4.2.1 Efficacy
The inclusion criteria for all four trials were consistent with the relevant Health Canada–approved indication for Ona A: adult patients with OAB with symptoms of urinary incontinence, urgency, and frequency with an inadequate response to or intolerance of anticholinergic medication. It should be noted that not all patients with OAB will suffer from urinary incontinence, but the manufacturer is specifically requesting a listing criterion for treatment of urinary incontinence. Excepting study P030438, all studies specifically enrolled patients with urinary incontinence.
The two phase 3 pivotal trials documented similar results in terms of incontinence and urge incontinence after 12 weeks; compared with placebo, Ona A reduced daily incontinence and urge-incontinence episodes by −1.7 to −1.9 and −1.7 to −2.0, respectively. In addition, a large proportion of patients (58% to 64%) in the Ona A group achieved a ≥ 50% reduction in daily frequency of incontinence episodes by week 12 after initial treatment, compared with 29% to 33% of patients in the placebo group (P < 0.001). Further, 23% to 31% of patients achieved 100% continence at week 12 after Ona A treatment compared with 7% to 10% in the placebo group. While there is no known value for the change or the difference in change of incontinence or urge incontinence to be judged clinically significant, the clinical expert consulted for this review considered the observed differences between Ona A and placebo in incontinence and urge incontinence to be clinically meaningful.
In addition to the beneficial effects of Ona A in reducing the frequency of urinary incontinence (for which the manufacturer is specifically requesting reimbursement), Ona A was observed to provide reductions in other common symptoms associated with OAB. Reductions in daily micturition and urgency episodes at 12 weeks were statistically significantly greater for Ona A compared with placebo in studies 095 and 520, ranging from 1.0 to 1.7 fewer micturitions and 1.5 to 2.4 fewer urgency episodes per day. The clinical expert consulted for this review considered the reduction in urgency episodes to be a large improvement and clinically meaningful; the clinical expert also considered the reduction in micturitions to be a notable improvement but not a large treatment effect. The change from baseline at week 12 between Ona A and placebo in daily nocturia episodes in studies 095 and 520 was ≤ 0.3 episodes per day in favour of Ona A; the clinical interpretation of fractional benefits is not clear. In addition, the clinical expert indicated that this difference is not impressive on the whole. In addition to the improvements in individual OAB symptoms, studies 095 and 520 reported statistically significant and clinically important improvements in disease-specific HRQoL measures (KHQ and I-QOL) for patients treated with Ona A versus placebo. Between-treatment differences in the SF-12, while statistically significant for the 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 approximately 5.1 to 5.7 incontinence 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. The clinical expert consulted for this review indicated that patients with a high frequency of incontinence are the best candidates for Ona A, and that these patients represent some of the hardest patients to treat. The clinical expert also noted there is no minimum number of incontinence episodes to qualify for Ona A; rather, eligibility should relate more to refractoriness to anticholinergic drugs. However, the CDR reviewer noted that the results of the included studies may not be generalizable to a patient population with less frequent OAB symptoms.
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. However, the Health Canada–approved monograph notes that OAB patients should be considered for reinjection when the clinical effect of the previous injection has diminished, but not sooner than three months after the prior injection. Among patients randomized to Ona A in studies 095 and 520, approximately 62% requested re-treatment between weeks 12 and 24 after initial treatment, and the median time to request re-treatment was 21.1 and 18.1 weeks, respectively. However, given the design of studies 095 and 520, the randomized controlled comparison of Ona A with placebo is restricted to the effect of a single treatment over 12 weeks. Patients completing either of the phase 3 pivotal trials (study 095 or study 520) were eligible to be enrolled in an open-label extension study. Results from the long-term extension appear to show consistent improvement from baseline in urinary incontinence, in addition to reduction in micturition, nocturia, and urgency episodes over the subsequent treatment cycles for which data are available. However, the validity of these findings is limited by the open-label non-comparative design of the extension trial.
Finally, no trials were identified that compared Ona A with other active treatments for OAB. Placebo may not be the appropriate comparator for patients with an inadequate response to anticholinergic medication, given that treatment with anticholinergic medications, while perhaps not providing sufficient or adequate response, may still provide more efficacy than placebo. In addition, for patients with an intolerance to anticholinergic medications, the recent introduction of mirabegron may provide an alternative.
4.2.2 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 treatment phase of the included trials; however, none of these deaths were considered to be 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 UTI, dysuria, urinary retention, bacteriuria, and increased residual urine volume. The clinical expert consulted for this review indicated that the higher incidence of UTI is likely due to the higher frequency of urinary retention observed among Ona A–treated patients, which would predispose patients to infection. Further, the higher incidence of urinary retention in the Ona A groups likely explained the higher incidence of CIC in the Ona A groups. It should be noted that the use of Ona A in bladder dysfunction is contraindicated in patients who are not willing and able to have CIC initiated, which may reduce the number of patients with OAB with an inadequate response or intolerance to anticholinergic medications who are appropriate candidates for Ona A. However, the clinical expert suggested that patients can accept indwelling catheterization for the duration of retention as an alternative to CIC.
No increased risk of cardiac events or anaphylaxis or hypersensitivity reactions was observed for Ona A compared with placebo. Limited data on adverse events were reported for P030438 study. Long-term harms data for the approved dose of Ona A in OAB are relatively limited, with the majority of randomized controlled comparative harms data restricted to 12 weeks. Bearing in mind the limitations of the open-label extension study (see APPENDIX 6: SUMMARY OF OPEN-LABEL EXTENSION STUDY), there do not appear to be any new safety signals from the extension trial data.
