Refractory Overactive Bladder: Sacral NEuromodulation v. BoTulinum Toxin Assessment (ROSETTA)

Primary Aim:

To compare the change from baseline in the number of urge urinary incontinence episodes
(UUIE) over 6 the six month follow-up period in women randomized to sacral neuromodulation
(InterStim®) therapy, versus those randomized to intra-detrusor injection with 200 units of
botulinum toxin A (Botox A®).

Secondary Aims:

- Long Term Efficacy: To compare the long-term (12 and 24 month) efficacy outcomes in
women randomized to sacral neuromodulation(InterStim®) therapy, versus those randomized
to intra-detrusor injection with 200 units of botulinum toxin A (Botox A®). Secondary
efficacy outcomes, collected at 12 and 24 months as well as 6 months,include adequate
control of their urge urinary incontinence, change in bothersome symptoms of urinary
urge incontinence (UUI), severity of urge incontinence, urinary frequency, nocturia,
subject satisfaction with therapy, quality of life measures and bowel and sexual
function.

- Cost Effectiveness: To compare utilization of medical resources for cost effectiveness
analysis and cost-utility between treatment groups.

- Treatment Safety and Burden: To assess safety profile and treatment burden of both
interventions by comparing adverse event incidence between treatment arms, and also by
obtaining estimates of incidence of treatment-specific safety and burden outcomes.
Safety and burden outcomes for Botox A® injections include receipt of additional
injections and intermittent catheterization due to voiding dysfunction/partial urinary
retention. Safety and burden outcomes for InterStim® device include infection, pain,
lead migration, reprogramming (and reasons for) and surgical revision (and reasons for).

Inclusion Criteria:

- Non-pregnant adult female at least 21 years old, with no plans to become pregnant
during the course of the trial) and if of child-bearing potential, with a negative
pregnancy test, and if sexually active, must be using medically acceptable
contraception.

- 6 urge urinary incontinence episodes on a 3-day baseline bladder diary, with these
urge incontinence episodes representing greater than 50% of the total incontinent
episodes recorded.

- Willing and able to complete all study related items and interviews.

- Refractory urinary urge urinary incontinence: defined as (1) Persistent symptoms
despite at least one or more conservative treatments (e.g. supervised behavioral
therapy, supervised physical therapy); and (2)Persistent symptoms despite the use of a
minimum of two anticholinergics, or unable to tolerate medication due to side effects,
or has a contraindication to taking anticholinergic medication.

- Currently not on an anticholinergic or antimuscarinic medication (e.g. oxybutynin,
tolterodine, and/or fesoterodine) or be willing to stop medication for 3 weeks prior
to completing baseline bladder diary and expected to remain off medications through
duration of study.

- Demonstrates ability (or have caregiver demonstrate ability) to perform clean
intermittent self-catheterization.

- Grossly neurologically normal on exam and no gross systemic neurologic conditions
believed to affect urinary function.

- Urodynamic assessment within the previous 18 months prior to enrollment or done after
enrollment, prior to randomization.

Exclusion Criteria:

- Neurologic diseases such as multiple sclerosis, Parkinson Disease, CVA within 6 months
prior to enrollment, myasthenia gravis, Charcot-Marie-Tooth disease, clinically
significant peripheral neuropathy, and complete spinal cord injury.

- Untreated urinary tract infection (UTI).

- Any prior use of either study therapy for treatment of urinary urge incontinence
(Botox A® or Interstim®).

- Current participation in any other conflicting interventional research study.

- PVR >150 ml on 2 occasions within 6 months prior to enrollment (If the PVR value was
obtained by ultrasound and was ≥150 ml, the PVR will be confirmed by catheterization
which will be the gold standard)

- Subjects with knowledge of planned MRIs or diathermy, except those allowable per
Medtronic guidelines.

- Current or prior bladder malignancy.

- Surgically altered detrusor muscle, such as augmentation cystoplasty.

- Subjects taking aminoglycosides.

- Currently pregnant or lactating.

- Subjects who are on ambulatory anticoagulant therapy, including aspirin, who are
unable to discontinue treatment for 24 hours prior to bladder injection and staged
InterStim® procedure.

- Serum creatinine level greater than twice the upper limit of normal within the
previous year prior to enrollment.

- Surgical treatment for stress incontinence (sling, Burch or urethral injection) or
pelvic organ prolapse recommended or planned at enrollment by study investigator(s).

- Prior stress incontinence or prolapsed surgery within the last 6 months prior to
enrollment.

- Allergy to lidocaine or bupivacaine.

- Prior pelvic radiation.

- Uninvestigated hematuria.

- Greater than or equal to Stage III vaginal prolapse.

- Known allergy to Botox A®.

- Use of a vaginal pessary.