Introduction
Overactive bladder (OAB) is a chronic condition of the lower urinary tract characterized by symptoms of urinary urgency, with or without urge incontinence, and usually with urinary frequency and nocturia. It is estimated that OAB affects 14% to 18% of Canadians. Anticholinergic medications are the mainstay of pharmacological treatment of OAB.
OnabotulinumtoxinA (Ona A) is a purified neurotoxin complex produced from the fermentation of Clostridium botulinum type A. Ona A is approved by Health Canada for the treatment of OAB (non-neurogenic) with symptoms of urinary incontinence, urgency, and frequency in adult patients who have an inadequate response to or are intolerant of anticholinergic medication. Mirabegron, sacral neuromodulation, and percutaneous tibial nerve stimulation are possible treatment options for patients who have an inadequate response to or are intolerant of anticholinergic medication.
The indication under review is listed in the following table:
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| Indication under review |
|---|
| For the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and frequency, in adult patients who have an inadequate response to or are intolerant of anticholinergic medication. |
| Listing criteria requested by sponsor |
|---|
| For the treatment of refractory urinary incontinence due to overactive bladder. |
The objective of this review was to evaluate the beneficial and harmful effects of onabotulinumtoxinA injection (Botox) at a dose of 100 units (U) for the treatment of OAB in patients with symptoms of urinary incontinence, urgency, and frequency in adult patients who have an inadequate response to or are intolerant of anticholinergic medications.
Results and Interpretation
Included Studies
Three manufacturer-sponsored studies and one study sponsored by the Assistance publique — Hôpitaux de Paris were included in this review. All studies were randomized, multi-centre, double-blind, placebo-controlled trials comparing Ona A with placebo. Two phase 3 pivotal trials (study 095: n = 557; study 520: n = 548) were of up to 39 weeks’ duration with only a 12-week placebo-controlled double-blind phase, and two phase 2 trials (study 077: n = 313; study P030438: n = 99) were of 36-weeks’ and six-months’ duration, respectively. All studies enrolled patients aged 18 years or older with symptoms of OAB and who were not adequately treated with anticholinergic therapy (inadequate response or intolerance). To be included, patients in studies 095 and 520 had to experience three or more urge-incontinence episodes in a three-day period, while those in study 077 had to experience eight or more urge-incontinence episodes in a one-week period, and those in study P030438 had to experience three or more episodes or urgency with or without urge incontinence in a three-day period. The co-primary efficacy outcomes in studies 095 and 520 were mean change from baseline in the number of incontinence episodes and the proportion of patients with a positive treatment response at week 12, while in study 077 it was mean change from baseline in the number of episodes of weekly urge-incontinence episodes. In study P030438, it was a > 50% reduction from baseline in both urge incontinence and urgency episodes at three months.
The trials are limited by the lack of an active comparator and their short duration. In addition, there was no clear definition of inadequate response to anticholinergic therapy and it was based on the judgment of the investigators. In the two phase 3 studies, there are no valid placebo-controlled data beyond 12 weeks. The number of patients treated with the Health Canada–approved dose in the phase 2 trials was relatively small and thus these studies are likely underpowered to identify important between-treatment differences for many outcomes of interest.
Efficacy
The two phase 3 pivotal trials reported statistically significantly greater reductions from baseline for Ona A compared with placebo in OAB symptom frequency (incontinence, urge incontinence, micturitions, urgency, and nocturia). While there is no known value for the change or the difference in change of OAB symptom frequency to be judged clinically significant, the clinical expert consulted for this review considered the magnitude of the observed differences between Ona A and placebo at week 12 in the daily frequency of incontinence (1.7 to 1.9 episodes), urge incontinence (1.7 to 2.0 episodes), and urgency (1.5 to 2.4 episodes) to be clinically meaningful. The clinical expert also indicated that the observed differences in the frequency of micturition episodes (1.0 to 1.7) are notable but not a large treatment effect, and that the difference in the frequency of nightly nocturia episodes (≤ 0.3) was not impressive on the whole.
Studies 095 and 520 reported statistically significant and clinically important improvements in disease-specific health-related quality of life measures (King’s Health Questionnaire [KHQ] and Incontinence Quality of Life Questionnaire [I-QOL]) for patients treated with Ona A versus placebo. Between-treatment differences in the 12-Item Short-Form Health Survey (SF-12), while statistically significant for the mental component summary (MCS) and utility scores, were of uncertain clinical significance.
The aforementioned study results should be interpreted in the context of the patient populations enrolled in the trials. Specifically, patients had an average frequency of incontinence of approximately 5.1 to 5.7 episodes per day (36 to 40 per week), and an average frequency of urge incontinence of approximately 4.5 to 5.2 episodes per day (32 to 36 per week), which may be higher than the general OAB population with incontinence.
Studies 095 and 520 are limited by the short duration (12 weeks) over which comparative efficacy can be determined. Studies 077 and P030438 provide longer-term comparative data (36 weeks and six months, respectively); however, Ona A did not demonstrate statistically significant improvements compared with placebo for many OAB symptoms at these time points. All four of the reviewed studies are limited to comparative efficacy (versus placebo) for a single treatment.
Patients completing either of two phase 3 pivotal trials (study 095 or 520) were eligible to be enrolled in an open-label extension study. The review of long-term efficacy and safety data from this open-label extension trial has several limitations: the open-label, non-comparative design of the extension trial; the repeated, cyclical administration of treatment in the extension trial, which was not a design feature of the phase 3 trials, which were limited to a single dose of treatment; and the non-availability of the most current data for the extension trial. Bearing in mind these limitations, the extension trial efficacy data seem generally supportive of the phase 3 trial findings.
Harms
There were no deaths during the double-blind phase in studies 095 and 520, but three deaths (two in the placebo group and one in the Ona A group) were reported in the open-label extension phase of the included trials; however, none of these deaths were considered related to study treatment.
The proportion of patients who experienced adverse events, serious adverse events, and withdrawals due to adverse events was higher in the Ona A groups. Overall, the most frequent adverse events associated with Ona A were urinary tract infection (UTI), dysuria, urinary retention, bacteriuria, and increased residual urine volume. The clinical expert consulted for this review indicated that the higher incidence of UTI in the Ona A groups is likely due to the higher frequency of urinary retention observed among Ona A–treated patients, which would predispose them to infection. Further, the higher incidence of urinary retention in the Ona A groups likely explained the higher incidence of clean intermittent catheterization (CIC) in the Ona A groups. The Health Canada–approved product monograph states that Ona A is contraindicated in patients with OAB who are not willing and able to have CIC initiated. No increased risk of cardiac events, anaphylaxis, or hypersensitivity reactions was observed for Ona A compared with placebo. Limited data on adverse events were reported for the P030438 study.
Bearing in mind the limitations of the open-label extension study mentioned earlier, there do not appear to be any new safety signals from the extension trial data.
Summary of Economic Analysis
The manufacturer submitted a cost-utility analysis of Ona A plus best supportive care (BSC) (which consisted of incontinence pads and treatment for adverse events such as skin and UTIs), compared with BSC alone, for the treatment of refractory urinary incontinence in adult patients with OAB.1 The analysis was based on a Markov model with five health states based on average number of daily urinary-incontinence episodes and a relative reduction in the average number of daily urinary-incontinence episodes from baseline, and one absorbing state (death). Efficacy and transition probabilities were derived from the patient-level data from the pooled study data set of two phase 3 trials (191622-520 and 191622-095) and an extension trial (191622-096). The median time to qualify for re-treatment was estimated at 34.10 weeks (approximately eight months) based on an analysis of the ongoing long-term extension study data (study 096). The proportion of patients receiving sacral nerve stimulation was estimated based on physician surveys. Modelled adverse events included catheterization (duration and frequency of use) and UTI. The manufacturer captured treatment costs associated with Ona A and BSC, as well as costs of medical resource utilization. Utility values for each health state were obtained by mapping quality of life data captured in the clinical trials to the European Quality Of Life Five Dimensions Questionnaire (EQ-5D) utility instrument. The time horizon for the analysis was set at five years with a cycle length of 12 weeks (i.e., three months).
Results of Manufacturer’s Analysis
The manufacturer reports that the incremental cost per quality-adjusted life-year (QALY) for Ona A plus BSC was $34,029 compared with BSC alone.
Interpretations and Key Limitations
A key limitation was the manufacturer’s modelling of health state utilities. Other limitations included the stopping rule for Ona A, proportion of patients receiving sacral nerve stimulation, time to initiation of sacral nerve stimulation, and efficacy of anticholinergics in the BSC group compared with real-life clinical practice. When accounting for these limitations, the CADTH Common Drug Review (CDR) found the incremental cost-utility ratio of Ona A plus BSC compared with BSC alone ranged from $56,932 to $60,451 per QALY gained, with a most likely incremental cost-utility ratio estimate of $59,388 per QALY gained. The place in therapy and cost-effectiveness of Ona A compared with mirabegron is unclear at this time.
Conclusions
Two phase 3 and two phase 2 placebo-controlled studies compared Ona A with placebo in adult patients with symptoms of idiopathic overactive bladder that had not been adequately managed with anticholinergic therapies. In the phase 3 studies (095 and 520), compared with placebo, Ona A resulted in statistically significantly greater reductions from baseline in incontinence episodes, urge-incontinence episodes, urgency episodes, micturitions, and nocturia episodes. There is no generally recognized standard for the change or the difference in change for these outcomes to be judged clinically significant. However, the clinical expert consulted for this review considered the observed differences to be of clinical importance. In addition, studies 095 and 520 reported statistically significant and clinically important improvements in disease-specific health-related quality of life measures (KHQ and I-QOL) for patients treated with Ona A versus placebo. In the phase 2 studies (077 and P030438), there was no statistically significant difference between Ona A and placebo in terms of urge incontinence frequency.
The proportion of patients who experienced adverse events, serious adverse events, and withdrawals due to adverse events was higher in the Ona A groups. Overall, the most frequent adverse events associated with Ona A were UTI, dysuria, urinary retention, bacteriuria, increased residual urine volume, and use of CIC for urinary retention. No increased risk of cardiac events or anaphylaxis or hypersensitivity reactions was observed for Ona A compared with placebo.
The trials, which assessed only a single dose, are limited by the lack of an active comparator and their short duration.
Table 1Summary of Results
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| Outcome | Study 191622-095a | Study 191622-520a | Study 191622-077b | Study P030438c |
|---|
| Ona A 100 U
(N = 280) | Placebo
(N = 277) | Ona A 100 U
(N = 277) | Placebo
(N = 270) | Ona A 100 U
(N = 54) | Placebo
(N = 44) | Ona A 100 U
(N = 22) | Placebo
(N = 29) |
|---|
| Mean frequency of micturition episodes |
|---|
| Baseline, mean (SD) | 11.98 (4.3) | 11.20 (3.1) | 12.01 (4.0) | 11.77 (3.6) | 80.3 (22.6) | 73.3 (23.0) | NR | NR |
| Change from baseline, mean (95% CI) | −2.0 (−2.4 to −1.6) | −1.0 (−1.3 to −0.6) | −2.4 (−2.7 to −2.0) | −0.6 (−1.0 to −0.2) | −21.7 (19.8) | −8.3 (22.9) | NR | NR |
| MD (95% CI), P value versus placebo | −1.0 (−1.5 to −0.6)
P < 0.001 | ref | −1.7 (−2.2 to −1.3)
P < 0.001 | ref | −8.2 (−16.5 to 0.12)
P = 0.053 | ref | P < 0.001 | ref |
| Mean frequency of incontinence episodes |
|---|
| Baseline, mean (SD) | 5.47 (3.6) | 5.09 (3.2) | 5.52 (3.8) | 5.70 (3.9) | NR | NR | NR | NR |
| Change from baseline, mean (95% CI) | −2.5 (−2.9 to −2.1) | −0.9 (−1.3 to −0.5) | −3.0 (−3.4 to−2.5) | −1.1 (−1.5 to −0.6) | NR | NR | NR | NR |
| MD (95% CI), P value versus placebo | −1.7 (−2.1 to −1.2)
P < 0.001 | ref | −1.9 (−2.4 to−1.4)
P < 0.001 | ref | NR | NR | NR | NR |
| Mean daily frequency of urge-incontinence episodes |
|---|
| Baseline, mean (SD) | 4.8 (3.2) | 4.5 (3.1) | 5.1 (3.7) | 5.2 (3.7) | 27.8 (22.7) | 32.5 (20.2) | NR | NR |
| Change from baseline, mean (95% CI) | −2.4 (−2.8 to −2.0) | −0.7 (−1.1 to −0.3) | −2.8 (−3.4 to −2.4) | −0.9 (−2.1 to −0.7) | −18.4 (20.2) | −17.4 (18.2) | NR | NR |
| MD (95% CI), P value versus placebo | −1.7 (−2.1 to −1.2)
P < 0.001 | ref | −2.0 (−2.5 to −1.5)
P < 0.001 | ref | −4.8 (−10.4 to 0.8)
P = 0.094 | ref | NR | NR |
| Percentage of patients with ≥ 50% reduction in urge-incontinence episodes | 61.2% | 29.1% | 64.8% | 31.5% | 70.4% | 52.3% | 65% | 29% |
| Percentage of patients with ≥ 75% reduction in urge-incontinence episodes | 48.3% | 15.5% | 48.1% | 20.8% | 55.6% | 36.4% | 40% | 18% |
| Percentage of patients with 100% reduction in urge-incontinence episodes | 28.9% | 7.8% | 31.8% | 13.1% | 37.0% | 15.9% | NR | NR |
| Mean frequency of nocturia episodes |
|---|
| Baseline, mean (SD) | 2.15 (1.5) | 2.01 (1.3) | 2.19 (1.5) | 2.08 (1.5) | 13.9 (6.9) | 12.3 (8.2) | NR | NR |
| Change from baseline, mean (95% CI) | −0.5 (−0.6 to −0.3) | −0.3 (−0.4 to −0.1) | −0.5 (−0.7 to −0.3) | −0.2 (−0.6 to 0.05) | −4.1 (SD 7.0) | −0.3 (SD 6.8) | NR | NR |
| MD (95% CI), P value versus placebo | −0.2 (−0.4 to −0.02)
P = 0.029 | ref | −0.3 (−0.5 to −0.08)
P = 0.007 | ref | −2.1 (−5.0 to 0.9)
P = 0.166 | ref | NR | NR |
| Mean frequency of urgency episodes |
|---|
| Baseline, mean (SD) | 8.54 (4.7) | 7.85 (3.7) | 9.11 (4.6) | 8.78 (4.5) | 69.9 (28.2) | 62.0 (26.6) | NR | NR |
| Change from baseline, mean (95% CI) | −2.8 (−3.3 to −2.2) | −1.3 (−1.8 to −0.7) | −3.4 (−3.9 to −2.8) | −1.0 (−1.5 to −0.4) | −30.5 (SD 27.6) | −14.1 (SD 30.2) | NR | NR |
| MD (95% CI), P value versus placebo | −1.5 (−2.2 to −0.9)
P < 0.001d | ref | −2.4 (−3.1 to −1.8)
P < 0.001d | ref | −11.7 (−23.0 to −0.4)
P = 0.043 | ref | NS | ref |
| Time to request re-treatment and proportion of patients who requested re-treatment |
|---|
| Patients who requested re-treatment, n (%) | 173 (61.8) | 223 (80.5) | 175 (63.2) | 229 (84.5) | NA | NA | NA | NA |
| Time to request re-treatment, median weeks (95% CI) | 21.1 (18.3 to 24.0) | 12.4 (12.3 to 13.0) | 18.1 (17.4 to 22.9) | 12.9 (12.4 to 13.1) | NA | NA | NA | NA |
| P value versus placebo | P < 0.001 | ref | P < 0.001 | ref | NA | NA | NA | NA |
| HRQoL outcomes |
|---|
| KHQ role limitations: MD (95% CI), P value versus placebo at week 12 | −20.6 (−25.6, −15.7).
P < 0.001 | ref | −19.8 (−24.8, −14.7).
P < 0.001 | ref | NA | NA | NA | NA |
| KHQ social limitations: MD (95% CI), P value versus placebo at week 12 | −13.9 (−18.1, −9.7).
P < 0.001 | ref | −13.2 (−17.8, −8.6).
P < 0.001 | ref | NA | NA | NA | NA |
| KHQ symptoms component: MD (95% CI), P value versus placebo at week 12 | NA | NA | NA | NA | −9.0 (−15.8, −2.3).
P = 0.009 | ref | NA | NA |
| I-QOL total summary score: MD (95% CI), P value versus placebo at week 12 | 14.9 (11.1, 18.7).
P < 0.001 | ref | 16.9 (13.2, 20.6).
P < 0.001 | ref | 14.8 (5.3, 24.4).
P = 0.002 | ref | 0.01 ≤
P < 0.05 | ref |
| Harms |
|---|
| N | 278 | 272 | 274 | 270 | 55 | 43 | 22 | 29 |
| Patients with at least one AE, n (%) | 171 (61.5) | 144 (52.9) | 142 (51.8) | 92 (34.1) | 44 (80.0) | 33 (76.7) | | |
| Patients with at least one SAE, n (%) | 9 (3.2) | 8 (2.9) | 13 (4.7) | 10 (3.7) | 5 (9.1) | 5 (11.6) | NR | NR |
| WDAEs, n (%) | 4 (1.4) | 2 (0.7) | 2 (0.7) | 1 (0.4) | 0 (0.0) | 1 (2.3) | NR | NR |
| Deaths, n (%) | 0 | 0 | 0 | 0 | 0 | 0 | | |
| AEs of special interest |
|---|
| Anaphylaxis/hypersensitivity reactions | 0 (0.0) | 1 (0.4) | 0 | 1 (0.4) | 0 | 0 | NR | NR |
| Use of CIC for urinary retention | 17 (6.1)e | 0e | 19 (6.9)e | 2 (0.7)e | 6 (10.9) | 1 (2.3) | 1 (4.5) | 1 (3.4) |
| UTI | 43 (15.5) | 16 (5.9) | 56 (20.4) | 14 (5.2) | 20 (36.4) | 7 (16.3) | 0f | 2 (8.7)f |
| Cardiac events | 1 (0.4) | 2 (0.7) | 3 (1.1) | 1 (0.4) | 3 (5.5) | 1 (2.3) | | |
AE = adverse event; CI = confidence interval; CIC = clean intermittent catheterization; HRQoL = health-related quality of life; I-QOL = Incontinence Quality of Life Questionnaire; KHQ = King’s Health Questionnaire; MD = mean difference; NA = not applicable; NR = not reported; NS = not statistically significant; Ona A = onabotulinumtoxinA; ref = reference group; SAE = serious adverse event; SD = standard deviation; UTI = urinary tract infection; WDAE = withdrawal due to adverse event.
- a
Daily frequency at week 12. P values for between-treatment comparisons are from an analysis of covariance model with treatment group as a factor, baseline outcome value, and site as covariates.
- b
Weekly frequency at week 12. P values are from pairwise contrasts from an analysis of covariance model with factors for treatment group and investigator, using baseline outcome value as covariates.
- c
Daily frequency at 90 days.
- d
P value is from stratified log-rank test with baseline urinary urge-incontinence episodes as stratification factor.
- e
During treatment cycle 1.
- f
