Single-arm, open-label, multicenter study to evaluate the safety and performance of Dura Sealant Patch in reducing CSF leakage following elective cranial surgery

The dura mater is the dense, leathery membrane covering and protecting the
brain and spinal cord. The dura is a collagenous connective tissue consisting
of numerous collagen fibres, fibroblasts, and few elastic fibres arranged in a
parallel form. Opening of the dura can be caused by several reasons. It occurs
in 30% of neurosurgical procedures, both intracranial as spinal. Also,
accidentally during some spinal procedures, where after surgery this defect
needs to be closed. Finally, trauma capitis or spinal trauma may damage the
dura mater.
The dura is marginally perfused with blood. Dura behaves totally different than
other, better-perfused tissue, like muscle or fascia.During surgery, the
temporary dry environment and the heat of the operation microscope cause the
dura to shrink. This makes stitching the dura to close it often difficult which
leads to suboptimal postoperative regeneration of the defect or even absence of
regeneration. Especially in the elderly, dura can be paper thin and impossible
to handle without damage. In case the dura is not closed watertight this can
potentially cause complications. First, the Cerebrospinal Fluid (CSF) can
accumulate under the skin (pseudomeningocele) which can hamper proper wound
healing and cause complaints like pain. Secondly, it can leak outside through
the wound (CSF leakage). This makes normal wound healing impossible. Both
complications often lead to an extra intervention and longer stay of the
patient in the hospital.

CSF leakage is one of the most common neurosurgical complications, occurring in
4-32% of surgical cases with a higher incidence in complicated skull base
surgery, intradural spine surgery and surgery of the posterior fossa.The
likelihood of CSF leakage as a surgical complication can also depend on age,
indication, location of surgery, and underlying pathology. Most patients with
CSF leakage necessitate a prolonged hospital stay, antibiotic treatment for
meningitis, external lumbar drainage, reoperation, or a combination of these
measures. CSF leakage leads to significant patient burden and expense, with an
estimated cost of 10,000*15,000 US dollars per patient per leakage.
The use of a dural sealant as an adjunct to primary dural closure is often
assumed to have value for preventing CSF leakage; yet, few empirical reports
describe such an effect.

In a systematic review on all available data in literature, twenty articles
were included; ten of these were comparative studies (sealant versus no
sealant) including 3 randomized controlled trials. In the 20 articles, a total
of 3682 surgical procedures were reported. The number of CSF leakages in
general did not differ between the sealant group (8.2%) and control group
(8.4%), RR 0.84 (0.50-1.42), I2=56%. Exclusion of non-RCT*s did not alter the
results. Meta-analyses for secondary outcomes showed no difference between
number of incisional CSF leakage, RR 0.30 (0.05-1.59), I2=38% and
pseudomeningocele formation, RR 1.50 (0.43-5.17), I2=0%. Surgical site
infection was less seen in the sealant group (1.0%) compared to the control
group (5.6%), RR 0.25 (0.13-0.48), I2=0%.

Closure of the dura involves several steps. First, the neurosurgeon tries to
primarily close the dura with continuous or interrupted stitches. This is
possible in 60-70% of intracranial cases and almost 95% of spinal intradural
cases (only not in meningioma surgery where the dura is excised or in
operations were surgeons on purpose had to increase the intradural space).
Watertight closure of the dura is, without any augmentation, per definition not
possible because of the puncture holes of the sutures. However, the dura has to
be closed as watertight as possible. No protocols exist when to apply an extra
substitute over a primarily closed dura instead of suturing only, this is
dependent on personal feeling of the operating surgeon. If primary closure is
impossible, an autograft (pericranium or muscle) [6] or allograft, xenograft or
synthetic substitutes are sometimes sutured in the defect to reduce openings in
the dura which are subsequently closed with a sealant. Native autologous tissue
grafts can perform as good as dural substitutes because they do not provoke
severe inflammatory or immunological reactions. Potential drawbacks in using
autografts are: difficulty in achieving a watertight closure, formation of scar
tissue, insufficiently accessible graft materials to close large dural defects,
and potential additional incisions for harvesting the graft.
As alternative to the use of an autograft, a non-autologous (allograft) dural
substitute can be used. Various xenografts have been studied for this purpose,
including bovine and ovine pericardium, porcine small intestinal submucosa, and
processed collagen matrices. However, these non-resorbable xenografts are often
associated with adverse effects, such as graft dissolution, encapsulation,
foreign body reaction, scarring, and adhesion formation.

If the quality of dural closure is improved, complications associated with CSF
leakage, including meningitis, pseudomeningocele, impaired wound healing, and
subgaleal fluid collection, could be reduced. CSF leakage leads to increased
morbidity, prolongation of hospital stay, surgical revision, and enhanced costs
as well as possible surgical revisions.

In daily practice, in approximately 25-50% of all intradural neurosurgical
procedures, any adjunct to dural sealing with or without graft is used to
prevent CSF leakage and to allow the dura to heal after surgery. This comes
down to, in the Netherlands only, 4000-10.000 procedures per year (estimated).

Polyganics BV (medical technology company, Groningen, The Netherlands) has
developed in close cooperation with the Brain Technology Institute
(Neurosurgical Research Institute, Utrecht, The Netherlands) the Dura Sealant
Patch for watertight dural closure after cranial surgery. This study will be
conducted, first time in humans, to clinically assess the safety and
performance of Dura Sealant Patch as a means to reduce CSF leakage after dural
closure in patients undergoing cranial surgery.

The objective of the study is to clinically assess the safety and performance
of the Dura Sealant Patch as a means of reducing intra- as well as
post-operative CSF leakage in patients undergoing elective cranial intradural
surgery with a dural closure procedure.
Intra-operative CSF leakage is defined as:
CSF leakage after closure of the dura before placement of the bone flap while
an elevated CSF pressure is induced.
Post-operative CSF leakage is defined as:
* percutaneous CSF leakage; leakage of CSF through the wound from the moment
the wound is surgically fully closed until 90 days post-operative, and
* pseudomeningocele; accumulation of CSF under the skin from the moment the
wound is surgically fully closed until 90 days post-operative.

This study will be conducted, first time in humans, to clinically assess the
safety and performance of Dura Sealant Patch as a means to reduce CSF leakage
after dural closure in patients undergoing cranial surgery.
The study will be conducted as an open-label, single-arm, multicenter study
with a 360 days follow up. Up to 40 patients will be enrolled at up to 3 sites
in Europe.

Each subject will receive one (1) Dura Sealant Patch after closure of the dura
mater. The dura mater will be closed with suturing. If deemed necessary by the
surgeon, a substitute (galea only) can be used.

Anticipated clinical benefits
In the current treatment of closure of dural opening after cranial surgery,
there is no defined standard of care within neurosurgery. Both sealants as well
as suturing only are treatments used. The added values of these different
treatments are often assumed, but rarely well described in the literature. This
is also reflected in no defined standard of care.
The investigational device adheres to the dura mater and provides a watertight
closure bridging small gaps. This adhesion avoids posterior CSF leakage.
Complications associated with CSF leakage, including meningitis,
pseudomeningocele and impaired wound healing could be reduced.
The clinical benefit may be the reduction of the accompanied complications with
CSF leakage. Another benefit may be the ease of use of the device as it can be
applied directly out of the package without extra actions regarding preparation.
Anticipated adverse device effects
During the preclinical testing in animals (pigs), there were 2 observations in
regards to a possible relation to the device, but had no clinical consequences
to the animals.
Adverse device effects in humans could occur, which are not yet known.
Residual risks associated with the investigational device
Even though this is a novel medical device with regards to safety and use in
the intended area, there is minor risk for extremely rare or unknown side
effects developing from the treatment.
The individual components of the device are well known and used in other
marketed products. The specific combination of components for the intended use
of this product has been extensively tested through in vivo, in vitro and
chemical testing.
However, there is still a residual risk that the barrier function of the device
might not be sufficient to reduce occurrence or recurrence of CSF leakage. This
residual risk will be mainly covered by lot release of the device, to ensure
proper adhesion to the dura mater; as well as various validations such as
packaging and sterilization, to ensure no loss of adhesion properties overtime.
Risks associated with participation in clinical investigation
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, 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, which will be covered by a device training
to be completed by all participating surgeons and general personnel, clear
labelling and by the provided IFU, before start of the study.
Possible interactions with concomitant medical treatment
Interactions with concomitant medications in humans are not known. However, in
the in-vivo studies no interactions were reported.
Risk mitigation
Pre-clinical studies demonstrate the device performs as intended and meets the
performance specifications including biological testing. This biological
testing demonstrated that the product is biologically safe for implementation
in humans and can be used as intended.
The clinical protocol incorporates several procedures to minimize the risks to
subjects and to ensure the benefits of the clinical study outweigh its
potential risks. These include:
* Subjects in the study will undergo frequent visits and routine medical
follow-up to help detect any abnormal changes and to provide appropriate
treatment if necessary.
* The study will be monitored to ensure the identification, documentation and
analysis of adverse events; and to ensure compliance with the protocol and
procedures that are in place for conducting research to protect the safety and
well-being of all subjects.
* Surgeons will be experienced with dural closure methods and will receive
training form the sponsor on device specific protocol.

Risk-to-benefit rationale
Based on preclinical studies, as well as the current known risks of dural
closure methods, the risk to benefit ratio for using the Dura Sealant Patch is
within reason for foreseeable risks. However, preclinical studies do not always
predict the side effects humans may experience. Additionally, complications due
to individual subject response to an implanted device may necessitate future
dural closure procedures. Close observation and follow-up of patients is
required as outlined in the protocol.
As previously mentioned, training procedures, lot release testing and various
validations will minimize the risks to patients and ensure the benefits of the
clinical use outweigh its potential risks. Since there is a low risk for safety
issues related to the use of the device and the risk of CSF leakage can be
reduced with this device post-operatively, the general safety risks associated
with a surgical intervention are outweighed by the benefit of absence of
post-operative CSF leakage.