1. OnabotulinumtoxinA (Botox®) for the Treatment of Overactive Bladder
Reema Shah
Thomas Jefferson University School of Pharmacy
Doctor of Pharmacy Candidate
March 13, 2013
-will refer to the medication by its brand name botox throughout the presentation, not the generic name
BOTOX was recently (Jan 2013) FDA approved for the treatment of overactive bladder in adults who do not have an adequate response to or are intolerant of an anticholinergic (which is considered 1st line therapy) medication so it is important for us to look at the evidence behind what got its approval to understand the clinical significance of this medication

2. Objectives
Describe the epidemiology, clinical presentation, pathophysiology, and diagnosis of overactive bladder
Review the current guidelines for the treatment of overactive bladder in adults according to the American Urological Association
Explain the pharmacology of Botox®
Evaluate the objectives, study design, results, and clinical significance of clinical trials conducted to examine the use of Botox® for the treatment of overactive bladder
Assess the overall risks and benefits of the use of Botox® for the treatment of overactive bladder
Will focus on non-neurogenic causes
Previously approved for OAB due to neurogenic causes (Parkinson’s disease, multiple sclerosis, or spinal cord injury (SCI), in adults who have an inadequate response to or are intolerant of an anticholinergic medication.
But FDA has expanded its approval

3. Epidemiology
Overactive bladder (OAB) affects 12%-17% of the general population in the U.S.
1/3rd suffer from urinary incontinence
Higher prevalence rates in women than men
Symptom prevalence and severity tends to increase with age
Significant burden for patients
Associated with high rates of morbidity
Higher prevalence rates in women than men: women twice as likely
Significant burden for patients: on QOL, work productivity, psychologically (can lead to depression & anxiety), socially, sleep quality, cost, socioeconomic burden
Carrying out the activities of daily life and engaging in social and occupational activities can be profoundly affected by lack of bladder
control and incontinence resulting in restricted activities and unwillingness to be exposed to environments where
access to a bathroom may be difficult.
Morbidity: One of the most important concerns of all physicians is that poor bladder control can cause complications and result in falls and fractures. Women who have weekly urge incontinence have a 26% greater risk of sustaining a fall and a 34% increased risk of fracture after adjusting for other causes.
About 40% of OAB cases remit during a given year, but the majority of patients have symptoms for years
Nitti VW, et al. J Urol doi: /j.juro
Tyagi S, et al. Urol Clin N Am :

4. Clinical Presentation
Urinary frequency
>8 micturitions/day
Urgency with OR without urge incontinence
Nocturia
>1 micturition/night or nocturnal incontinence (enuresis)
Urgency: sudden compelling desire to urinate that is difficult to delay
Urgency with OR without urge incontinence:
when they experience a sensation of urgency, they may leak urine if they are unable to reach the bathroom quickly
Rovner, et al. Pharmacotherapy: A Pathophysiological Approach

5. Pathophysiology Involuntary bladder contractions
Detrusor muscle is overactive and contracts inappropriately during the filling phase
Contraction controlled through activation of muscarinic receptors (primarily M3) by ACh
Neurogenic causes: Damage to central inhibitory pathways->Muscarinic receptors are constantly being stimulated
Acetylcholine, Sensitization of peripheral afferent terminals in the bladder, Increased peripheral afferent activity, Increased peripheral sensitivity to efferent impulses
Myogenic causes: Changes in bladder pressure due to changes in the bladder smooth muscle (detrusor muscle)
Ex: bladder outlet obstruction
Increased pressure causes destruction of the efferent nerve endings → detrusor muscle hyper-excitability
Acetylcholine activation of muscarinic receptors to contract the detrusor appears to be the most important physiologic control system for urinary bladder contraction. Muscarinic receptors, found on presynaptic nerve terminals, may be excitatory or inhibitory. To date, ≥3 muscarinic receptor subtypes (M1 to M3) have been identified in the human bladder by receptor-binding assays. M1 receptors appear to facilitate the release of acetylcholine in the bladder. M2 receptors predominate in the human bladder, but M3 receptors mediate the cholinergic-induced contractions of the detrusor. The M2 and M3 receptors are functionally coupled14 and act synergistically.15 Activation of M2 receptors inhibits sympathetically mediated detrusor relaxation; therefore, coactivation of M2 receptors may enhance the detrusor response to M3 receptors. There is some evidence that M2 receptors may also partially stimulate bladder contraction directly.The relative contribution of the muscarinic receptors may be altered during aging, disease, or neurogenic lesions; muscarinic receptor functions may upregulate mechanisms that normally have little clinical importance, and contribute to the pathophysiology of OAB.
Rovner, et al. Pharmacotherapy: A Pathophysiological Approach

6. Etiology Idiopathic (most common) Normal aging Neurologic disease
Stroke
Parkinson’s disease
Multiple sclerosis
Spinal cord injury
Myogenic
Bladder outlet obstruction
BPH
Prostate cancer
Idiopathic: in the absence of causative infection or pathological conditions
Normal aging: diabetes (polyuria), sleep disorders (apnea) can contribute to nocturia, disorders of pelvic floor muscles (fecal incontinence)
Neurogenic: changes within the central or peripheral nervous system
Myogenic: changes within the smooth muscle of the bladder wall itself
Rovner, et al. Pharmacotherapy: A Pathophysiological Approach

7. Diagnosis Based on patient’s symptoms
Urinalysis and urine culture should be negative
rule out urinary tract infection as cause of frequency
Urodynamic studies are the gold standard for diagnosis
Mainly for detrusor overactivity
investigation of function and dysfunction of the lower urinary tract is referred to as “urodynamics.” – checking bladder pressure, measure how much the bladder can actually hold, how much urine is left in bladder after urination
The overactive bladder has to be differentiated from detrusor overactivity, which is a urodynamic diagnosis: only 50% of patients with OAB have detrusor overactivity, on the other side 50% of those who show detrusor overactivity in urodynamics, have no clinical symptoms. Overactive bladder is a symptomatic diagnosis, the symptoms can be caused by a broad spectrum of various path physiologies: polyuria due to exaggerated fluid intake may cause the same symptoms as they are reported by a patient, in whom,
when exposed to the cold, detrusor overactivity is provoked—two totally different path physiologies, but both patients have the same symptoms.
Rovner, et al. Pharmacotherapy: A Pathophysiological Approach

8. Current Guidelines for Treatment of Overactive Bladder
1st /2nd line for treatment:
Nonpharmacological
lifestyle modifications such as toilet scheduling regimens and pelvic floor muscle rehabilitation
Anticholinergic medications
Oxybutynin, tolterodine, trospium, solifenacin, darifenacin
3rd line for treatment:
Botox® injection
Currently, anticholinergic agents are the mainstay of pharm treatment for OAB; however, they are not always sufficiently effective and have numerous systemic side effects (dry mouth), leading to poor patient compliance/adherence and high discontinuation rates in clinical practice. Botox use for this condition may offer a new treatment option for patients with UUI who are inadequately managed with anticholinergics (inadequate efficacy or intolerable side effects) by only treating the bladder and minimizing the potential for systemic side effects.
Drugs with anticholinergic activity act by antagonizing muscarinic cholinergic receptors, through which efferent parasympathetic nerve impulses evoke detrusor contraction. Anticholinergics have been demonstrated to improve quality of life, with no significant differences between agents
SIDE EFFECTS OF ANTICHOLINERGIC: DRY MOUTH, CONSTIPATION, DIZZINESS, VISION IMPAIRMENT, CONFUSION, COGNITIVE DYSFUNCTION, UTI, Urinary retention
GUIDELINES:
One of the main limitations of anti-muscarinic therapy is that the majority of patients discontinue after a few weeks or months.
Although there may be several factors involved in this decision, side effects are commonly cited as the reason for discontinuation.
Guidelines:” Clinicians may offer intradetrusor onabotulinumtoxinA as third-line treatment in the carefully
selected and thoroughly counseled patient who has been refractory to first and second line OAB treatments. The patient
must be able and willing to return for frequent post void residual evaluation and able and willing to perform self catheterization if necessary”
Gormley EA, et al. American Urological Association

9. Pharmacology of Botox®
Mechanism of Action
Cleaves SNARE protein
SNAP-25
Prevents assembly of vesicles
Inhibition of ACh release
Detrusor muscle relaxation
Pharmacokinetics
Onset of action: ~ 2 weeks
Duration: ~ 24 weeks
MOA: Acetylcholine in nerve terminals is packaged in vesicles. Normally, vesicle membranes fuse with those of the nerve terminals, releasing the transmitter into the synaptic cleft. The process is mediated by a series of proteins collectively called the SNARE proteins. Botulinum toxin, taken up into vesicles, cleaves the SNARE proteins, preventing assembly of the fusion complex and thus blocking the release of acetylcholine.
Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release. (package insert)
BOTOX blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to
the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity.
In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX. Neuromuscular transmission is prevented, resulting in flaccid paralysis and muscle weakness.
Onset of action: 2 weeks to see improvement
Duration for OAB: studies have shown about 24 weeks,
may consider retreatment with diminishing effect but no sooner than 12 weeks from the previous administration (median time until second treatment in studies: ~24 weeks)
OnabotulinumtoxinA. Lexi-Comp, Inc
Rowland LP. N Engl J Med. 2002; 347:

10. Dosing and Administration
Botox® 100 units reconstituted with 10 ml normal saline
Administered as 20 evenly distributed intradetrusor injections
0.5 ml per injection site
using a cytoscope
Injections spaced ~ 1 cm apart
Needle inserted ~ 2mm into detrusor
Local anesthesia usually administered into the bladder prior to treatment
OnabotulinumtoxinA has been evaluated in a placebo-controlled dose-ranging trial in OAB patients with urinary incontinence (UI), and the dose of 100U was demonstrated to provide the appropriate benefit-risk balance.
Dose ranging trial (50U,100U,150U,200U,300U) -> >100U not significantly more efficacious, increased risk of ADR with higher doses
Botox® [package insert]. Allergan. Irvine, CA; January 2013.

11. Nitti VW, Dmochowski R, Herschorn S, et al. J Urol. 2012.
Clinical Trial #1
OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results of a Phase 3 Randomized Placebo-Controlled Trial
Nitti VW, Dmochowski R, Herschorn S, et al. J Urol
Purpose:
To assess the safety and effectiveness of onabotulinumtoxinA in treating patients with idiopathic overactive bladder with incontinence who were inadequately managed with anticholinergics
Currently,anticholinergic agents are the mainstay of pharmacologic treatment for OAB; however, they are
not always sufficien tly effective and have numerous systemic side-effects,7 leading to poor patient compliance and high discontinuation rates in clinical practice.8 OnabotulinumtoxinA
delivered directly to the detrusor muscle may represent a new treatment paradigm for OAB
patients with UUI who are inadequately managed with anticholinergic therapy (inadequate
efficacy or intolerable side-effects), by treating only the bladder and minimizing the potential
for systemic side-effects.
Nitti VW, et al. J Urol doi: /j.juro

12. Study Design Total: 557 Botox® = 280 Placebo: = 277
Double blind, placebo controlled, randomized trial at 72 sites in the US and Canada
Intention to treat
Patients received one of the following interventions:
Botox® 100 unit intradetrusor injection
Placebo: 10ml normal saline intradetrusor injection
Stratified by site and ≤9 or >9 UUI episodes at baseline
Follow up visits
Occurred at weeks 2, 6, and 12 and thereafter every 6 weeks until exit at week 24 unless retreatment occurred
Retreatment only considered after week 12
Sample population and demographics:
Total: 557
Botox® = 280
Placebo: = 277
Baseline characteristics were balanced across treatment groups
About 90% were female
Average age: 61.3 years
Duration of OAB: about 6.7 years
Prior anticholinergic use:
Duration: 2.4 years
# of anticholinergics: 2.5
Daily UI episodes: 5.3
Of those, 4.6 episodes/day were UUI
Intention to treat: Includes all patient randomized in the trial; Takes into consideration patients that dropped out in both groups
Characteristics show that severe symptoms, really effecting patients lives
RETREATMENT could occur from 12 weeks onward if the patient requested it and had at least 2 UUI episodes over 3 days (all of these patients received Botox)
The appropriate period for placebo-controlled comparison was up to week 12 because retreatment was only permitted thereafter
Nitti VW, et al. J Urol doi: /j.juro

13. Study Design Idiopathic OAB ≥18 years old
Inclusion Criteria
Exclusion Criteria
Idiopathic OAB
≥18 years old
≥3 urgency UI episodes in 3 days
≥8 micturitions/day
Symptoms of OAB with urinary incontinence for at least 6 months
Inadequate response or intolerable side effects with anticholinergics
PVR volume of ≤100ml
Be willing to use clean intermittent catheterization (CIC) if required
Use of anticholinergic within 7 days of screening or throughout the study
Patient has predominance of stress incontinence
History or evidence of pelvic or urological abnormality
Nitti VW, et al. J Urol doi: /j.juro

14. Power set at 82% (N=227) to detect a between group difference
Endpoints & Results
Primary outcome:
Change from baseline in average UI episodes/day (Weeks 2, 6, 12)
Botox® significantly reduced the daily frequency of UI episodes vs. placebo (-2.65 vs -0.87)
Mean % reductions from baseline of 47.9% with Botox vs. 12.5% with placebo
Analyzed using ANCOVA model
Covariates: baseline value and site
Factor: treatment group
Significant between group differences were observed from the first post treatment evaluation at week 2 and continued thru week 12
By week 12, there were 3 to 4 fold greater reductions from baseline in the mean daily frequency of UI episodes with Botox VS. placebo (-2.65 vs -0.87), which corresponded to mean percent reductions from baseline of -47.9% with Botox vs % with placebo.
Power
A sample size of 227 patients per treatment group was expected to provide
82% (change from baseline in daily UI episodes)
99% (TBS responders) power to detect a between group difference
Significance level =0.05
Power analysis done to determine how large of a sample size is required to detect an actual difference of some magnitude (Smaller the difference you want to detect, the larger the sample size that will be needed)
ANCOVA appropriate because analyzing continuous, parametric data of 2 groups; Can “control” for any differences there may be between the groups
ANCOVA evaluates whether population means of a dependent variable (DV) are equal across levels of a categorical independent variable(IV), while statistically controlling for the effects of other continuous variables that are not of primary interest, known as covariates (CV). Therefore, when performing ANCOVA, we are adjusting the DV means to what they would be if all groups were equal on the CV
Power set at 82% (N=227) to detect a between group difference
Significance level=0.05
p <0.001 vs placebo.
Error bars are ± 95% CI.
Nitti VW, et al. J Urol doi: /j.juro

15. Endpoints & Results Secondary outcome: efficacy
All parameters showed statistically significant improvement of outcomes with Botox® use compared to placebo
↓ micturition episodes/day
↓urgency episodes/day
↓nocturia episodes/day
↑volume voided/micturition
Evaluated using ANCOVA
Significant improvements were observed from the first post treatment evaluation at week 2 for all OAB symptoms that continued thru week 12.
Significant Increase in volume voided=>improved ability of the bladder to store urine more effectively
ANCOVA: stratification factor (using UUI Stratification factor) used rather that the baseline value. The % change from baseline for OAB symptoms was also calculated
P<0.05
Nitti VW, et al. J Urol doi: /j.juro

16. Endpoints & Results Secondary outcome: efficacy HRQOL (week 12)
Incontinence-Specific Quality of Life Instrument (I-QOL)
King’s Health Questionnaire (KHQ)
Use of Botox® significantly improved patients’ HRQOL across all measures compared to placebo
Analyzed using ANCOVA
These are 2 validated patient questionnaires.
The KHQ is a valid instrument for measuring the quality of life of patients with different types of UI. Improvements in urinary frequency, urinary urgency, number of leakage episodes, produces an increase in HRQOL.
The I-QOL is a useful instrument for the investigation of incontinence related quality of life in the community setting. The I-QOL measures the effect of urinary incontinence on quality of life. The I-QOL is divided into 3 subscales: 1) avoidance and limiting behavior (ALB); 2) psychosocial impact (PSI); and 3) social embarrassment (SE).
All HRQOL scales are reported on a scale (higher score->better HRQOL for the I-QOL and the reverse for the KHQ)
The pre-defined clinically relevant change from baseline in these HRQOL measures, or minimally important difference (MID), was >10 point increase for the I-QOL and >5 point decrease for the KHQ
All secondary and other efficacy outcomes were met with large significant differences between onabotulinumtoxinA and placebo.
The patients’ HRQOL at baseline was low as reflected by the I-QOL and KHQ scores in both treatment groups . Importantly, large and clinically significant improvements in all IQOL scores and KHQ multi-item domain scores following onabotulinumtoxinA were observed
versus placebo (p <0.001 for all). Improvements from baseline with onabotulinumtoxinA were considerably greater than the predefined MIDs, in contrast to placebo.
p <0.001
Nitti VW, et al. J Urol doi: /j.juro

17. Endpoints & Results Secondary Outcome: Side effect profile (safety)
Most common ADR: UTI (15.5% in Botox® group vs. 5.9% in placebo group)
Urinary retention (5.4% in Botox® group vs. 0.4% in placebo)
Significant increase in PVR urine volume in Botox® group
Evaluated at weeks 2,6,12 post treatment or at any other time depending on clinical need.
AE of urinary retention was defined as PVR urine volume >200ml that required CIC
AE UTI defined: +urine culture with bacteriuria count of >10^5 colony forming units/ml (REGARDLESS OF SYMPTOMS)
The most frequently reported AE was UTI, most of which occurred in the first 12 weeks (15.5 vs 6%). All UTIs were uncomplicated, with no upper urinary tract involvement.Other AEs that occurred at a higher incidence with Botox in the first 12 weeks were dysuria (12.2%), bacteriuria (5%), urinary retention (5.4%)
PVR urine volume significantly increased with onabotulinumtoxinA versus placebo, with the highest volume at week 2 post-treatment (+49.5, +42.1, and ml with onabotulinumtoxinA at weeks 2, 6, and 12 vs +1.1, +3.1, and +2.5 ml with placebo at weeks 2, 6, and 12, respectively; p <0.001). We observed 8.7% of patients (24/276) with an increase from baselineof ≥200 ml in PVR urine volume at any time following initial treatment with onabotulinumtoxinA (none withplacebo)
Nitti VW, et al. J Urol doi: /j.juro

18. Endpoints & Results Secondary outcome:
Proportion of patients who initiated clean intermittent catheterization (CIC) at any time during treatment cycle
6.1% (17/278) in the Botox® vs. 0% in the placebo group
Protocol: Initiated if PVR urine volume was ≥200ml and <350ml with associated symptoms (voiding difficulties or sensation of bladder fullness) or if PVR urine volume was ≥350ml regardless of symptoms
Associated symptoms: voiding difficulties or sensation of bladder fullness
The proportion of patients who initiated CIC at any time during treatment cycle 1 was 6.1% (17/278) versus none in the placebo group; for over half the patients who initiated CIC (10/17), the duration of CIC was ≤6 weeks (figure 4). Interestingly, while all 10 patients who had a PVR ≥350 mL initiated CIC (in accordance with the protocol guidance), only 6/21 (28.5%) patients with PVR urine volumes between 200 mL and <350 mL initiated CIC.
Nitti VW, et al. J Urol doi: /j.juro

19. Author’s Conclusions
The results of this study suggest that Botox® is an important new alternative treatment option for OAB patients with UI who are inadequately managed by anticholinergic therapy
demonstrated significant and clinically relevant improvements in all OAB symptoms and HRQOL in patients
Overall well tolerated
But high incidence of UTI and urinary retention
These results are notable given that currently, there are very few pharmacologic treatment options for patients who have had an inadequate response to anticholinergics.
Nitti VW, et al. J Urol doi: /j.juro

20. Critique of Study Strengths Weaknesses Intent to treat Randomized
Use of appropriate HRQOL measures
Large sample size
Sponsored/funded by Allergan
Failed to mention other medications patient’s were currently on
Mostly women took part in trial (~ 90%)
Strengths:
Randomized-minimizes bias
Intent to treat: takes into acct all patients, includes patients who dropped out
Medications influencing lower urinary tract function: diuretics, antipsychotics, use of alcohol, CCB (retention)
Placebos may be used in clinical trials where there is no known or available (i.e. FDA approved) alternative therapy that can be tolerated by participants.

21. Visco AG, Brubaker L, Richter HE, et al. N Engl J Med. 2012.
Clinical Trial #2
Anticholinergic Therapy vs. OnabotulinumtoxinA for Urgency Urinary Incontinence
Visco AG, Brubaker L, Richter HE, et al. N Engl J Med
Purpose:
To directly compare/contrast the use of a Botox® injection with the use of an oral anticholinergic for the treatment of urgency urinary incontinence by assessing the reduction in episodes of incontinence, improvement in quality of life, and side effect profiles
Visco AG, et al. N Engl J Med :

22. Study Design Sample population and demographics:
10 center, randomized, double blind, double placebo, controlled trial
Intention to treat
Sample population and demographics:
Enrollment: 249 underwent randomization
Anticholinergic group: 126 treated
Botox® group: 121 treated
None of the characteristics differed significantly between the treatment groups
Average age: years
100% women
78.5% caucasian
Mean urgency incontinence episodes/day: 5.0
41% had not previously received anticholinergic therapy
Visco AG, et al. N Engl J Med :

23. Study Design
Assigned into one of the following groups for a period of 6 months:
Oral anticholinergic daily + one time intradetrusor saline injection (placebo)
Solifenacin 5mg PO daily, with possible dose escalation
Oral placebo daily + one time Botox® 100 unit intradetrusor injection
Randomization was stratified according to:
previous exposure or no previous exposure to anticholinergic drugs
baseline severity of UUI
5-8 episodes vs. ≥ 9 episodes of urgency urinary incontinence in a 3 day period
site
Visco AG, et al. N Engl J Med :

24. Study Design Inclusion Criteria Exclusion Criteria Idiopathic
Females ≥ 21 years of age
≥5 urge urinary incontinence episodes on a 3-day voiding diary
Demonstrated ability (or have caregiver demonstrate ability) to perform clean intermittent self-catheterization
Undergone 3-week washout period if subject were on anticholinergic therapy prior to enrollment
Any previous therapy with trospium chloride, solifenacin, or darifenacin
Failed 3 or more anticholinergic drugs
Contraindication or allergies to any of the therapies used in the study
Current symptomatic urinary tract infection that has not resolved prior to randomization
PVR >150ml on 2 occasions with void(s) of greater than 150ml
Any prior urinary incontinence therapy with onabotulinumtoxinA
known neurologic disease
Visco AG, et al. N Engl J Med :

25. Study Design Follow Up Evaluation: Month 6:
Office visits scheduled every 2 months
Patient Global Symptom Control (PGSC)
used to assess whether current treatment was providing adequate control of urinary leakage
Patient’s answered this statement:
“This treatment has given me adequate control of my urinary leakage”
Range from 1 (disagree strongly) to 5 (agree strongly)
Dose escalation was allowed at months 2 and 4 only if
inadequate symptom control (if PGSC score was 1 to 3)
side effects were intolerable
Month 2: switch to solifenacin 10mg daily
Month 4: switch to trospium XR 60mg daily
PGSC score > 3: continue same regimen until next 2 month visit
Month 6:
all oral medications were discontinued
Participants that had adequate symptom control and who did not receive off protocol treatment for OAB were followed monthly for up to 6 additional months in order to assess the duration of effect of the medications
-Chose these anticholinergic medications because different MOA: solifenacin (selective M3 anticholinergic), trospium (non-selective anticholinergic), BOTH once daily dosing
-PGSC instument was used to assess whether the current treatment was providing adequate control of urinary leakage; Patient’s answered this statement “This treatment has given me adequate control of my urinary leakage”Range from 1 (disagree strongly) to 5 (agree strongly) responses to the statement “This treatment has given me adequate control of urinary leakage” range from 1 (disagree strongly) to 5 (agree strongly)
Botox group was offered same dose escalation of the oral placebo based on same criteria
Participants in both groups who had adequate control of symptoms (PGSC score of 4 to 5) and who did not receive off protocol treatment for OAB were followed monthly for up to 6 additional months in order to assess the duration of effect of the medications
Visco AG, et al. N Engl J Med :

26. Endpoints & Results
Primary outcome:
Mean reduction from baseline in # of episodes of UUI per day over the 6-month, as reported for 3 day periods in monthly bladder diaries
Anticholinergic group: reduction of 3.4 episodes/day
Botox® group: reduction of 3.3 episodes/day
Reduction in episodes per day was similar in the two groups
Evaluated using linear mixed model
P value =0.81 (statistically insignificant)
Linear mixed model: similar to linear regression, but takes into account missing data “at random”, used for stratified data
For the primary analyses, we used a linear mixed model with participant-month in the study (1 through 6) as the unit of analysis and the change from baseline in the number of episodes of urgency urinary incontinence as the outcome, with terms for treatment group, month, and the interaction of treatment group with month and categorical covariates of previous or no previous exposure to anticholinergic drugs, baseline severity of urgency urinary incontinence, and site consistent with the randomization stratification variables. Study participant was treated as a random effect to account for the correlation in outcomes over time within a participant. The model generated adjusted estimates of change in the number of episodes of urgency urinary incontinence from baseline for each treatment group and month, and an F-test was used to test the hypothesis that the mean change from baseline across the 6 months differed between the treatment groups. Terms for the interaction of treatment with the stratification factors were added to evaluate whether the treatment effect differed according to these factors.
Power
Estimated that 121 participants in each treatment group would give 80% or greater power to detect a mean between group difference in the reduction from baseline if episodes of UUI of at least 0.8 episodes/day
Two sided type 1 error rate of 0.05
Power analysis done to determine how large of a sample size is required to detect an actual difference of some magnitude
Smaller the difference you want to detect, the larger the sample size that will be needed
Power set at ≥80% (N=121) to detect a between group difference in reduction of UUI
Two sided type 1 error rate of 0.05
(Significance level=0.05)
Bars indicate 95% CI
Visco AG, et al. N Engl J Med :

27. Endpoints & Results Secondary outcome: (efficacy)
Change in QOL outcomes from baseline
Overactive Bladder Questionnaire (OABq-SF)
Pelvic Floor Distress Inventory (PFDI-SF)
Pelvic Floor Impact Questionnaire (PFIQ-SF)
Patient Global Impression of Improvement (PGI-I)
No statistically significant differences in the magnitude of improvement between both groups
P<0.05
OABq-SF: overactive bladder questionnaire short form: includes symptom severity scale and QOL scale
-scores range from 0-100, with higher scores on the symptom severity scale indicating greater severity of symptoms and higher score on the QOL scale indicating better QOL
Symptom Severity scale: decrease in score (positive effect)
Quality of life scale: increase in scores (improved quality of life)
OAB-SF symptom severity score: minimum clinically important difference of 10 points needed
PFDI-SF: pelvic floor distress inventory short form: measures level of distress from pelvic floor disorders
-higher scores indicate more severe symptoms and more bothersome symptoms
PFIQ-SF:pelvic floor impact questionnaire short form: measures the effect of pelvic floor disorders on daily life
-higher scores indicating a more negative effect on activities, relationships, and feelings
PGI-I: patient global impression of improvement: patient reported measure of perceived improvement with treatment, on a scale of 1 (very much better) to 7 (very much worse) (via telephone). Included here are participants who had adequate improvement, defined as a rating of 1 or 2 (very much better, much better)
**Both groups had increases in scores on the OABq-SF QOL score (indicating improved quality of life) and decreases in scores (indicating a positive effect on the participant) on the OABq-SF symptom severity scale, the PFDI-SF, PFIQ-SF, and the PGI-I.
-However, there were no significant between group differences in the magnitudes of these improvements
-both had response by 1 month
All validated tools used to assess incontinence in patients; appropriate to use these instruments because QOL outcomes are subjective and different to each patient.
PGI-I: The PGI scales are robust and valid instruments to assess disease severity, bother and improvement after treatment in women with OAB.
Visco AG, et al. N Engl J Med :

28. Endpoints & Results Secondary Outcome: (safety) Side effect profile
Statistically significant side effects
-Dry mouth: Higher rates in anticholinergic group (46%)
-# of patients requiring catheterization: higher rates in Botox ® group
-Due to PVR urine volume > 300ml or >150ml in patients who felt moderately bothered
Evaluated using Mantel-Haenszel test
Mantel-Haenszel test: used for all the safety results; outcomes were evaluated with the use of contingency tables, with differences between treatment groups assessed with the use of Mantel-Haenszel (test used to calculate the p value) that accounted for randomization strata.
APPROPRIATE TO use because its used in the analysis of stratified categorical data
Randomization was stratifed according to previous exposure or no previous exposure to anticholinergic drugs, baseline severity of urgency urinary incontinence (5 to 8 episodes vs. ≥ 9 episodes or urgency urinary incontinence in a 3 day period) and site.
For the majority of side effects, there was no statistically significant difference in side effect profile between both groups.
Dry mouth occurred significantly more in anticholinergic group than Botox group (46% to 31%, P=0.02)
Intermittent catheterization was recommended according to protocol criteria at scheduled visits in the Botox group only
However, additional women in both groups performed catheterization off protocol.
Visco AG, et al. N Engl J Med :

29. Endpoints & Results Secondary Outcome: (safety) Side effect profile
Statistically significant side effects in Botox® group
Urinary tract infection (33%)
Residual volume after voiding >150ml (Urinary retention)
P<0.05
More women in the Botox group developed a UTI (33% vs 13%m;P<0.001, which shows that it is a statisically significant side effect)
and more women in the Botox group had post void residual urine volume>150ml ( which suggests urinary retention, which could have lead to the cause of developing a urinary tract infection)
Two significant side effects of Botox compared to anticholinergic -> higher rates of urinary retention (primarily upto 2 months post treatment) and UTI
Visco AG, et al. N Engl J Med :

30. Endpoints & Results Secondary Outcome:
Duration of effect of medications after cessation of treatment
% of participants with adequate symptom control (PGSC score of 4 or 5) with time
evaluated with the use of Kaplan-Meier product limit estimates and associated log rank tests
% of Adequate control of symptoms during off-treatment follow up
Botox®
Anti-cholinergic
P value
Significance
Month 7
62%
50%
0.006
Significant
Month 12
38%
25%
0.61
Insignificant
Kaplan-Meier: (Survival analysis), Is appropriate for this because patients followed over time until they experience the outcome which is dichotomous (either pt. has adequate control of symptoms or NOT)
Log rank: Tests used to compare curves to determine statistical significance
At 6 months, oral study drugs, active or placebo, were discontinued. To determine the duration of effect, participants were contacted by phone monthly from that point until 12 months after initiation of treatment or until they reported inadequate symptom control (PGSC score of 1 to 3).
At 6 months, 89 of the 126 participants (71%) who were randomly assigned to and received the anticholinergic medication and 85 of the 121 (70%) who were randomly assigned to and received Botox had adequate control of symptoms, as defined by PGSC score of 4 or 5 and no off study treatment for urgency incontinence at or before 6 months entered the follow up phase. At 6 months, all oral medications were discontinued.
Within 1 month after discontinuation of the oral medication, significantly fewer women in the anticholinergic group than in the onabotulinumtoxinA group had adequate control of symptoms (50% vs. 62%, P = 0.006). At 12 months, 25% in the anticholinergic group, as compared with 38% in the onabotulinumtoxinA group, had adequate control of symptoms (P = 0.61)
1 month after discontinuation, significantly fewer women in the anticholinergic group than in the Botox® group had adequate control of symptoms
at month 12, results considered insignificant
Duration of effect of Botox is longer
Visco AG, et al. N Engl J Med :

31. Author’s Conclusion
No significant difference between oral anticholinergic drug and Botox® injection therapy in regards to:
reduction of the frequency of episodes of urgency incontinence
improvements in quality of life
both were effective treatments and the magnitude of the reductions did not differ significantly between the groups
Choice between these therapies should take into account:
Route of administration
Side effect profile
Anticholinergic: more frequent occurrence of dry mouth
Botox®: higher risks of catheterization because of urinary retention and higher risk of urinary tract infection
-shows that Botox can be used as alternative therapy to anticholinergics because it produced similar efficacy results
Visco AG, et al. N Engl J Med :

32. Critique of Study Strengths Weaknesses
No industry support (funding or provision of medications) was received
Randomized, double blind, comparative effectiveness study
Inclusion of possible dose escalation/switching medication
represents usual clinical practice
Did not include patient adherence rates of the oral medications
Did not compare cost-effectiveness of the therapies
Only women used
Strengths:
Funded by the Eunice Kennedy Shriver National Institute of child health and human development and the national institutes of health office of research on Women’s health.
Randomized-minimizes bias, especially since a lot of the tools used to assess efficacy of the medications were subjective measurements; if a patient already knows anticholinergics are mainstay of therapy, maybe more inclined to answer positively in regards to that medication
Generalizability of study findings: included patients that had not been on anticholinergic therapy before & pts who had exposure to up to 2 anticholinergic meds, multiple sites
QOL tools: (OAB is symptomatic, subjective to patient)- weakness too?
Inclusion of possible dose escalation/switching medication-
Represents the usual clinical practice of using more than one anticholinergic and also because data suggest that failure after one drug does not predict failure of another drug
Weaknesses:
Weaknesses
Results may not be generalizable to other anticholinergic medications. However reviews have shown there are relatively few clinically significant differences among currently available anticholinergic medications. But other meds may be dosed BID compared to QD
Only women used: although prevalence is higher in women, would have been better to include men too in order to use it in clinical practice in general
Placebo effect: since the trial compared 2 active treatments, we cant determine to what extent the observed improvements reflect a placebo effect
Visco AG, et al. N Engl J Med :

33. Clinical Significance
Botox® serves as an effective alternative treatment for overactive bladder with urge incontinence episodes for patients who have treatment failure with anticholinergic medications
Should not be first line in treatment of OAB due to higher incidence of serious side effects
UTI and urinary retention
Recommend: Should only use for patients with URGE (mod to severe) incontinence episodes since that was most of type of incontinence episodes experienced by the patients in the trials

34. Benefits/Risks of Botox® Use
Good alternative for treatment failure with anticholinergics
Do not have to worry about daily adherence
Longer duration of effect
Invasive
Presents risk for infection
Potential need for self catheterization
Higher risk of side effects: urinary retention, UTI
Higher cost
Need to assess risks and benefits for each patient
High cost: 1000/treatment
Not covered by insurance

35. References
Nitti VW, Dmochowski R, Herschorn S, et al. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3 randomized placebo-controlled trial, J. Urol doi: /j.juro
Tyagi S, Thomas CA, Hayashi Y, Chancellor MB. The overactive bladder: epidemiology and morbidity. Urol Clin N Am :
Rovner ES, Wyman J, Lackner L, Guay,D. Urinary Incontinence. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiological Approach. 7th ed. New York, NY: McGraw-Hill;
Gormley EA, Lightner DJ, Burgio, KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. American Urological Association. May Available at : Accessed March 7, 2013.
OnabotulinumtoxinA. In: Lexi-Drugs Online [database on the internet]. Hudson, OH: Lexi-Comp, Inc.; Available at: Accessed March 7, 2013.
Rowland LP. Stroke, spasticity, and botulinum toxin. N Engl J Med :
Botox® [package insert]. Allergan. Irvine, CA; January Available at: Accessed March 7, 2013.
Visco AG, Brubaker L, Richter HE, et al. Anticholinergic therapy vs. onabotulinumtoxinA for urgency urinary incontinence. N Engl J Med (19):

36. Questions?