OnabotulinumtoxinA (onaBoNT-A) Versus Oral Oxybutynin ER

Current treatment of neurogenic bladder dysfunction (NGB) is limited by the suboptimal
results achieved using standard antimuscarinic agents. A prominent role for the actions of
alternative transmitters/growth factors in peripheral micturition pathways is emerging from
the growing number of pharmacologic and localization studies in humans. For example,
recently published data demonstrates a significant increased expression of Nerve Growth
Factor and chemokine/cytokine levels in patients with detrusor overactivity and NGB.
Treatment with onabotulinumtoxinA (onaBoNT-A) not only was shown to reduce detrusor
overactivity and improve urinary symptoms but also significantly reduced tissue and urine
levels of factors such as NGF. Up to this point, no study has directly compared the effects
of front-line therapy of antimuscarinic agents versus onaBoNT-A on urinary symptoms in
patients with NGB resulting from spinal cord injury (SCI). In addition, no investigation has
examined the effects that antimuscarinic agents or onaBoNT-A have on urinary levels of NGF
and chemokines/cytokines, whether changes in urinary levels predict a clinical response or a
return in symptoms, and if changes in urinary levels predate changes in clinical response.

Access to selective and reliable urine testing of NGF and chemokines/cytokines provides the
unique opportunity to assess the impact that modulating these agents has on bladder
function. The main purpose of this proposal is to incorporate novel urine biomarker testing
into existing clinical methodologies in order to: 1) evaluate the safety and efficacy of 200
U onaBoNT-A injected into the detrusor versus oral oxybutynin for the treatment of urinary
incontinence (UI) caused by neurogenic detrusor overactivity (NDO) in spinal cord injured
patients and 2) to determine the potential role of urine biomarkers in guiding the process
of patient selection and identify surrogate predictors of treatment outcomes.

This will be a double-blind, randomized, placebo-controlled, parallel-group study to assess
the safety and efficacy of onaBoNT-A or 15 mg per day of oral oxybutynin hydrocholoride in
spinal cord injured patients diagnosed with neurogenic detrusor overactivity.

Volunteers will include both males and females with spinal cord injuries who are 18 to 80
years of age.

Volunteers will be randomized using a blocked randomization approach to either:

ARM 1: onaBoNT-A 200 U bladder injection and placebo oral capsule daily or

ARM 2: Placebo bladder injection (saline) and oxybutynin ER 15mg capsule daily.

Subjects will be randomized into one of the two treatment arms, using a block size of 4. The
order in which the treatments are assigned in each block is randomized and this process is
repeated for consecutive blocks of subjects until all subjects are randomized. This process
ensures that after every fourth randomized subject, the number of subjects in each treatment
group is equal.

There will be five study visits over approximately 6-7 months.

The significance of these experiments begins with the fact that our proposed intervention is
the first randomized clinical trial comparing the effects of onaBoNT-A (onabotulinumtoxinA)
bladder injection versus anticholinergic medication for detrusor hyperreflexia (DH). In
addition, this is the first study profiling urine levels of the signaling protein nerve
growth factor (NGF) and chemokines/cytokines as possible bio-markers of bladder overactivity
in patients with neurogenic detrusor overactivity. Finally, this is the only study to date
comparing the effects that onaBoNT-A or anticholinergic medications have on urine NGF and
chemokine/cytokine levels. If our hypotheses prove to be correct, the significance to
treating patients with spinal cord injury with botulinum toxin A will be less incontinence,
the requirement of lower doses or avoidance of anticholinergic medication and its associated
side effects, and the ability to prevent the complications of DH/DESD (Detrusor-External
Sphincter Dyssynergia) including urinary tract infections, decubiti, and impairment of
quality of life. Although this study as written is of moderate length (i.e. total 4 years),
we hope that by finding significant results, we will be able to capture a longitudinal
history of this population by extending follow-up to a longer duration (i.e. over 10 years).

Inclusion Criteria:

- male or female, aged 18 to 80 years old, weighing 110 pounds or more.

- urinary incontinence as a result of neurogenic detrusor overactivity for a period of
at least 3 months prior to screening as a result of spinal cord injury

- must have a stable neurological injury occurring at least 6 months or more.

- has detrusor overactivity demonstrated during the screening period or within 6 months
of screening if patient is off antimuscarinic/ anticholinergic drugs at the time of
urodynamic testing.

- has a negative pregnancy result if female and of childbearing potential.

The following criteria are also required for entry into the study at Randomization/Day 1:

- experiences at least 14 episodes or more of urinary incontinence per week with no
more than 2 incontinent-free days.

- currently uses or is willing to use clean intermittent catheterization (CIC) to empty
the bladder (indwelling catheter is not permitted).

- Volunteers with a negative urine culture result must take an antibiotic medication
for 3 days immediately prior to Randomization/Day 1 and agree to continue antibiotic
medication for at least 3 days following treatment. Volunteers with a positive urine
culture result indicating urinary tract infection (UTI), must take an antibiotic to
which the identified organism is sensitive for at least 3 days immediately prior to
Randomization/Day 1, on Randomization/Day 1, and continue for 3 days following the
procedure (or longer as needed).

Exclusion Criteria:

- has history or evidence of any pelvic or urological abnormalities including but not
limited to the following:

1. elevated serum creatinine more than 2 times the upper limit of normal (reference
range)

2. current or history of hematuria, 1) if the hematuria is determined to be a
pathologic condition or 2) is uninvestigated

3. interstitial cystitis in the opinion of the investigator bladder stones within 6
months of screening

4. surgery or bladder disease other than detrusor overactivity that may impact
bladder function with the exception of surgeries for bladder stones (more than 6
months) and stress incontinence, uterine prolapse, rectocele, or cystocele (more
than1year) from screening.

- has had previous or current botulinum toxin therapy within 3 months.

- has been immunized for any botulinum toxin serotype.

- discontinued anticholinergic medication for overactive bladder less than 14 days
prior to Randomization/Day 1.

- has a history or current diagnosis of bladder cancer.

- male with previous or current diagnosis of prostate cancer or has a Prostate Specific
Antigen (PSA) level greater than 10.0 ng/mL.

- has 24 hour total volume voided more than 3000 mL of urine

- has a post void residual volume above 200 mL.

- has an active genital infection, other than genital warts, either concurrently or
within 4 weeks prior to screening.

- uses any anti-platelet or anticoagulant therapy or is using medications with
anticoagulative effects within 3 days prior to treatment.

- has hemophilia or other clotting factor deficiencies or disorders that cause bleeding
diatheses.

- has had concurrent treatment or treatment within 6 months of Randomization/Day 1 with
capsaicin or resiniferatoxin.

- currently using or plans to use an implanted or non-implantable electrostimulation/
neuromodulation device for treatment of overactive bladder.

- has a known allergy or sensitivity to any components of the study medication,
anesthetics or antibiotics or any other products associated with the treatment and
general study procedures.

- has any medical condition that may put the volunteer at increased risk with exposure
to onaBoNT-A including diagnosed myasthenia gravis, Eaton-Lambert syndrome or
amyotrophic lateral sclerosis.

- female and pregnant, nursing or planning a pregnancy during the study, or of
childbearing potential and unable or unwilling to use a reliable form of
contraception during the study.

- currently or has previously participated in another therapeutic drug or device study
within 30 days of screening.