Urge Urinary Incontinence, Overactive Bladder
Conditions
Keywords
incontinence, overactive bladder, botox, anticholinergic
Brief summary
Urinary incontinence is a prevalent condition that markedly impacts quality of life and disproportionately affects women. Overactive Bladder syndrome (OAB) is defined as symptoms of urgency and frequency with urge urinary incontinence (OAB-wet) and without urge incontinence (OAB-dry). Conservative first line treatments for urge incontinence combined with other OAB symptoms (OAB-wet) include behavioral therapy, pelvic floor training +/- biofeedback, or the use of anticholinergic medications. These treatment modalities may not result in total continence and often drug therapy is discontinued because of lack of efficacy, side effects and cost or because of not wanting to take a pill. Behavioral therapy and pelvic muscle exercises require consistent, active intervention by the patient which is often not sustained. Thus, the objective of the Anticholinergic vs Botox Comparison Study (ABC) is to determine whether a single intra-detrusor injection of botulinum toxin A (Botox A®) is more effective than a standardized regimen of oral anticholinergics in reducing urge urinary incontinence. The null hypothesis is that there is no difference in the change from baseline in average number of urge urinary incontinence episodes over 6 months between groups.
Detailed description
This study is a 6-month double-blind randomized trial comparing intra-detrusor botulinum toxin A (Botox A®) and anticholinergic therapy in women without neurologic disease with urge incontinence. Subjects will be followed up to an additional six months off study drug to determine duration of treatment effect. The primary aim is to compare the change in urge incontinence episodes over 6 months between women receiving a single intra-detrusor injection of 100 unit of botulinum toxin A (Botox A®) plus daily oral placebo tablets versus women receiving a single intra-detrusor injection of saline plus daily anticholinergic therapy.
Interventions
DRUGBotulinum toxin A (Botox A®)
A single intradetrusor injection of 100U botulinum toxin A in 10 mL plus 0.1 mL of indigo carmine administered during cytoscopy. Between 100 and 200ml of saline is instilled into the bladder prior to injection to allow adequate visualization of the entire bladder urothelium. The treating physician will inject a total of 10.1 mL of the masked substance into approximately 15 to 20 different detrusor muscle sites under direct visualization using disposable needles. Injections will be spread out to equally cover the posterior bladder wall and dome, but spare the bladder trigone and ureteral orifices.
DRUGSolifenacin 5mg
Oral Solifenacin 5mg once a day for up to 6 months
DRUGSolifenacin 10mg
Oral Solifenacin 10mg once a day for up to 4 months
Oral Trospium chloride XR 60mg once a day for up to 2 months
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD Pelvic Floor Disorders Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject has signed informed consent. * Females at least 21 years of age * Five or more urge urinary incontinence episodes on a three-day voiding diary. Urge incontinence episodes will be determined based on voiding diary and subject indication of coincident urge symptoms, allowing self-characterization of incontinence type. * Urge predominant (urge \>50% of total incontinent episodes) urinary incontinence based on self-reported characterization of incontinent episodes on diary. * Demonstrated ability (or have caregiver demonstrate ability) to perform clean intermittent self-catheterization in the event that this would be required. * Request for treatment for urge urinary incontinence. The patient may have tried other non-pharmacologic treatments for urge incontinence, such as supervised behavioral therapy, supervised physical therapy, unsupervised physical therapy, supervised biofeedback, and transvaginal electrical stimulation. * Subject has undergone 3-week washout period if subject were on anticholinergic therapy prior to enrollment. * Subject is able to complete all study related items and interviews.
Exclusion criteria
* Any previous therapy with trospium chloride, solifenacin, or darifenacin * Failed three or more anticholinergic drugs. * Contraindication to anticholinergic therapy, specifically with solifenacin or trospium. * Current symptomatic urinary tract infection that has not resolved prior to randomization. * Uncontrolled narrow-angle glaucoma * Gastric retention * Baseline need for intermittent self catheterization * PVR \>150ml on 2 occasions with void(s) of greater than 150ml * Surgical treatment for stress incontinence (sling, Burch or urethral injection) or pelvic organ prolapse recommended or planned at enrollment by study investigator(s). * Any prior intra-detrusor botulinum toxin A injections * Previous or currently implanted neuromodulation (sacral or tibial). * Surgically altered detrusor muscle, such as augmentation cystoplasty. * Known allergy to botulinum toxin A. * Women with known neurologic disease believed to potentially affect urinary function (Multiple sclerosis, spinal cord injuries, myasthenia gravis, Charcot-Marie-Tooth disease). * Known allergy to lidocaine. * Currently pregnant or lactating patients or patients planning pregnancy within the next year. * Sexually active premenopausal women with a uterus who have either not had a tubal ligation or are not on a medically approved form of contraception for at least 3 months prior to and throughout the duration of the study. * Cystoscopic findings that preclude injection, in the opinion of the investigator. * Current or prior bladder malignancy. * In the opinion of the investigator, inability to understand diary instructions and complete 3-day voiding diary. * Subjects who are on anticoagulant therapy,excluding aspirin * Subject has been previously diagnosed with interstitial cystitis or chronic pelvic pain syndrome. * Subjects with hematuria who have not undergone a clinically appropriate evaluation. * Subjects taking aminoglycosides at the time of injection. * Serum creatinine level greater than twice the upper limit of normal within the previous year. * Two or more hospitalizations for medical conditions in the previous year. * Plans to move out of area in the next 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urge Urinary Incontinence (UUI) Episodes | Baseline through 6 months | Change from baseline in mean number of UUI episodes over 6 month double-blind period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Score on OABq-SF | Baseline through 6 months | Values for the Overactive Bladder Questionnaire Short Form (OABq-SF) are changes from baseline in the adjusted mean scores for months 1 to 6. Scores on the OABq-SF range from 0 to 100, with higher scores on the symptom-severity scale indicating greater severity of symptoms and higher scores on the quality-of-life scale indicating better quality of life. Data were available for 123 participants in the Standardized Anticholinergic Regimen group and 119 in the Botox A A group. |
| Efficacy | 6 months | Efficacy outcomes assessed reduction and resolution of incontinence, including urgency urinary incontinence (UUI). |
| Change in PFDI-SF and PFIQ-SF Total Scores | Baseline through 6 months | Values for Pelvic Floor Distress Inventory Short Form (PFDI-SF) are changes from baseline in the adjusted mean scores for months 3 to 6. Scores on the PFDI-SF range from 0 to 300, with higher scores indicating more symptoms and more bothersome symptoms. Values for the Pelvic Floor Impact Questionnaire Short Form (PFIQ-SF) are changes from baseline in the adjusted mean scores for months 3 to 6. Scores on the PFIQ-SF range from 0 to 300, with higher scores indicating a more negative effect on activities, relationships, and feelings. |
| Patient Global Impression of Improvement | 3 and 6 months | The Patient Global Impression of Improvement (PGI-I) is a patient-reported measure of perceived improvement with treatment, as assessed on a scale of 1 (very much better) to 7 (very much worse). Included here are participants who had adequate improvement, defined as a rating of 1 or 2 (much better). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Botox A A single intradetrusor injection of 100U botulinum toxin A (Botox A®) plus daily oral placebo tablets
Botulinum toxin A (Botox A®): A single intradetrusor injection of 100U botulinum toxin A in 10 mL plus 0.1 mL of indigo carmine administered during cytoscopy. Between 100 and 200ml of saline is instilled into the bladder prior to injection to allow adequate visualization of the entire bladder urothelium. The treating physician will inject a total of 10.1 mL of the masked substance into approximately 15 to 20 different detrusor muscle sites under direct visualization using disposable needles. Injections will be spread out to equally cover the posterior bladder wall and dome, but spare the bladder trigone and ureteral orifices. | 121 |
| Standardized Anticholinergic Regimen A standardized 3-step anticholinergic regimen of daily oral solifenacin 5mg, solifenacin 10mg, and/or trospium XR 60mg, as well as a single intradetrusor injection of saline (placebo). All subjects will begin on solifenacin 5 mg for 2 mo. If a subject's symptoms are not adequately controlled at 2 mo, she will be escalated to solifenacin 10mg, and similarly at 4 mo to trospium XR 60mg. If a subject's symptoms are adequately controlled on solifenacin 5 mg, she may continue that study medication for the entirety of the study (6 mo). Additionally, if a subject is dose-escalated to solifenacin 10mg at study mo 2 or 4, and her symptoms are adequately controlled, she may continue the solifenacin 10mg dose for the remainder of the study.
Solifenacin 5mg: Oral Solifenacin 5mg once a day for up to 6 months
Solifenacin 10mg: Oral Solifenacin 10mg once a day for up to 4 mon | 126 |
| Total | 247 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Phase: 1st 6 Months | Lost to Follow-up | 0 | 4 |
| Double-blind Phase: 1st 6 Months | Not treated | 1 | 1 |
| Double-blind Phase: 1st 6 Months | Withdrawal by Subject | 8 | 4 |
| Off Treatment Follow-up Phase | Lack of Efficacy | 29 | 52 |
| Off Treatment Follow-up Phase | Lost to Follow-up | 4 | 2 |
| Off Treatment Follow-up Phase | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Botox A | Total | Standardized Anticholinergic Regimen |
|---|---|---|---|
| Age, Continuous | 59.3 Years STANDARD_DEVIATION 10.8 | 57.9 Years STANDARD_DEVIATION 11.3 | 56.7 Years STANDARD_DEVIATION 11.6 |
| Educational level at least some college | 86 Participants | 176 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 22 Participants | 44 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 99 Participants | 203 Participants | 104 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Marital Status Divorced, separated, or widowed | 44 Participants | 92 Participants | 48 Participants |
| Marital Status Married or living as married | 58 Participants | 115 Participants | 57 Participants |
| Marital Status Not reported | 4 Participants | 8 Participants | 4 Participants |
| Marital Status Other | 0 Participants | 1 Participants | 1 Participants |
| Marital Status Single, never married | 15 Participants | 31 Participants | 16 Participants |
| Menopausal status Not sure | 4 Participants | 16 Participants | 12 Participants |
| Menopausal status Postmenopausal | 102 Participants | 194 Participants | 92 Participants |
| Menopausal status Premenopausal | 15 Participants | 37 Participants | 22 Participants |
| No prior anticholinergic therapy | 48 Participants | 102 Participants | 54 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 41 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) White | 96 Participants | 194 Participants | 98 Participants |
| Sex: Female, Male Female | 121 Participants | 247 Participants | 126 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking status Current smoker | 15 Participants | 27 Participants | 12 Participants |
| Smoking status Never smoked | 66 Participants | 140 Participants | 74 Participants |
| Smoking status Not reported | 1 Participants | 1 Participants | 0 Participants |
| Smoking status Previous smoker | 39 Participants | 79 Participants | 40 Participants |
| Type of health insurance Combination of several types | 21 Participants | 37 Participants | 16 Participants |
| Type of health insurance Medicare or Medicaid only | 10 Participants | 26 Participants | 16 Participants |
| Type of health insurance Not reported | 1 Participants | 1 Participants | 0 Participants |
| Type of health insurance Other only | 28 Participants | 62 Participants | 34 Participants |
| Type of health insurance Private only | 61 Participants | 121 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 121 | 97 / 126 |
| serious Total, serious adverse events | 5 / 121 | 7 / 126 |
Outcome results
Primary
Change in Urge Urinary Incontinence (UUI) Episodes
Change from baseline in mean number of UUI episodes over 6 month double-blind period.
Time frame: Baseline through 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Botox A | Change in Urge Urinary Incontinence (UUI) Episodes | 6 Months | -3.27 Mean change in UUI episodes from baselin | Standard Error 0.2864 |
| Botox A | Change in Urge Urinary Incontinence (UUI) Episodes | 2 Months | -3.32 Mean change in UUI episodes from baselin | Standard Error 0.2854 |
| Botox A | Change in Urge Urinary Incontinence (UUI) Episodes | 3 Months | -3.22 Mean change in UUI episodes from baselin | Standard Error 0.2854 |
| Botox A | Change in Urge Urinary Incontinence (UUI) Episodes | 4 Months | -3.36 Mean change in UUI episodes from baselin | Standard Error 0.2857 |
| Botox A | Change in Urge Urinary Incontinence (UUI) Episodes | 5 Months | -3.42 Mean change in UUI episodes from baselin | Standard Error 0.2881 |
| Botox A | Change in Urge Urinary Incontinence (UUI) Episodes | 1 Month | -3.13 Mean change in UUI episodes from baselin | Standard Error 0.2851 |
| Standardized Anticholinergic Regimen | Change in Urge Urinary Incontinence (UUI) Episodes | 4 Months | -3.40 Mean change in UUI episodes from baselin | Standard Error 0.2766 |
| Standardized Anticholinergic Regimen | Change in Urge Urinary Incontinence (UUI) Episodes | 3 Months | -3.55 Mean change in UUI episodes from baselin | Standard Error 0.278 |
| Standardized Anticholinergic Regimen | Change in Urge Urinary Incontinence (UUI) Episodes | 6 Months | -3.33 Mean change in UUI episodes from baselin | Standard Error 0.2775 |
| Standardized Anticholinergic Regimen | Change in Urge Urinary Incontinence (UUI) Episodes | 1 Month | -3.15 Mean change in UUI episodes from baselin | Standard Error 0.2761 |
| Standardized Anticholinergic Regimen | Change in Urge Urinary Incontinence (UUI) Episodes | 5 Months | -3.49 Mean change in UUI episodes from baselin | Standard Error 0.2777 |
| Standardized Anticholinergic Regimen | Change in Urge Urinary Incontinence (UUI) Episodes | 2 Months | -3.25 Mean change in UUI episodes from baselin | Standard Error 0.2762 |
Secondary
Change From Baseline in Score on OABq-SF
Values for the Overactive Bladder Questionnaire Short Form (OABq-SF) are changes from baseline in the adjusted mean scores for months 1 to 6. Scores on the OABq-SF range from 0 to 100, with higher scores on the symptom-severity scale indicating greater severity of symptoms and higher scores on the quality-of-life scale indicating better quality of life. Data were available for 123 participants in the Standardized Anticholinergic Regimen group and 119 in the Botox A A group.
Time frame: Baseline through 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Botox A | Change From Baseline in Score on OABq-SF | OABq-SF Symptom Severity Score | -44.08 Change from baseline in score on OABq-SF | Standard Error 2.54 |
| Botox A | Change From Baseline in Score on OABq-SF | OABq-SF Quality of Life Score | 37.13 Change from baseline in score on OABq-SF | Standard Error 2.578 |
| Standardized Anticholinergic Regimen | Change From Baseline in Score on OABq-SF | OABq-SF Symptom Severity Score | -44.55 Change from baseline in score on OABq-SF | Standard Error 2.44 |
| Standardized Anticholinergic Regimen | Change From Baseline in Score on OABq-SF | OABq-SF Quality of Life Score | 37.05 Change from baseline in score on OABq-SF | Standard Error 2.479 |
Secondary
Change in PFDI-SF and PFIQ-SF Total Scores
Values for Pelvic Floor Distress Inventory Short Form (PFDI-SF) are changes from baseline in the adjusted mean scores for months 3 to 6. Scores on the PFDI-SF range from 0 to 300, with higher scores indicating more symptoms and more bothersome symptoms. Values for the Pelvic Floor Impact Questionnaire Short Form (PFIQ-SF) are changes from baseline in the adjusted mean scores for months 3 to 6. Scores on the PFIQ-SF range from 0 to 300, with higher scores indicating a more negative effect on activities, relationships, and feelings.
Time frame: Baseline through 6 months
Population: Data were available for 111 participants in the Standardized Anticholinergic Regimen group and 102 in the Botox A group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Botox A | Change in PFDI-SF and PFIQ-SF Total Scores | Change from baseline in PFDI-SF total score | -48.20 Changes in adjusted mean scores | Standard Error 5.56 |
| Botox A | Change in PFDI-SF and PFIQ-SF Total Scores | Change from baseline in PFIQ-SF total score | -33.85 Changes in adjusted mean scores | Standard Error 6.313 |
| Standardized Anticholinergic Regimen | Change in PFDI-SF and PFIQ-SF Total Scores | Change from baseline in PFDI-SF total score | -43.69 Changes in adjusted mean scores | Standard Error 5.34 |
| Standardized Anticholinergic Regimen | Change in PFDI-SF and PFIQ-SF Total Scores | Change from baseline in PFIQ-SF total score | -32.82 Changes in adjusted mean scores | Standard Error 6.065 |
Secondary
Efficacy
Efficacy outcomes assessed reduction and resolution of incontinence, including urgency urinary incontinence (UUI).
Time frame: 6 months
Population: Efficacy outcomes were assessed in the modified intention-to-treat population, which included all participants who underwent randomization and received a study medication and who had a baseline measure and at least one follow-up measure for the outcome. Proportions were based on data from participants who returned at least four follow-up diaries.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Botox A | Efficacy | >75% reduction in UUI episodes | 61 Participants |
| Botox A | Efficacy | Complete resolution of UUI | 30 Participants |
| Botox A | Efficacy | Complete resolution of all incontinence | 26 Participants |
| Standardized Anticholinergic Regimen | Efficacy | Complete resolution of UUI | 16 Participants |
| Standardized Anticholinergic Regimen | Efficacy | Complete resolution of all incontinence | 13 Participants |
| Standardized Anticholinergic Regimen | Efficacy | >75% reduction in UUI episodes | 48 Participants |
Secondary
Patient Global Impression of Improvement
The Patient Global Impression of Improvement (PGI-I) is a patient-reported measure of perceived improvement with treatment, as assessed on a scale of 1 (very much better) to 7 (very much worse). Included here are participants who had adequate improvement, defined as a rating of 1 or 2 (much better).
Time frame: 3 and 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Botox A | Patient Global Impression of Improvement | Month 3 | 61 Participants |
| Botox A | Patient Global Impression of Improvement | Month 6 | 60 Participants |
| Standardized Anticholinergic Regimen | Patient Global Impression of Improvement | Month 3 | 59 Participants |
| Standardized Anticholinergic Regimen | Patient Global Impression of Improvement | Month 6 | 67 Participants |