BIOTRONIK - Safety and Clinical Performance of the Sirolimus-Eluting Resorbable Coronary Magnesium Scaffold System (DREAMS 3G) in the Treatment of Subjects with de Novo Lesions in Native Coronary Arteries: BIOMAG-I

Standard of care treatment of coronary artery disease with state of the art
drug-eluting stents (DES) delivers good clinical outcomes with low target
lesion failure (TLF) and stent thrombosis rates. Nevertheless the use of DES
presents some limitations, mainly due to the permanent presence of foreign
material in the vessel wall. In particular there is a long term risk of stent
failure, thrombosis, chronic inflammation due to the metal or polymer
components and neoatherosclerosis. Moreover the metal cage can impair the
vessel geometry, access and flow into side branches and can inhibit a normal
vasomotor function, which may hinder compensatory positive re-modelling and
limits use of imaging and future treatment options. Bioresorbable scaffolds
(BRS) were developed to overcome these problems, enabling vessel restoration
and reducing long term risks. BRS are meant to provide a temporary drug eluting
scaffold, which supports the vessel after implantation as long as needed,
limiting acute recoil and negative re-modelling, and enable a natural biologic
reconstruction of the arterial wall and restoration of the vascular function
once the scaffold is resorbed, which may also reduce the need of prolonged dual
antiplatelet therapy and the occurrence of related bleeding complications.
The ability of scaffolds to meet these expectations however have been partly
questioned by suboptimal results of the Absorb BVS (Abbott Vascular, Santa
Clara, CA) showing higher incidence of scaffold thrombosis and target
vessel-related myocardial infarction. Notably, while ABSORB BVS Bioresorbable
Vascular Scaffold (BVS) consists solely of a poly-L-lactic acid (PLLA) polymer
which resorbs over a period of more than 24 months, other scaffolds have
different materials and designs. In particular, the Magmaris (here after
refered to also as DREAMS 2G) (BIOTRONIK AG, Bülach, Switzerland) consist of a
magnesium alloy which resorbs in approximately 12 months. Data from clinical
trials thus far have demonstrated the clinical safety and performance of
Magmaris and have not shown the same safety concerns as Absorb. DREAMS 2G
gained CE-Mark in 2016 and is since then marketed as Magmaris.
Moreover, there are several indicators that Magmaris is less thrombogenic, e.g.
•In 30 patients assessed up to 6 months and 11 up to 12 months, no intraluminal
mass was detected by OCT. Furthermore, at 6 months, no malapposed struts were
detected because the struts were already embedded in the vessel wall
•DREAMS is laser polished, leading to a very smooth surface
•The strut cross section is rectangular with rounded edges, which might result
in better embedding into the vessel wall
•DREAMS does not require stepwise inflation as required for polymeric
scaffolds, which may result in better expansion and apposition
•A porcine arterio-venous shunt model compared the acute thrombogenicity of
DREAMS 2G, the ultrathin Orsiro DES that uses the same polymer/drug combination
as DREAMS 2G, and the ABSORB BVS scaffold. It demonstrated that DREAMS 2G had
significantly less (a) platelet adherence, (b) thrombus deposition, and (c)
inflammatory cell adhesion than the ABSORB BVS scaffold. Despite a greater
strut thickness of DREAMS 2G as compared to Orsiro, the findings were similar
in both devices with the exception of significantly less inflammatory cell
adhesion in DREAMS 2G.
•Similarly, a study in porcine and rabbit models showed an increased
endothelialization and decreased thrombus formation for DREAMS 2G compared to
Absorb. Inflammation for DREAMS 2G peaked at 90 days and decreased thereafter;
at one and two years, inflammation was lower for DREAMS 2G versus an
everolimus-eluting cobalt-chromium stent.
•In-vitro tests showed an improved deliverability of DREAMS 2G as compared to
the ABSORB BVS scaffold due to the metallic properties of DREAMS 2G, with less
bending stiffness despite higher radial strength, indicating a better vessel
conformability and no time dependent recoil of DREAMS 2G in contrast to ABSORB
BVS and DESolve, a novolimus-eluting bioresorbable coronary scaffold system.
So far, the clinical trial results have demonstrated very low adverse event
rates for Magmaris. While other bioresorbable scaffolds showed relatively high
rates of thrombosis, thrombosis rates were low across all Magmaris and
precursor studies and consistent with contemporary DES thrombosis rates.
Potential factors contributing to this difference in clinical outcomes, include
different scaffold design and materials, reduced thrombogenicity, as shown in
animal models, shorter resorption time, and the BIOlute* coating as that is
also used in the Orsiro Sirolimus Eluting Coronary Stent that has demonstrated
consistently low TLF rates in randomized clinical trials.
Despite these positive results, iterative improvement of Magmaris, to enhance
performance and usability led to the development of the next generation
scaffold, DREAMS 3G. This scaffold is built with a refined magnesium alloy and
enhances some scaffold properties, such as radial strength, scaffolding time
and marker visibility, broadens the size range and reduces crossing profile and
strut thickness. All of these changes are meant to improve the overall clinical
outcomes.
BIOTRONIK is proposing to evaluate the safety and performance of next
generation DREAMS 3G in a clinical trial program in a first in man study:
BIOMAG-I.
NOTE: Please kindly see the introduction section in the study protocol where
all Prior BIOTRONIK Bioresorbable Vascular Scaffold (BVS) Investigations and
other Manufacturers* prior investigations are presented.

Assessment of safety and clinical performance of the DREAMS 3G in de novo
coronary artery lesion in order to achieve and to obtain CE-approval

A prospective, multi-center, first-in-man trial.
Up to 115 subjects will be enrolled.
Clinical follow-up visits will take place at 1, 6, and 12 months and annually
thereafter until 60 months post procedure.
All subjects will undergo an angiographic follow-up at 6- and 12-month follow
up.
IVUS, (including IVUS-VH documentation) and OCT will be performed for all
subjects at 6-month and 12-month follow-up (if the safety of the subject allows
it and as per the investigator*s decision).
Vasomotion will be assessed angiographically with Acetylcholine followed by
Nitroglycerine at 12 months follow up in a subgroup of subjects, upon the
investigators discretion and if subject consents.

Percutaneous transluminal coronary angioplasty (PTCA) including concomitant
anticoagulation medication according to protocol and implantation of the DREAMS
3G scaffold

Risks
The risk assessment, bench testing and pre-clinical animal testing used to
support the safety of the DREAMS 3G are documented in the Investigators
Brochure.
As with any subjects undergoing percutaneous coronary intervention, subjects
may experience adverse events and/or outcomes that are listed in the IFU and do
not differ from other contemporary drug eluting stent implantation procedures.

Potential adverse events related to sirolimus (following oral administration)
include but are not limited to: Abnormal liver function, anemia, arthralgia,
diarrhea, hypercholesterolemia, hypersensitivity, including anaphylactic/
anaphylactoid type reactions, hypertriglyceridemia, hypokalemia, infections,
interstitial lung disease, leukopenia, lymphoma and other malignancies,
thrombocytopenia. Appropriate contraindications and warnings are included in
the IFU provided with the study device.
For all subjects, quantitative coronary angiography including IVUS and OCT will
be performed at 6 and 12 months follow-up. Coronary angiography, IVUS and OCT
are common medical tests. They rarely cause serious problems. However,
complications can occur and include, but are not limited to:
Bleeding, infection, pain at the catheter insertion site, damage to blood
vessels (including dissections), allergic reaction to contrast media or
medication.
Other, less common complications include: arrhythmias, kidney damage, blot
clots that can trigger a stroke, heart attack, or other serious problems, low
blood pressure, pericardial effusion
The vasomotion test involves an infusion of acetylcholine, which can provoke a
pathological narrowing of the vessel, which in turn may lead to chest pain,
reduced blood supply to the heart, cardiac arrhythmia or an occlusion of the
blood vessel. As the vasomotion test is performed during the coronary
angiography, these side effects are generally easily controlled.
Benefits:
Coronary stents have improved significantly the immediate and long-term results
of percutaneous coronary interventions. However, once the vessel has healed,
the scaffolding function of the stent is no longer needed, and the presence of
a permanent metallic stent poses important disadvantages.
One benefit of bioresorbable scaffolds is that the artery would not be
permanently caged and late positive remodeling in response to physiological
stimulus (restoration of vasomotion) would be possible. Persistent impairment
of endothelial vasomotor function after treatment has been associated with
adverse cardiovascular events at the long-term follow-up. Therefore, the
restoration of coronary vasomotion is essential after percutaneous coronary
intervention. In the BIOSOLVE II trial, angiographically discernible vasomotion
was documented after implantation of the Magmaris (DREAMS 2G) scaffolds in 80%
of the patients evaluated at 6 months.
The resorption of the scaffold would also allow future treatments in the
vessels if needed (either percutaneous or surgical) and would facilitate the
access to side branches initially jailed by the scaffold. Moreover it would
avoid that subjects have several metal layers in their arteries. The
resorbability of the scaffold also has important psychological implications.
Many patients are concerned about having a permanent implant in their coronary
arteries and would prefer a device that is able to disappear after a determined
time.
The implantation of a resorbable device may also facilitate non-invasive
imaging technologies, like CT or MRI, because they do not create any of the
artefacts originating from permanent metallic stents.
Permanent stents are associated with a certain risk of stent thrombosis and
in-stent restenosis. For bioresorbable scaffolds, the risks associated with
stent thrombosis and in-stent restenosis would theoretically be removed once
the scaffold has been fully degraded.
To determine its thrombogenicity, Magmaris was tested against the ABSORB in an
ex-vivo arteriovenous porcine shunt model. Despite a similar scaffold strut
thickness, the Magmaris scaffold was significantly less thrombogenic compared
with the ABSORB .
Similarly, a study in porcine and rabbit models showed an increased
endothelialization and decreased thrombus formation for DREAMS 2G compared to
ABSORB.
Clinical evidence from several trials associated the ABSORB BRS with an
elevated thrombosis risk compared to DES and its commercial distribution was
stopped. For Magmaris, no elevated thrombosis risk was identified in clinical
experience. No definite or probable scaffold thrombosis was reported in the
BIOSOLVE-II and BIOSOLVE-III studies up to 36 and 12 months, respectively. In
the BIOSOLVE-IV study, the definite/probable scaffold thrombosis rate was 0.5%,
whereby 4 of the 5 scaffold thrombosis cases were associated to early DAPT
interruption, in the full cohort up to 12 months which is comparable to DES.
For DREAMS 3G, the scaffold structure design was adapted and a Magnesium alloy
with increased mechanical strength was developed. Magnesium has superior
mechanical properties with its higher tensile strength and greater %
elongation-at-break compared with polymeric material. The Magnesium alloy used
in the Magmaris offers higher deformation resistance and lighter weight as
compared with pure Magnesium. The improved Magnesium alloy of DREAMS 3G
scaffold contains Aluminum to support the required material characteristics
regarding mechanical performance and resorption behavior. Accordingly, the
DREAMS 3G scaffold alloy has an increased mechanical strength compared to the
Magmaris alloy and provides a more uniform resorption. The improved scaffold
acute mechanical properties are expected to support treatment of complex
lesions with DREAMS 3G. In addition to higher mechanical strength, the improved
Mg alloy of DREAMS 3G will provide an increased scaffolding period. At the same
time, the Mg resorption period of 12 months is maintained. The increased
scaffolding period is expected to further improve chronic luminal outcome for
DREAMS 3G in comparison to Magmaris without compromising safety.
In comparison to Magmaris, the scaffold strut dimensions of DREAMS 3G were
further decreased to further reduce the risk of thrombosis. Compared to the 150
µm strut thickness of Magmaris, the strut thickness of DREAMS 3G is 117 µm for
scaffolds with a diameter of 3 and 3.5 mm. Additional sizes were added to the
device portfolio of DREAMS 3G. The increased size range of the DREAMS 3G
product portfolio will allow for treatment of smaller/larger vessels and
longer/shorter lesions in comparison to Magmaris. The new Ø 2.5 mm DREAMS 3G
scaffold has a strut thickness of 99 µm and the Ø 4 mm DREAMS 3G scaffold has a
strut thickness of 147 µm.
The polymeric scaffolds ABSORB and DESolve have a strut thickness of 150 µm and
a strut width of 190 µm and 165 µm, respectively. With a maximum strut
thickness of 147 µm and strut width of 150 µm, DREAMS 3G will have a lower
vessel coverage than the polymeric scaffolds.
The reduced scaffold strut dimensions will also contribute to improved
deliverability of the device. In terms of deliverability, DREAMS does not
require stepwise inflation as required for polymeric scaffolds. Which
contributes to a better scaffold expansion and apposition. To further improve
scaffold deliverability of DREAMS 3G, the profile of the crimped scaffold was
further reduced to support deployment in challenging vessel anatomy. In
preclinical testing, trackability/deliverability of DREAMS 3G was rated
excellent, same as the drug-eluting stent Orsiro.
To increase the scaffold marker x-ray visibility, the marker material density
and marker dimensions were increased compared to Magmaris. This will support
scaffold positioning and post-dilatation for DREAMS 3G.

Risk / Benefit Conclusion
Pre-clinical findings indicate that the Mg based scaffold is less thrombogenic,
provokes less inflammatory response and reduces formation of new
artherosclerosis when compared to other available scaffolds and DES which
eventually results in improved endothelial integrity. Available data on DREAMS
2G on more than 1000 subjects with a low rate of target lesion failure and
scaffold thrombosis further support these beneficial findings and show that the
device is safe and efficient when used according to the instructions of use.
The iterations of the device from DREAMS 2G to DREAMS 3G have addressed
potential disadvantages of DREAMS 2G while maintaining the characteristic
features that are thought to be responsible for the beneficial pre-clinical
and clinical findings. This FIM trial will provide further evidence of the safe
use of bioresorbable Mg based scaffolds in the treatment of coronary artery
lesions. The device will be used under controlled conditions and subjects will
be closely monitored. Every precaution has been taken to protect the health and
safety of the subjects.
Moreover, subjects will be closely monitored throughout the clinical
investigation duration. They will be evaluated at pre-determined time points to
assess their clinical status and follow-up angiographies (including additional
imaging by IVUS and OCT) will be performed to assess the status of both target
lesion and the scaffold.
An independent Data Monitoring Committee (DMC) will monitor safety throughout
the clinical investigation. Stopping rules will be discussed with the DMC and
applied for subject safety throughout enrollment.

Therefore we conclude that the benefits of the new DREAMS 3G device outweigh
the risks that are involved within this study.


NOTE: for a full risk - benefice information, please kindly see section 3.
RISK-BENEFIT-ANALYSIS of the study protocol