Cycling Versus Continuous Mode in Neuromodulator Programming

Study Overview
=================
Brief Summary
-----------------
The investigators objective is to compare patient outcomes as changes in validated symptom measures of overactive bladder, the Overactive Bladder Questionnaire Short Form (OABq-SF) symptom scale, between women who are set on cycling versus continuous programs for their neuromodulator. Specifically, the investigators propose to perform a randomized double blind crossover study in women who are successfully treated with neuromodulation to either continuous or cycling mode on the modulator and compare differences between groups on the validated OABq-SF symptom questionnaire. In addition, the investigators will compare differences in urinary frequency and pad counts between women randomized to cycling versus continuous stimulation as measured by a 3 day voiding diary. This investigation will provide evidence-based guidelines for neuromodulator programming.

Detailed Description
-----------------
Background and Significance: The purpose of this research proposal is to evaluate the effect of cycling versus continuous neuromodulator programming on overactive bladder syndrome. s.In 1997, the Federal Drug Administration (FDA) approved the sacral nerve stimulator as a treatment for refractory urge incontinence. Sacral Neuromodulation works via stimulation of the sacral nerve roots 2-4, (S-2, S-3 and S-4), although the exact mechanism of action is unknown. While implanted electronic stimulators have been used increasingly in the last twenty years, little investigation has documented the actual programming of the stimulator. Prospective trials examining the ideal programming parameters for a specific condition are needed to better identify optimal use of sacral nerve modulation therapy. In brief, women with overactive bladder who are refractory to treatment are eligible for a trial placement of a neuromodulator. The modulators are placed in two stages; in stage one, a temporary lead is placed in the 3rd sacral foramen. Each neuromodulator has 4 electrodes that are placed via a single lead into the 3rd sacral foramen. The patient will generally return to clinic one week following stage 1 for a post-op evaluation. If the patient reports a 50% improvement in frequency as measured on a 3-day voiding diary, the modulator is permanently implanted. This is stage 2. After placement, the modulator is programmed in the recovery room. Patients are trialed on four set programs for their stimulator. Each program differs in electrode combination, pulse width, amplitude and rate as well as direction of current. Each of the four programs is tested with the patient to determine which is felt by the patient in the perineum and is comfortable. Finally, patients can either have their modulator set on a cycling or continuous mode. Currently, decisions regarding programming are made by whoever is assessing the patient and are not data driven. Typically, cycling means the neuromodulator stimulation is on for 16 seconds & off for 8 seconds. Continuous means the patient receives constant stimulation. A single retrospective study described program parameters for programming of the modulator for treatment of Over Active Bladder (OAB). It described 67 patients who had good response to neuromodulation, and determined the mean pulse width was 204 microseconds, the pulse width ranged between 120-270 microseconds; the average rate was 9 with a range of 2-20 pulses/second. The majority of women were on cycling mode. Program cycling is purported to decrease the incidence of patients reporting that their modulator is no longer working and thought to extend battery life. No other study has investigated whether or not cycling of the stimulator improves patient outcomes. Our objective is to compare patient outcomes using in validated symptom measures of OAB between women who are set on cycling versus continuous programs. Investigators propose to perform a randomized crossover study in women who are successfully treated with neuromodulation to either continuous or cycling mode and compare differences between groups on the OAB-q SF symptom questionnaire. The investigators will also compare differences in urinary frequency and pad counts between women randomized to cycling versus continuous stimulation using voiding diaries. Specific Aims and Objectives: Aim #1: To compare OAB improvement as measured by the Overactive Bladder Questionnaire Short Form Symptom questionnaire (OAB-q SF symptom questionnaire) between women with continuous versus cycling stimulation of their neuromodulator. Hypothesis #1: Investigators hypothesize that women on cycling programs will report higher OAB-q SF symptom scores than women on continuous programs. Aim #2: To compare urinary frequency as recorded on 3 day voiding diaries between women placed on continuous versus cycling stimulation of their neuromodulator. Hypothesis #2: Investigators hypothesize that women on cycling programs report less urinary frequency as measured on 3 day voiding diaries than women on continuous programming. Aim #3: To compare pad usage between women on cycling programs versus those on continuous programs. Hypothesis #3: Investigators hypothesize that women on cycling programs will report less pad use than women on cycling programs. Methods:The investigators will conduct a double-blinded crossover randomized controlled clinical trial. Up to 50 women will need to be recruited in order to randomize twenty-three women who are successful with the Stage 1 implant of their neuromodulator. After written consent, clinical data will be collected and questionnaires administered. After successful Stage 1 placement women will complete a 3-day voiding diary. The recording of symptoms and completion of a voiding diary are standard of care for women undergoing neuromodulation treatment. These data will be collected and recorded. Randomization will occur after successful Stage 2 implantation. Study personnel not otherwise involved in patient care will assign it. Randomization assignment will be by random number table in permutated blocks of four, to ensure that equal numbers of women will be assigned to each group. Assignments will be kept in sealed opaque envelopes and will be opened in sequential order once women have undergone successful Stage 2 implantation. Study personnel programming the modulator after implantation will either program the modulator to continuous or cycling programs. Patients will be blinded to randomization assignment. Prior to their 3 month visit, study subjects will complete another voiding diary. At the visit, women will complete the OAB-q SF symptom questionnaire as well as the Patient Global Impression of Improvement (PGI-I). At this visit, women who were assigned to continuous stimulation will be switched to cycling stimulation and women who were assigned to cycling stimulation will be switched to continuous stimulation. Women again will report for clinical follow-up at six months. Women will be asked to complete their voiding diary. At this clinic visit women will once again complete the OAB-q SF symptoms questionnaire and PGI-I Investigators obtain a written consent from qualifying patient. Patients will then be randomized to Cycling or Continuous mode at Stage II implantation. Statistics: Analysis: Descriptive statistics will be used to describe patient characteristics. The analysis of the change in OAB-q SF scores in this 2 group, 2 period (2x2) crossover design will be a repeated measures (RM) Analyses of Variance (ANOVA) with both the treatment group (cycling versus continuous) and period (first treatment versus second treatment) as repeated factors. The possibility of a cross over effect will be accounted for in the analysis by an order effect covariate (equal to 1 if cycling is first and 0 if not.) Analysis of urinary incontinence episodes and pad counts as recorded on 3 day voiding diaries will be analyzed by repeated measures Poisson regression. (Using SAS's PROC GEN MOD with a Poisson distribution) Significance is set at p = 0.05. Power analysis: In our cross over randomized controlled trial the investigators assume that a clinically important difference between changes in OAB-q SF scores between women on continuous versus cycling stimulation, with a standard deviation of the paired differences of 15 points between groups with an alpha error of 0.05 and power of 80%, 20 women are needed to be randomized into equal groups. (Hintze, J (2011) PASS11. NCSS, LLC< Kaysville Utah, US. www.ncss.com)(9), Assuming that 15% of women will be lost to follow-up the investigators will need to randomize 23 women to the study. 2. Expected outcome: This randomized control trial will demonstrate that women on the cycling program mode will report higher OAB-q SF Symptom scores, and will report less urinary frequency and less pad usage as measured on 3-day voiding diaries.

Official Title
-----------------
Cycling Versus Continuous Mode in Neuromodulator Programming

Conditions
-----------------
Urinary Incontinence, Urge

Intervention / Treatment
-----------------
* Device: sacral neuromodulator


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women at least 21 years old or older eligible for implantation of a neuromodulator Women with successful Stage #1 implantation for treatment of refractory OAB Subjects may be enrolled in other studies as long as there are no changes to the neuromodulation device. Women may continue other OAB therapies that they are on, but as asked to not start new therapies. Not currently pregnant and with no plans to become pregnant during the course of the trial. Willing as well as mentally and physically capable of completing all study related procedures and materials Exclusion Criteria: Males (we do not care for males in our urogynecology clinic) Incarcerated women Non-English speakers Pregnant women Scheduled or planned MRIs or diathermy

Ages Eligible for Study
-----------------
Minimum Age: 21 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cycling<br>Sacral neuromodulator devices (implanted pulse generator) will be programmed to on-off cycles (on 16 seconds, off 8 seconds). This means the devices are not continuously on. Rather they are on a cycling program. | Device: sacral neuromodulator<br>* The Implanted Pulse Generator will be set via randomization to continuous vs cycling stimulation.<br>* Other names: Interstim;|
| Active Comparator: Continuous<br>Sacral neuromodulator devices (implanted pulse generator) will be programmed to be on continuously. This means the devices are continuously on. They are on a continuous program. | Device: sacral neuromodulator<br>* The Implanted Pulse Generator will be set via randomization to continuous vs cycling stimulation.<br>* Other names: Interstim;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overactive Bladder Questionnaire-Short Form (OABq) Short Form Symptom Bother Scale Result | The Overactive Bladder Questionnaire (OAB-q) assesses symptom bother & health-related quality of life (HRQL) for overactive bladder. The short form OAB-q SF, provides a quick assessment of symptom bother, consisting of a 6-item symptom bother scale. The questionnaire is on a 6 point scale, 1 indicates symptom is not bothersome (best outcome), 6 indicates symptom bothers the participant a very great deal (worst possible outcome). The majority of the participants were missing the HRQL portion of the questionnaire, so this portion of the questionnaire was not included in the analysis. These are the raw scores ranges for each question prior to being transformed. The possible scores for complete surveys range from 13 (if the participant marked not bothersome for all 6) to 78 (if the participant marked a very great deal for all 6 questions) once transformed. The reported numbers are the transformed scores [(actual raw score-lowest possible score)/possible raw score range] X 100. | Three months after change in program from cycling to continuous or vice versa. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Voiding Diary: Urge Incontinence Episodes | Bladder Diaries (BD) are a useful clinical tool and one of the most common outcome measure used in studies of urinary incontinence and other forms of lower urinary tract dysfunction. The patient is asked to prospectively record the frequency, number and volume of voids and incontinence episodes. The National Institutes of Health (NIH) recommends diary duration of at least three days for research studies. | Three months after change in program from cycling to continuous or vice versa. | 
| Patient Global Impression of Improvement (PGI-I) Questionnaire Scale Results | The Patient Global Impression of Improvement (PGI-I) scale is a global index that may be used to rate the response of a condition to a therapy. It is a transition scale that is a single question asking the patient to rate their urinary tract condition now, as compared with how it was prior to before beginning treatment on a 7 point scale, 1 indicating the participant's condition is Very much better (best possible outcome), and 7 being Very much worse (worst possible outcome). The answers to the 7 questions were then averaged to a score. | Three months after change in program from cycling to continuous or vice versa. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Urge Urinary Incontinence, sacral neuromodulation