Prospective, non-randomized, multicentre clinical evaluation of the recharge free Axonics SNM System (INS Model 4101)

INTRODUCTION AND BACKGROUND

Sacral Neuromodulation (SNM) is a guideline-recommended treatment for
Overactive Bladder (OAB) including urinary urgency incontinence (UUI) and
urinary frequency (UF), and for nonobstructive urinary retention (NOUR) and
fecal incontinence (FI). While these conditions are not life-threatening, they
do have a significant impact on quality of life and may limit a person from
being able to participate in daily activities. Long-term data support the
safety, efficacy, and durability of the therapy. Recent innovations in SNM
therapy, such as a long-lived device and the ability to undergo a full body
MRI, have made the therapy more accessible and attractive to patients and
physicians. This section describes the clinical background of overactive
bladder and fecal incontinence as well as guideline-recommended treatment
options.

Overactive Bladder (OAB)

Overactive bladder is a chronic condition that encompasses several bothersome
urinary symptoms that may occur alone or in combination. The hallmark symptom
of OAB is urinary urgency, a sudden compelling urge to urinate that is
difficult to defer. Urgency may lead to one or more OAB symptoms, including:

-Urinary frequency (voiding 8 or more times a day)

-Urinary urgency incontinence (involuntary loss of urine associated with a
sudden compelling desire to void)

According to the European Institute of Women*s Health, approximately 60 million
adults experience urinary incontinence which is twice as common on women than
in men. The European Association of Urology Guidelines (EAU) refers to
conditions such as overactive bladder, stress urinary incontinence and mixed
urinary incontinence as Lower Urinary Tract Symptoms (LUTS). In the US, OAB has
been estimated to affect over 40 million adults and the prevalence increases
with age in both men and women. It has been estimated that less than 50% of
patients suffering from OAB seek treatment and that up to 80% discontinue OAB
medications within one year of initiation. Although not life-threatening, OAB
can have a significant impact on a patient*s quality of life, as well as having
medical consequences associated with this condition including a higher risk of
falls and hip fractures which increase by 28% and 32% respectively.

The Guidelines state that most cases of OAB can be diagnosed based on history,
physical exam, and a urinalysis. Initiation of non-invasive treatment does not
require an extensive evaluation. In some patients, additional evaluation and
diagnostic procedures may be necessary to validate an OAB diagnosis, exclude
other disorders and fully inform the treatment plan. These may include a urine
culture, post-void residual, bladder diaries, cystoscopy, and/or urodynamics.
The most common cause of OAB is considered to be idiopathic. For these
patients, the EAU guidelines provide a strong rating and recommend SNM for
patients who have OAB refractory to medications. The AUA guidelines list SNM as
a third-line therapy for patients who have failed conservative therapy and
medications.

Fecal Incontinence (FI)

According to the American Society of Colon and Rectal Surgeons, fecal
incontinence is generally defined as the uncontrolled passage of feces for a
duration of at least 3 months in an individual who previously had control3.
Other common terms used to describe this condition include anal incontinence
and accidental bowel leakage. The prevalence of FI varies widely depending on
the specific definition used and the population surveyed, ranging between 1.4%
and 18% in women. FI in men is not as prevalent and is most commonly a result
of evacuatory dysfunction and rectal hyposensitivity.

The highest incidence of incontinence is reported in nursing home populations,
in which rates of FI can reach as high as 50%. A notable fact is that FI is the
second leading cause of nursing home placement in the United States. Fecal
incontinence is a very undertreated condition that can have a severe impact on
quality of life, yet less than one-third actually seek medical care. Of those
that do, more than half do so with their primary care provider who often is
unaware of advanced treatment options such as SNM. Causes of FI are
multifactorial and include four main categories: anatomical (e.g., anal
sphincter trauma, rectal mucosal prolapse), neurological (pudendal nerve
injury, diabetes), functional (chronic diarrhea), and idiopathic. Most causes
are likely multifactorial and fall under the idiopathic category. Treatment
options are limited and are dependent on the underlying etiology. Both the
American Society of Colon and Rectal Surgeons as well as the American College
of Gastroenterology have a strong recommendation for SNM for patients who have
failed conservative therapy.

The objective of this trial is to confirm that there are no new safety and
performance outcomes for participants receiving the Axonics SNM System INS
Model 4101 for the treatment of OAB and FI. The only notable difference between
the existing, approved INS Model 1101, also known as R15, and Model 4101, known
as F15, is that Model 4101 is a non-rechargeable system (due to using a primary
cell battery) whereas Model 1101 uses a rechargeable battery source that
requires monthly recharging by the patient. The mechanism of action is
identical in that the therapy is delivered to the sacral nerve, typically the
3rd sacral nerve root,. Both models use the same exact stimulation waveform.

This clinical pivotal trial is a single-arm, multi-center, prospective,
non-randomized trial to be conducted throughout Europe and the United States.
Regulatory approval will be obtained in each region prior to the start of the
trial in that region. If specific requirements are identified beyond those
already defined in the body of this protocol, they may be added to the protocol
in an Appendix and will be applicable to that region only.

Participants with primary diagnosis of OAB and FI who require an Axonics SNM
device will be included. Participants must meet the eligibility requirements
specified in this protocol. Up to 110 participants (approximately 55 for each
indication) will be enrolled and implanted at 20 participating sites. Per
physician discretion, participants may undergo an external trial period prior
to full implant. The data collected for the study endpoints will be submitted
for each indication separately once completed for that indication.

Safety and performance/effectiveness data will be analyzed when participants
have completed the protocol-specified timepoint (e.g., upon 3-month primary
endpoint completion for each indication) and will be submitted to the Notified
Body/Approved Body for review and product approval in Europe. Participants will
continue follow-up in the trial per the visits specified in this protocol. Once
all participants have completed the 12-month secondary endpoint, the complete
trial data set will be submitted to the applicable IRB/EC and regulatory
agencies and the participants will exit the trial. Active participants may then
consent to be enrolled in a post-market clinical follow-up study sponsored by
Axonics, Inc. as approved by the applicable IRB/EC and regulatory agencies.

The Axonics SNM System is an implantable device comprised of implantable and
non-implantable components. The implantable Neurostimulator (INS) (Model 4101)
is a non-rechargeable device which provides electrical pulses to stimulate the
sacral nerve. It is connected to the Axonics Tined Lead, which conducts
stimulation pulses from the INS to a sacral nerve, typically the 3rd and
occasionally the 4th sacral nerve root.

The indicated duration of the device is 15 years; however, this can vary
depending on the energy use settings.

The Axonics SNM system includes the following non-implantable components:

1801 Lead implantation kit

2301 Patient Remote Control

2501 Clinician Programmer

The benefits of the INS Model 4101 include reducing symptoms of bladder and
bowel dysfunctions and improvement in quality of life. One additional benefit
of Model 4101 is that it has a primary cell battery in which the patient does
not need to charge their device.

As with all SNM devices, serious complications may occur including risks that
could require a reoperation (revision) and/or explant of the device.
This clinical investigation will be conducted under the direction of qualified
physicians experienced with SNM surgery including the Axonics SNM System. All
participating investigators and sites are screened and qualified. They must be
experienced in conducting clinical research and have adequate personnel to
ensure compliance to this protocol. No special training is required to implant
the INS Model 4101 given the investigators selected are experienced using both
Axonics and other SNM devices.

Additional burden to study participants will be as follows:
- Attending study required follow-up visits
- Traveling to the study sites for study required follow-up vists
- Completing Quality-of-Life Questionnaires
- Completing Participants Satisfaction Questionnaire