Prospective, multicenter study to evaluate the Safety and performance of a syntHetic tissue sealant in reducing fluid lEakage following elective hepatobiLiary anD pancreatic Surgery

During and after Hepato-Pancreato-Biliary (HPB) surgery, surface related
complications can occur such as leakage of bile and pancreatic juices and
bleeding (Koyabashi 2016; De Boer 2012). During surgery, uncontrolled bleeding
is one of the major complications that can influence both the surgeon*s ability
to succeed in the surgery and the patient*s recovery (Schuhmacher 2015). Major
complications post-operatively are leaking of bile and pancreatic juices into
the abdominal cavity, which are directly related to other morbidities and
mortality causing enlarged health care need. In the clinical field, the most
important complications associated with HPB surgery are considered to be
post-operative pancreatic juice leakage in pancreas surgery, post-operative
bile leakage in liver surgery and intra-operative bleeding in liver surgery
(Koch 2011; Koyabashi 2016). The most optimal management for treatment of bile
leakage and bleeding associated with HPB surgery is still not defined (Fischer
2011).

Bile leakage can be classified into 3 grades (grade A or biochemical leak,
grade B and grade C) depending on treatment requirement of the defect (Koch
2011). A bile leakage is defined as clinically relevant by Koch et al. if the
bilirubin levels in the drained fluid is 3 times higher than the baseline in
serum. Biochemical leak, previously known as grade A bile leakage, causes no
change in patients* clinical management, while Grade B and C require
respectively active therapeutic intervention or bile leakage relaparotomy (Koch
2011).
Pancreatic juices leakage is described and graded by Bassi et al. (2017). Their
definition of clinically relevant pancreatic leakage is *a drain output of any
measurable volume of fluid with an amylase level >3 times the upper limit of
institutional normal serum amylase activity, associated with a clinically
relevant development/condition related directly to the postoperative pancreatic
fistula* and graded into biochemical leaks and Grade B and C pancreatic
fistula*s, in which Grade B and C fistula*s require medical intervention (Bassi
2017). Bile or pancreatic leakage is currently mostly aimed to be prevented by
administration of a sealant to the defect (Koyabashi 2016). Known fibrin
sealants are considered ineffective as of the interference of the leaking
fluids with the sealant components (i.e. ineffective sealing caused by
breakdown of the sealant and/or ineffective tissue adherence) (Figueras 2007).
The interference of the leaking fluids with the hemostatic agents may lead to
ineffective control of possible post-operative bleeding after placement
(Schuhmacher 2015; Figueras 2007).

The solution would be a device to be placed on the wound surface of the liver
or pancreas that prevents leakage of fluids (e.g. bile, pancreatic juices,
blood) into the abdominal cavity. It should therefore withstand the
interference of bile and pancreatic fluids that exits the damaged fluid
channels in and around the liver and the resected surface of the pancreas. In
this way minimal-moderate post-operative bleedings can be controlled as well.
Polyganics has therefore developed the Sealing Device: a bioresorbable device
that can reduce the leakage of fluids into the abdominal cavity after liver
surgery and control minimal-moderate bleeding after HPB surgery. The primary
mode of action of this device is the reduction of leakage of fluids from the
site of surgery into the abdominal cavity after surgery. In addition, the
product controls minimal to moderate bleeding after application. Target group
for this device are currently patients scheduled for HPB surgery, which is
represented by elective liver and pancreas surgery. The device should at least
provide support during the critical wound healing period (up to 10 days after
surgery).

Polyganics BV (Groningen, The Netherlands) , in close collaboration with
University Hospital-Eppendorf (UKE) Hamburg, has developed the Sealing Device
for use in hepato-pancreato-bilary (HPB) surgery to reduce leakage of fluids
from the site of surgery into the abdominal cavity and as an adjunctive
hemostatic device to control minimal to moderate bleeding at the surgical site.
The Sealing Device has been challenged in pre-clinical testing (laboratory and
in-vivo work), but has not been evaluated for safety and performance in humans.

This investigation will be conducted to clinically assess the safety and
performance of Sealing Device as a means to reduce bile and pancreatic juice
leakage in HPB surgery. Secondarily, the control of minimal to moderate
bleeding will be assessed. To achieve adequate representation of the primary
objective, the study will contain two separate surgical patient groups: Liver
and Pancreas.

The primary objective of the study is to demonstrate safety and performance in
reducing intra- and post-operative leakage (bile and pancreatic juices) by
using the Sealing Device in patients undergoing elective hepatic resection or
distal pancreatectomy.

This first-in-human feasibility study will be conducted, first time in humans,
to clinically assess the safety and performance of Sealing Device as a means to
reduce intra- and post-operative leakage (bile, pancreatic juices and blood) in
patients undergoing hepatobiliary or pancreatic surgery.
The study will be conducted as an open-label, single-arm, multicenter study
with a 16 months follow up. Up to 80 patients (40 liver and 40 pancreas
patients) will be enrolled at up to 7 sites in Europe. The first 10 patients (5
liver and 5 pancreas patients) will be part of the first phase (first-in-human)
and will be enrolled sequentially with at least 72 hours between the surgeries.
These 72 hours need to be free of device-related SAEs. In case a device-related
SAE occurs, enrolment will continue after this SAE has been resolved. After
the 10th patient has been discharged, an initial analysis of safety and
performance will be performed up till the Discharge follow-up and communicated
to the applicable authorities before enrolment is continued in Germany.
The list of participating sites will be maintained by Polyganics during the
execution of the study, with the final list being part of the Clinical Study
Report.
This study has been designed primarily to demonstrate safety and performance of
the investigational device in HPB surgery to support the design dossier
approval for CE-marking.
In this study, each subject will receive a maximum of three (3) Sealing Devices
(10 x 5cm) on either liver or pancreas in one (1) procedure. The defect will be
closed with standard of care method.
The assessments performed in this study as well as the time points are
described in the flowchart (see section 1) and the accompanied description in
section 6.2.
Based on clinical considerations and literature, a 30 day follow-up is widely
regarded as a standard follow up period for most liver- and pancreatic
operations and assessments. In order to add a safety margin on this standard
follow up and considering the resorption profile of this device of 15 months, a
total follow up period of 16 months is planned (15 months + 1 month safety
margin). Follow-up of the subjects will be performed at 3 days, discharge, 30
days, 90 days, 180 days and 16 months after surgery.

All surgeries must be recorded by video, to be able to assess bleeding rates
and correct application of the devices. The following instructions for
placement of the Sealing Device are mandatory for a successful result with the
Sealing Device:

Pre-operative
1. Take the package with the Sealing Device out of the freezer at least 10
minutes and maximum of 8 hours, before use.
2. Immediately remove the outer box and keep the pouch closed until Sealing
Device can be applied. For sterile transfer of the Sealing Device: only the
product inside the transparent blister is sterile.
3. Per procedure, it is allowed to use up to 3 Sealing Devices of 10 x 5 cm
simultaneously to cover the defect(s).

A. Intra-operative - liver
NOTE: The procedure should be filmed.
1. Liver defect should be closed with standard everyday method of the hospital,
which should comply to the state of the art.
2. Rinse the liver surface from particles with physiological saline.
3. Liver surface should be moist (remove excessive fluid if applicable).
4. In case of bleeding, this should be controlled up to mild to moderate
bleeding.
5. Open both the aluminum pouch and the inner blister (both are non-sterile).
6. DO NOT apply manual pressure on the Sealing Device before application (the
white foam layer should not be compressed since it will not expand after being
compressed and this impacts the adhesive function).
7. If the size of the liver defect is smaller than the Sealing Device, cut to
the required size with an additional margin of at least 1 cm (this size is
needed to ensure overlap of the device with the defect to ensure adhesive
function).
8. NOTE: In case the defect is larger than the patch(es), apply the Sealing
Device to the area(s) where you expect a bile leak with at least 1 cm overlap
into the non-critical area. This critical area should be determined according
to the standard practice at the hospital. At least approximately 80% of the
total treated area should be covered with the device material (up to 3 devices
maximally).
9. Cutting should be done by using a dry and sterile instrument (e.g. scissors).
10. Place the white side of the dry Sealing Device against the liver defect,
without pre-moistening the patch.
a. Place on the liver defect
b. Cover at least 1 cm beyond the margins of the critical defect at all edges.
c. In case of misplacing, do not re-position the device but remove the device
gently and use another immediately.
11. To position the Sealing Device correctly, compress the Sealing Device with
the fingers onto the tissue; compression of the foam fixates the patch and is
necessary for adhesion.
12. For an equal pressure distribution;
a. Use gauze and cover the complete Sealing Device with this gauze.
b. Hold down the Sealing Device with light pressure; for a minimum of one (1)
minute.
13. Remove the light pressure and gauze carefully after at least one (1)
minute. There is no residual product which needs to be removed since the entire
Sealing Device will fully resorb.
14. In case the Sealing Device is (slightly) dislocated during application or
partly insufficient pressure was applied, it might partly not adhere to the
surface. In that case, the Sealing Device should be gently removed and replaced
with a new Sealing Device.
15. Wrap up the surgery and close the wound with standard every day method of
the hospital, which should comply to the state of the art.


B. Intra-operative - advised application pancreas
NOTE: The entire procedure should be filmed.
1. The pancreatic stump should be closed with standard every day method of the
hospital, which should comply to the state of the art. Please assess whether
the margin between the defect and the portal vein is >=1 cm. If the margin is <
1 cm, the patient should be excluded.
2. Rinse the pancreatic stump resection surface from particles with
physiological saline.
3. Pancreatic stump resection surface should be moist (remove excessive fluid
if applicable).
4. In case of bleeding, this should be controlled up to mild to moderate
bleeding.
5. Open both the aluminum pouch and the inner blister (both are non-sterile).
6. DO NOT apply manual pressure on the Sealing Device before application (the
white foam layer should not be compressed since it will not expand after being
compressed and this impacts the adhesive function).
7. If the size of the pancreatic stump resection defect is smaller than the
Sealing Device, cut to the required size, with an additional margin of at least
1 cm (this size is needed to ensure overlap of the device with the defect to
ensure adhesive function)
8. Cutting should be done by using a dry and sterile instrument (e.g. scissors).
9. Place the white side of the dry Sealing Device against the pancreatic stump
resection surface, without pre-moistening the patch.
a. Place on the pancreatic stump resection surface, fold it from retro
pancreatic over the stump and attach it to the pancreatic tissue directly.
b. Wrap a second patch around the first parch and the stump from ventral
to dorsal side, adhering to the first patch and thus securing the edges of the
patch.
c. Cover at least 1 cm beyond the margins of the defect at all edges.
d. In case of misplacing, do not re-position the device but remove the device
and use another immediately.
10. To position the Sealing Device correctly, compress the Sealing Device with
the fingers onto the tissue; compression of the foam fixates the patch and is
necessary for adhesion.
11. For an equal pressure distribution;
a. Use gauze and cover the complete Sealing Devices with this gauze.
b. Hold down the Sealing Devices with light pressure; for a minimum of one (1)
minute.
12. Remove the light pressure and gauze carefully after at least one (1)
minute. There is no residual product which needs to be removed since the entire
Sealing Device will fully resorb.
13. In case the Sealing Device is (slightly) dislocated during application or
partly insufficient pressure was applied, it might partly not adhere to the
surface. In that case, the Sealing Device should be removed and replaced with a
new Sealing Device.
14. Wrap up the surgery and close the wound with standard every method of the
hospital, which should comply to the state of the art.

A risk analysis according to the ISO 14971:2007 - Application of risk
management to medical devices, has been conducted. Risks are minimized or
eliminated through appropriate design control, confirmed by pre-clinical bench,
laboratory and animal testing.

In the current treatment of closure after liver or pancreas surgery, there is
no defined standard of care within general surgery. Adjuncts as well as
suturing, stapling or other methods are treatments used for closure of resected
organ surfaces after liver- or pancreas surgery. The added values of these
different treatments are often assumed, but rarely well described in the
literature as outcomes are inconclusive. This is also reflected in no Consensus
with regards to defined standard of care for closure of resected organ surfaces
in liver- or pancreas surgery.
The clinical benefit of the Sealing Device for the patient is expected to be
the reduction of post-operative leakage after HPB surgery and therefore
accompanied complications such as inflammation and fever. This is achieved by
formation of a physical barrier after applying the Sealing Device on the
surgical wound. This is supported by pre-clinical animal (porcine) study
results with a bile leakage model and a pancreas leakage model developed by the
University of Hamburg and a modified hemostasis model in the liver. Briefly,
the bile leakage study demonstrated that in 16,7% of the animals a bile leak
was observed compared to 83.3% of the animals in the control group (Veriset,
Medtronic) after 7 days follow-up. The pancreas leakage study demonstrated that
no clinically relevant leakage was observed as there were no signs of
pancreatitis, severe adhesion or hematoma in the Sealing Device group, which
were however observed in the control group (Veriset, Medtronic) during necropsy
after 14 days follow-up. The hemostasis study indicated that the Sealing Device
outperformed the controls (Veriset, Medtronic and Tachosil, Takeda/Baxter) in a
heparinized porcine bleeding model for intra-operative bleeding control as well
as post-operative bleeding control (72 hours follow-up). There were no
device-related Adverse Events regarding the Sealing Device in both studies.
Another benefit is the ease of use of the device as it can be applied directly
out of the package without extra actions regarding preparation, which has been
confirmed in a usability study addressing application of the Sealing Device in
open (manual) fashion.

The potential risks of the device are covered through the harm list in the
table below, describing the residual occurrence of each potential effect to the
patient.
# Harm Severity Residual occurrence
1 Allergic reaction Severe Improbable
2 Carcinoma formation Severe Improbable
3 Infection Severe Improbable
4 Organ fluid leakage Severe Remote
5 Re-bleeding Severe Improbable
6 Inflammation/irritation Moderate Remote
7 Systemic toxicity Moderate Remote
8 Lengthened procedure Limited Improbable
9 Pain Limited Improbable
10 Tissue adhesions Limited Improbable
11 Customer dissatisfaction Negligible Occasional
12 No effect Negligible Remote
13 Unknown Unknown Occasional

Although this is a novel medical device with regard to safety and intended area
of use, there is minor risk for side effects developing from the treatment.
The individual components of the device are developed and selected to be
biocompatible and the specific combination of components for the intended use
of this product has been and is currently being extensively tested through in
vivo, in vitro and chemical testing.
During preclinical testing in an intramuscular rabbit implantation model, the
Sealing Device showed a moderate tissue reaction compared to high density
polyethylene (HDPE) controls after 4, 13, 26, 40 67 weeks. When compared with
the control Tachosil®, the Sealing Device demonstrated no reaction to the
tissue after 4 weeks, slight reaction after 13 weeks and moderate reaction
after 26 and 40 weeks. The Sealing Device displayed comparable moderate signs
of resorption at 4 and 13 weeks, while it appeared slightly more resorbed at 26
and 40 weeks. These differences in tissue reaction can be expected, as
Tachosil® is a collagen that is prone for assimilation (scaffolding) as opposed
to the Sealing device, which is a biodegradable product. At 67 weeks, it was
markedly degraded with more than 90% material degradation. Slight to moderate
mineralization at 13 and 26 weeks was observed. However, a trend toward
reversibility of the mineralization was observed at 40 weeks and the
reversibility was confirmed after 67 weeks of implantation. The signs of
mineralization were localized, not extensive, temporary, and not coupled with
remarkable degenerative, fibrotic and encapsulation process. Similar extent of
dystrophic mineralization was also observed with the control article at 4 weeks
before being completely resorbed with no side effects left. Intramuscular
implantation is associated with more intense tissue reaction than subcutaneous
implantation. Comparable degradation was observed in an in vivo degradation
study in a superficial liver defect model (Aachener mini pig) after 56 weeks
follow-up. Next to the possibility of some local tissue reaction generally
associated with implants, other anticipated adverse device events are those
generally recognized for implantable devices such as allergic reactions and
procedure related infections.
There is a residual risk that the Sealing Device is not functioning as
intended. From a design point of view, this residual risk will be mitigated and
controlled by lot release of the device and design verification, including
stability testing and animal performance testing as previously described to
ensure proper adherence and barrier functionality.
At the same time, from an application point of view, the physicians will be
properly trained before being allowed to use the device. The device will be
accompanied by a clinical IFU and label.

The risks of the surgical procedure include post-operative complications, as
well as any potential complications during the surgery which is performed under
anesthesia. The risks include but are not limited to, infection, inflammation,
discomfort at the surgical site, leakage, and neurological complications
resulting from the procedure (none device related).
In terms of application of the device, the potential risks are mainly
associated to untrained personnel leading to improper placement or use of the
device, which will be mitigated by device training to be completed by all
participating surgeons and general personnel, clear labelling and by the
provided IFU, before study start.

As previously mentioned, training procedures, lot release testing and various
device validations will minimize the risks to patients and ensure the benefits
of the clinical use outweigh those potential risks. Since there is a low risk
for safety issues related to the use of the device and the risk of
post-operative leakage (bile, pancreatic juice and blood) can be reduced with
this device, the general safety risks associated with a surgical intervention
are outweighed by the benefit of reducing of post-operative leakage (bile,
pancreatic juice and blood) in HPB surgery.