The use of a Polycaprolactone Based Bulking Agent for the Treatment of Female Stress Urinary Incontinence, a Pivotal Trial

Stress urinary incontinence (SUI) is an involuntary leakage of urine resulting
from increased intra-abdominal pressure such as coughing, laughing, sneezing,
lifting, running, or changing of body position from horizontal to vertical and
may be caused by urethral hypermobility or intrinsic sphincter deficiency
(ISD). It is suggested that the cause of ISD lies in weakened urethral
sphincter muscles and is the inability of the urethra to provide adequate
urethral closure pressure that prevents involuntary loss of urine during
increases in abdominal pressure. Additionally, altered collagen production has
also been suggested to contribute to SUI. The main constituent in the ligaments
and the sub-urethral wall is fibrous connective tissue. Collagen of types I,
III, and VI are the predominant component of this connective tissue. It has
been found that women with urinary incontinence have an altered connective
tissue metabolism causing decreased collagen production, which may result in
insufficient support of the urogenital tract. Activation of collagen production
by bulking agents due to neocollagenesis may contribute to a long lasting
natural way of increasing support of the urogenital tract.
There is a wide spectrum of treatment options available for SUI, including
conservative non-surgical therapy (pelvic floor muscle training, electric
stimulation, fluid and dietary, and drug therapy) and surgical procedures. The
most commonly used surgical treatment for SUI is the mid-urethral sling
procedure; the retropubic (tension-free vaginal tapes (TVT) or the
transoburator sling (tension-free vaginal tapes obturator (TVT-O). According to
literature, the reported complication rates range from 4.3% to 75.1% for
retropubic, and 10.5% to 31.3% for transobturator mid urethral slings. Due to
the high complication rate there is a need for less invasive treatments for
SUI. Bulking agents are very promising as a minimally invasive therapy because
they may be performed under local anesthesia in an outpatient setting, have a
low complication rate, have shorter procedure time, shorter inpatient stay and
more rapid recovery.

The primary objectives of the trial are to:
- Evaluate the efficacy of the PCL-based bulking agent treatment as determined
by the Stamey Grading System (SGS). The SGS will be determined at baseline, 3,
6, 12, 18, and 24 months follow-up.
- Evaluate the safety of the PCL-based bulking agent treatment via any reported
adverse events at baseline, 3, 6, 12, 18, and 24 months follow-up.

The secondary objectives of the trial are to:
- Evaluate the effect on Quality of Life (QoL) after the PCL-based bulking
agent treatment. QoL will be determined with the use of Incontinence Quality of
Life questionnaire (I-QoL). The I-QoL will be determined at baseline and at 3,
6, 12, 18, and 24 months follow-up.
- Evaluate the efficacy after the PCL-based bulking agent treatment. Efficacy
will be determined with the use of the International Consultation on
Incontinence Questionnaire - Short Form (ICIQ-SF). The ICIQ-SF will be
determined at baseline and at 3, 6, 12, 18, and 24 months follow-up.
- Evaluate the efficacy after the PCL-based bulking agent treatment. Efficacy
will be determined with the use of the Patient*s Global Impression of
Improvement scale (PGI-I) and Patient*s Global Impression of Severity scale
(PGI-S). The PGI-I will be determined at 3, 6, 12, 18, and 24 months follow-up.
The PGI-S will be determined at baseline, 3, 6, 12, 18, and 24 months follow-up.
- Evaluate efficacy as determined by the non-invasive cough test. The
non-invasive cough test will be performed at baseline, after treatment, and at
3, 6, 12, and 24 months follow-up.
- Evaluate safety via an additional cystoscopic examination at 12 and 24 months
follow-up.
- Long-term safety and efficacy will be assessed by extending the follow-up
visits annually up to 5 years (SGS, I-QoL, PGI-I, PGI-S, and ICIQ-SF).

This is a prospective pivotal trial to study the safety and efficacy of a
PCL-based bulking agent (Urolon*) for stress urinary incontinence (SUI).

Eligible subjects will receive injections of the PCL-based bulking agent
(Urolon*-12, Urolon*-24, or Urolon*-48). The use of topical, spinal, or general
anesthesia is permitted at the discretion of the Investigator. The PCL-based
bulking agent injection will be administered into the submucosa of the urethra
at the bladder neck using the transurethral technique. Three injections (2, 6,
and 10 o*clock positions) will be administered in order to achieve optimal
coaptation of the urethral mucosa. A second injection only with the
corresponding PCL-based bulking agent (Urolon*-12, Urolon*-24, or Urolon*-48)
used for initial treatment is permitted if the patient was not dry after the
first treatment. If required, a second injection is permitted at 3 month
follow-up and or trial exit.

At baseline, 3, 6, 12, 18, and 24 months post treatment the treated subjects
have an assessment of safety and efficacy as determined by subjective and
objective methods. Long-term safety and efficacy will be assessed by extending
the follow-up visits annually up to 5 years (SGS, I-QoL, PGI-I, PGI-S, and
ICIQ-SF).

Expected side effects, risks, and/or discomforts are:

1. mild (treatment related) (short term) complications:

• urinary tract infection,
• haematuria,
• dysuria,
• urinary retention,
• urgency,
• headaches,
• pain,
• risks associated with anesthesia, outlet obstruction (slow prolonged stream),
• fever,

2. rare severe (long term) complications:

• periurethral granuloma,
• erosion
• dislocation,
• embolization,
• urethral prolapse,
• formation of abscesses, cysts, and other masses.
• worsening of incontinence

There may be other procedure or device related problems that are not known yet.
If during the trial new information becomes available about other problems,
every effort will be made to inform the patient.

The patient will receive the best medical care available during and after this
trial, but because this is still a clinical trial, unexpected side effects may
occur. In the unlikely event that the patient experiences any research-related
harm as a result of taking part in this trial, the patient will be provided
with medical treatment/care at no cost to the patient. The term *research-
related harm* means both physical and mental injury caused by the trial device
or trial procedures required by the trial.