24 months: freedom from C-TLR,
primary patency, MAE, change in ABI,
RC, Amputation-free survival, QoL
Principal Investigator: Prof. Patrice Mwipatayi, Perth Australia Study Design: Prospective, multicentre feasibility study investigating safety and efficacy of BMS + DCB in SFA TASC C/D lesions. N=65 enrolled (51pts reached 24m f/u) Study Devices: Pulsar-18 SE stent (full segment coverage), followed immediately by Passeo-18 Lux DCB (full segment coverage) Primary Endpoint: Primary Patency (PP) at 12 and 24 months. Defined as an increase in the PSVR ≥ 2.5 with no clinically driven re-intervention at the stented segment ± within 5mm of each side of the stented area
24m Results Primary Patency (51pts) PARAMETER N (%) RANGE
Total Lesion Length
(mm) 187.55 80-300
Calcification
Minimal 31.4 --
Moderate 43.1 --
Severe 23.5 --
No. of Stents 1.57 1-3
No. of DEBs 2.45 1-5
Source: Mwipatayi P. Presented at LINC 2015
DEBAS
12m: 99.2%
24m: 88.2%
BIOLUX 4EVER study Investigate Passeo-18 Lux DCB combined with Pulsar SE stent
DESIGN: Multicentre, international registry of 120 patients to evaluate the short- and long-term (up to 24 months) outcome of treatment with Passeo-18 Lux drug-coated balloon and Pulsar-18 stent implantation in symptomatic (RC 2-4) fem-pop arterial lesions.
PRINCIPAL INVESTIGATOR: Dr M. Bosiers, Dendermonde, Belgium
PRIMARY ENDPOINT: Primary patency at 12 months, (freedom from >50% restenosis as indicated by an independently verified PSVR <2.5 in the target vessel with no re-intervention)
SECONDARY ENDPOINTS: (selected) Primary patency rate at 6- & 24-month follow-up, Freedom from TLR at 1-, 6-, 12- & 24-month follow-up Technical Success Puncture Site Complications Clinical success at follow-up (improvement of RC)
120 patients in c.6 clinical sites in Europe 37% enrolled
12 months: PP, FTLR, change in ABI, RC
6 months: PP, FTLR, change in ABI, RC
Passeo-18 Lux + Pulsar
24 months: PP, FTLR, change in ABI, RC
Lux coating technology
Summary:
– The Lux coating formulation and process have been optimized to ensure sufficient
drug is delivered to the target lesion site
– The Lux technology achieves homogeneous drug concentration to the vessel wall
– Lux coating is safe and clinically proven to reduce restenosis in both coronary and
peripheral arteries
