STOP NEUROMA
Surgical Treatment Of symPtomatic NEUROMA:
Open non-randomized clinical investigation to evaluate the safety and effectiveness of the nerve capping device to prevent neuroma formation after traumatic nerve section

Symptomatic neuroma may develop after a nerve dissection following any trauma
to a peripheral nerve, whether accidental or planned (i.e. surgery).
Neuroma-induced neuropathic pain and morbidity seriously affect the patient*s
daily life and socioeconomic functioning (van der Avoort, 2013). The incidence
of symptomatic neuromas after peripheral nerve injury is estimated to be 3-5%,
however certain surgeries (e.g. autograft procedures, amputations) may have up
to a 30% incidence rate (Stokvis 2010). Autograft procedures, where the nerve
is harvested from a donor site, are at risk of subsequent neuroma formation.
In the US, amputation resulting from trauma (45%), and diabetes and/or vascular
diseases (55%) had a prevalence of 1.6 million patients in 2005 and is
projected to rise to 3.6 million patients by 2050 (Radtke 2013).

There are several surgical procedures possible to treat symptomatic
end-neuromas, but none are considered gold standard for both treatment and
prevention. The most common procedure is surgical removal of the neuroma and
surrounding scar tissue, and subsequent capping of the nerve with a nerve graft
or a nerve conduit, or placing the proximal stump into an area subjected to
minimal mechanical stimulation.

Covering the nerve stump with a cap of autologous (vein, muscle, fascia, bone)
or synthetic (silicone, collagen) material prevents both neuroma development
and regeneration (Lewin 2006), but also has limitations. Placing the nerve
stump into a vein, requires a suitable vein to be available and sacrificed and
the stability of the treatment depends upon consistent venous integrity (i.e.
the vein does not collapse). Muscle capping is often performed as this tissue
is easily available, however the recurrence of very painful sensory neuroma has
been reported (Lewin 2006). Replacing the refreshed nerve end into bone is a
technically demanding option. The nerve stump must be properly placed into a
drilled hole, with no kinking at the hole entrance, and requires the nerve to
be fixed to prevent dislocation. A newer method for treating peripheral
neuroma is coverage with a vascularized flap. The flaps can be either fascial,
fasciocutaneous, muscle or adipose tissue flaps. These flaps are technically
demanding and should only be considered in specific cases (Watson 2010).

Unfortunately, even following treatment, patients with symptomatic neuromas
following amputation had an average of 2.8 re-operations to treat pain (van der
Avoort, 2013) and the surgeries have a failure rate of 10% or more (Elliot
2011).

Covering the nerve stump in artificial material was introduced in 1976 when
silicon rubber caps were used (Swanson, 1977). However, this treatment was
subject to problems of dislocation of the caps and combined with current issues
regarding biocompatibility with silicon, they are not present on the commercial
market. Collagen nerve conduits as an adjunct to the resection of a painful
neuroma were successful in treating neuromas of the foot and ankle (Gould,
2013), however these procedures require the use of materials based on animal
derived tissue. More recently, silk fibroin blended with poly(L-lactid
acid-co-*-caprolactone (SF/P(LLA-CL)) nanofiber conduits used in animal models
show promising results regarding the nerve fiber organization (Yan, 2014).

Based on the success of the NEUROLAC® nerve guide for treatment of peripheral
nerve lesions, it was considered to use this material to cap a nerve for the
treatment symptomatic neuromas. A capping device can prevent dislocation of
the stump by suturing the nerve end into the cap. Consequently, the end of the
cap can be sutured to surrounding tissue. This allows an effective capping
technique without the necessity of drilling a hole into bones, or sacrificing
other tissue. This led Polyganics to design the poly-DL-lactide-caprolactone
nerve capping device. By developing a conduit with a closed end (cap) it is
expected that the formation of neuromas will be better controlled (compared to
the use of a nerve conduit) by preventing axonal sprouting and escape at the
open end and lowering the neurotrophic effect by preventing regeneration of
nerve tissue on the surrounding tissue.
The procedure will be less invasive and relatively simple in comparison with
current techniques described above. The risk of dislocation is reduced as a
result of the fixating techniques and the risk of biocompatibility issues is
mitigated by the materials which are composed of non-animal derived products
that are resorbable by the human body (Meek, 2012).

This study is conducted to clinically assess safety and performance of the
Polyganics nerve capping device for the treatment of symptomatic neuroma. There
is sufficient clinical experience with regard to the safety of the commercially
available nerve guide, NEUROLAC®. This new nerve capping device is identical in
material and manufacturing. The exception is in design, where NEUROLAC® has two
open ends, the nerve capping device has one closed (sealed) end. This study
will be conducted to obtain data on the clinical performance of the capping
device*s ability to isolate the nerve end, resulting in a reduction of pain of
experienced from the symptomatic neuroma and prevention of the reoccurrence of
a symptomatic neuroma.

Primary clinical investigation objectives
[Safety]
The primary safety objective of the clinical investigation is to provide data
that demonstrates safety of the device, defined as < 8.3% serious adverse
device effects, up to 6 weeks following the procedure.

[Effectiveness]
The primary effectiveness objective of the clinical investigation is to provide
data that demonstrates effectiveness of the device, including:
1) Reduction of pain caused by symptomatic neuroma up to 6 weeks following the
procedure, as compared to pain before the procedure.
2) Improvement of quality of life at 6 weeks follow-up, as compared to the
quality of life before the procedure.
3) Reduction or stabilization of quantity/class of pain medication used to
treat neuroma pain at 6 weeks, as compared to the use before the procedure.

Secondary clinical investigation objectives
The secondary objectives of the clinical investigation are to provide data that
demonstrate safety, effectiveness and usability of the device, including:
1) [Safety] < 8.3% serious adverse device effects, up to 3 months, 6 months and
12 months following the procedure.
2) [Effectiveness] Reduction of pain caused by symptomatic neuroma after 3
months, 6 months and 12 months following the procedure, as compared to pain
before the procedure.
3) [Effectiveness] Improvement of quality of life at 3 months, 6 months and 12
months follow-up, as compared to the quality of life before the procedure.
4) [Effectiveness] *20% recurrence of symptomatic neuroma within 12 months.
5) [Effectiveness] Reduction of pain medication used to treat neuroma pain at 3
months, 6 months and 12 months, as compared to the pain medication used for the
neuroma pain before the procedure.
6) [Usability] Ease of placement of the device.

Note: All follow-up time points are post-implantation of the device i.e. post
procedure (e.g. 6-week follow-up means a follow-up at 6-week post-implantation
of the device).

This clinical investigation is a prospective, multicentre, open-label
non-comparative clinical investigation, conducted in a minimum of 2 clinical
sites in Europe.

A nerve capping device will be placed over the nerve ending after the
end-neuroma is removed. It is intended to protect the nerve end and separate
the nerve from surrounding tissue to prevent the development of a symptomatic
neuroma. The nerve capping device is a tubular device with one open end and one
sealed end as shown below. The nerve is attached with sutures to the cap, and
then the cap is attached with sutures to the surrounding tissue. This holds the
nerve securely in the cap, and stabilizes the cap in the body while the nerve
repairs. The cap is made of a material that will slowly and safely degrades
over 16 months, therefore it doesn*t require surgical removal.

Potential Risks Associated with Surgical Procedures
These risks include post-operative complications, as well as any potential
complications during the surgery which is performed under local anesthesia.
The risks include but are not limited to, infection, inflammation, discomfort
at the surgical site, and neurological complications resulting from the
procedure. As a new device, the implantation procedure is new to the field of
nerve defect repair techniques and to surgeons, however a full physician
training and practical will be completed by all participating physicians before
the study start.

The Potential Risk Associated with the Investigational Device
Reactions to the device itself may occur including: allergic, foreign body, or
inflammatory reactions, or delayed wound healing.
Dislocation of early silicone-rubber nerve caps have been reported. NEUROLAC®
(a biologically similar predicate device used as a sheet rather than a cap)
exhibited a 1/12 extrusion rate through the surgical incision site.
There is one risk that is still considered significant and needs to be analyzed
for the risk-benefit. If the capping device fails to provide a sufficient
barrier, it could lead to the formation of symptomatic neuroma. This clinical
investigation is designed to assess this risk. However, there is still a
residual risk that the barrier function of the device is not sufficient to
prevent occurrence or recurrence of a symptomatic neuroma, since there is no
data available to support this.
As with any novel medical device, there is always a risk of extremely rare or
previously unknown side effects developing from the treatment.

Benefit Analysis
The current standard of care for treatment of neuroma-induced neuropathic pain
is surgical removal, including the surrounding scar tissue and if possible
repairing the nerve with either a nerve graft or a nerve conduit or placing the
proximal stump into an area that is subjected to minimal mechanical stimulation.
The potential benefits of this device include a less invasive, simpler
procedure abandoning the need for nerve grafting, harvesting flaps or drilling
holes into bones tissue. This optimized surgery time reduces the patients*
stressful operative exposure, as the procedure is performed under local
anesthetic. The investigational device also removes the need to sacrifice any
other organic tissue from the patient.
Benefits of the investigational device may be realized from the avoidance of
neuroma re-treatment (additional surgery and its inherent risks) which occur in
10% of patients under the current technique resulting from neuroma regrowth or
surgical failure.
Subjects may benefit from a dramatic improvement in acute and chronic pain
reduction, and subsequent improvements in quality of life and daily life
activities.

Risk-benefit for subjects participating in the clinical investigation
Participation in the study requires the subject to comply with the study
procedures andtravel to be available for all follow up visits over a 12-month
period including travel to the investigational site at 10 days, 6 weeks, 3,6
and 12 months following the surgical procedure. It also requires the subjects
to complete 4 different questionnaires at screening, discharge and at 6-weeks,
3, 6 and 12 months follow-up.
Many of the surgical procedure related risks are similar between non-study and
study patients as surgery is the only current treatment for neuromas. The
study subjects may be benefit from reduced surgery time, less invasive surgical
techniques, and improved pain relief post-surgery. The residual risks for the
subject with the investigational device is that of rare or previously unknown
side effects or the inability to provide a suitable barrier to prevent
reoccurrence of a painful neuroma.