3.2. Included Studies
3.2.1. Description of Studies
Four randomized controlled trials met the criteria for inclusion in this systematic review: three were manufacturer-sponsored, and one study was sponsored by the Assistance publique — Hôpitaux de Paris. All included studies were multi-centre, randomized, double-blind, placebo-controlled trials comparing Ona A with placebo. Study 191622-095 (referred to as study 095) and study 191622-520 (referred to as study 520) were phase 3 trials, while study 191622-077 (referred to as study 077) and study P030438 were phase 2 trials. All trials investigated the efficacy and safety of Ona A for the treatment of idiopathic overactive bladder (iOAB) in patients who had not been adequately treated with anticholinergic therapy (inadequate efficacy or intolerance) and were 18 years of age or older.
The phase 3 trials (study 095, n = 557; and study 520, n = 548) were of identical study design.16,17,20,21 Patients were randomized in a 1:1 ratio to receive Ona A 100 U, or placebo; randomization was stratified by centre and number of incontinence episodes reported at baseline (≤ 9 or > 9 episodes, over the three-day diary). Ona A or placebo was administered as 20 evenly distributed intradetrusor injections of 0.5 mL per injection site. The co-primary efficacy outcomes were change from baseline in the daily episodes of incontinence, and the proportions of patients with a positive treatment response on the treatment benefit scale. The double-blind phase of the two studies was 12 weeks; the minimum study duration was 24 weeks, with a maximum duration of 39 weeks. Patients who received only one treatment were evaluated at week two, six, 12, 18, and 24. After week 12, all patients who were eligible for a second treatment received Ona A 100 U; hence, the appropriate period for placebo-controlled comparison was up to week 12, with treatment cycle 1 defined as the period between the receipt of first treatment and re-treatment, or study exit when there was no re-treatment. Data presented in the systematic review are from the 12-week double-blind treatment phase from each trial. Patients completing either of two phase 3 trials were eligible to be enrolled in an open-label extension study (study 191622-096). Data from this open-label extension study are summarized in APPENDIX 6: SUMMARY OF OPEN-LABEL EXTENSION STUDY.
The phase 2 trials (study 077: n = 313; study P030438: n = 99) were of a 36-week and six-month duration, respectively.18,19,22 Patients in study 077 were randomized in a 1:1:1:1:1:1 ratio to receive Ona A 50 U, 100 U, 150 U, 200 U, or 300 U, or placebo. Ona A or placebo was administered as 20 evenly distributed intradetrusor injections of 0.5 mL per injection site. Patients were evaluated at week one, two, six, 12, 18, 24, and 36, with primary end point at week 12. The primary efficacy outcome was change from baseline in the number of weekly episodes of urge incontinence. Patients in study P030438 were randomized in a 1:1:1:1 ratio to receive Ona A 50 U, 100 U, or 150 U, or placebo; randomization was stratified by centre. Ona A or placebo was administered as 15 homogeneously distributed injections in the detrusor. Patients were evaluated at day eight and months one, three, five, and six with primary end point at week 12 (month three). The primary efficacy outcome was proportion of patients with a greater than 50% reduction from baseline of both urge incontinence and urgency episodes at three months. Because Ona A 100 U is the Health Canada–approved dose for the treatment of OAB, only data for this dose are included in the current report from studies 077 and P030438.
3.2.2. Populations
a. Inclusion and Exclusion Criteria
Studies 095 and 520 enrolled patients aged 18 years or older with symptoms of iOAB and who had experienced three or more urge-incontinence episodes in a three-day period (three-day patient bladder diary completed during the screening period) and who were not adequately managed with anticholinergic therapy (defined as inadequate response after at least four weeks of anticholinergic therapy or limiting side effects after at least a two-week period). Study 077 enrolled patients aged 18 years or older with symptoms of iOAB and who had experienced eight or more urge-incontinence episodes in a one-week period (based on patient bladder diary entries collected over seven consecutive days during the screening period), and who had inadequate response or intolerable adverse effects after at least one month of anticholinergics therapy. Study P030438 enrolled patients aged 18 years or older with symptoms of iOAB with three or more episodes of urgency with or without urge incontinence in a three-day period (based on a three-day micturition diary completed during the screening period) and who were refractory or had contraindications to anticholinergics, or who discontinued anticholinergics because of adverse events. Patients had to have used anticholinergics for at least three months, but not more than 12 months before inclusion.
Patients were excluded if they had used anticholinergics or any other medications or therapies to treat symptoms of OAB within seven days of the start of the screening period for studies 095 and 520, and within 21 days of randomization for study 077. However, in study P030438, a stable regimen of anticholinergics was maintained during the study period in patients already using anticholinergics. Patients who had a history of two or more urinary tract infections (UTIs) within six months of randomization were excluded from studies 095, 520, and 077, while patients with symptomatic UTI were excluded from study P030438. Patients were excluded from studies 095 and 520 if they had a post-void residual (PVR) of more than 100 mL, while those with PVR > 150 mL were excluded from study P030438, and those with PVR > 200 mL were excluded from study 077. Patients with predominance of stress incontinence were excluded from all four studies, and patients who used clean intermittent catheterization (CIC) or an indwelling catheter to manage their urinary incontinence, or had any pelvic or urological abnormalities, or bladder surgery or disease other than OAB, were excluded from studies 095, 520, and 077.
b. Baseline Characteristics
Baseline characteristics were similar across treatment groups within studies (). The mean age per treatment group ranged from 58.7 to 62.5 years, and the percentage of females ranged from 82% to 93%.
Summary of Baseline Characteristics.
In the two phase 3 trials, the majority were Caucasian. The mean duration of OAB ranged from 6.6 to 6.8 years in study 095, and from 5.2 to 5.7 years in study 520. The mean daily frequency of incontinence episodes at baseline ranged from 5.1 to 5.5 in study 095, and from 5.5 to 5.7 in study 520. The mean daily frequency of micturition episodes at baseline ranged from 11.2 to 12.0 in study 095, and from 11.8 to 12.0 in study 520 (). Mean number of prior anticholinergic medications used ranged from 2.4 to 2.5 in study 095, and from 2.3 to 2.5 in study 520. A total of 34.5% of all patients previously used one anticholinergic, 27.0% previously used two anticholinergics, 18.0% previously used three anticholinergics, 9.8% previously used four anticholinergics, 5.7% previously used five anticholinergics, and 5.1% previously used five or more anticholinergics. The mean duration of prior anticholinergic use was approximately 2.4 years (range: 0.3 weeks to 1,058.6 weeks) in study 095, and 2.1 years (range: 2 weeks to 857.3 weeks) in study 520 ().
Prior Anticholinergic Medications.
In study 077, the majority of patients were Caucasian. The duration of OAB ranged from 0.7 to 30.2 years in the Ona A group, and from 1.5 to 47.6 years in the placebo group. The mean weekly frequency of urge-incontinence episodes at baseline ranged from 27.8 to 32.5. The mean weekly frequency of micturition episodes at baseline ranged from 73.3 to 80.3 (). In study P030438, the mean daily frequency of urge-incontinence episodes at baseline was around 5.9 (); data on duration of disease, micturition, or race were not reported in this study. Data on the previous use of anticholinergics medications were not reported for either of the phase 2 studies.
3.2.3. Interventions
According to treatment-group assignment, patients in the two phase 3 studies received vials of Ona A 100 U or placebo, while those in study 077 received vials of Ona A 50 U, 100 U, 150 U, 200 U, 300 U, or placebo. The investigational materials of Ona A or placebo were packaged and labelled in vials that appeared identical and were prepared by an independent drug reconstitutor. Under cystoscopic guidance, a total 20 injections of 0.5 mL each, approximately 1 cm apart and 2 mm deep, were injected into the detrusor, avoiding the trigone and the dome.
Patients in study P030438 received vials of Ona A 50 U, 100 U, 150 U, or placebo. Under cystoscopic guidance, a total of 15 homogeneously distributed injections were performed into the detrusor, avoiding the trigone.
For studies 095 and 520, patients were allowed to receive a second treatment if the following pre-defined re-treatment criteria were met: patients had to initiate the request for treatment 2; patient experienced two or more urge-incontinence episodes, with no more than one urge incontinence–free day, as recorded in a three-day diary in the week prior to the qualification for treatment 2 visit; a minimum of 12 weeks had elapsed since the previous treatment and a maximum of 27 weeks since randomization; and a post-void residual urine volume < 200 mL. Only one additional treatment was allowed for both studies. All patients who were eligible for the second treatment received Ona A 100 U. In the phase 2 studies 077 and P030438, patients received only one cycle of treatment upon study entry; no re-treatment was allowed throughout the study.
In studies 095, 520, and 077, anticholinergics or any other medications (including sympathomimetic medications) used for the treatment of symptoms of OAB were prohibited before study treatment was received and throughout study participation. However, in study P030438, for patients who were receiving anticholinergic therapy at the start of the study, a stable regimen was maintained during the study period.
3.2.4. Outcomes
For the phase 3 studies 095 and 520, the co-primary efficacy outcomes were the proportion of patients who had a positive treatment response on the treatment benefit scale and the change from baseline in daily average frequency of incontinence episodes at the primary end point (week 12) (frequency of incontinence episodes was measured by patients using a three-day bladder diary during the 21 days preceding randomization and during the three days preceding each scheduled clinic visit). The patient’s three-day bladder diary also measured micturition episodes, urgency episodes, and nocturia episodes. There were four secondary efficacy outcomes: the change from baseline in daily average frequency of micturition episodes, the change from baseline in daily average frequency of urgency episodes, Incontinence Quality of Life Questionnaire (I-QOL) total score, and King’s Health Questionnaire (KHQ) domain scores for role limitations and social limitations. Patients’ quality of life was also assessed using the 12-Item Short-Form Health Survey (SF-12) and other domain scores of the KHQ. Other efficacy analyses assessed were the change from baseline in nocturia episodes, the change from baseline in urge-incontinence episodes, duration of treatment effect, and the proportion of patients achieving a 50% or greater reduction from baseline, or a 100% reduction from baseline, in incontinence episodes and in urge-incontinence episodes. Study baseline values were determined based on the three-day bladder diary completed during the 21 days preceding randomization (screening period). If re-treatment was received, patients were followed for at least 12 weeks after treatment 2, but not exceeding 39 weeks after the initial treatment.
In study 077, the primary efficacy outcome was the change from baseline in weekly frequency of urge-incontinence episodes at the primary end point (week 12) as measured by the patient bladder electronic diary (e-diary) during the seven consecutive days throughout the screening period and during the seven consecutive days preceding each scheduled visit. The e-diary also captured micturition episodes, nocturia episodes, and urgency episodes. Secondary efficacy outcomes included the change from baseline in the weekly frequency of micturition, urgency, and nocturia episodes, and proportion of patients achieving various thresholds of change from baseline in incontinence episodes. Patients’ quality of life was also assessed using KHQ (symptoms component only), I-QOL, and the European Quality of Life Scale Visual Analogue Scale (EQ-VAS). Study baseline values were determined based on the diary completed by the patient for seven consecutive days prior to randomization.
In study P030438, the primary efficacy outcome was the proportion of patients achieving > 50% reduction, compared with baseline, of both urgency and urge-incontinence episodes at month three. Bladder function outcomes were captured in a micturition diary completed by patients over three days during the 15 days preceding inclusion (baseline), at day eight, and at months one, three, five, and six. Secondary outcomes included micturition episodes, urge-incontinence episodes, urgency episodes, I-QOL, and EQ-VAS.
Health-related quality of life (HRQoL) scales used in the trials are described below.
The standard version of KHQ is a 21-item disease-specific questionnaire that has been developed and validated for participants with urinary incontinence.27 The KHQ consists of nine domains: general health perceptions, impact on life, role limitations, physical limitations, social limitations, personal relationships, emotions, sleep and energy, and incontinence severity measures. Item scores are converted to a standardized scale. Scores for the KHQ domains range from 0 to 100, where 0 indicates the best outcome or response and 100 indicates the worst outcome or response.27 A within-group minimal clinically important difference (MCID) of 5 points has been reported for each domain in patients with OAB.28,29 (See APPENDIX 5: VALIDITY OF OUTCOME MEASURES for additional information regarding the description and validation of the KHQ.)
The I-QOL measure is used in patients with chronic urinary incontinence (i.e., urge, stress, and mixed) to assess the impact of incontinence on HRQoL.30,31 The I-QOL is a 22-item scale consisting of three domains: avoidance and limiting behaviour (eight items), psychosocial impacts (nine items), and social embarrassment (five items).31 Each item is scored according to a 5-point scale (1 = extremely and 5 = not at all).28 Scores (range: 0 to 100) are calculated for each domain along with an overall composite score for the 22 items. The higher the I-QOL score, the higher the quality of life and the lower the impact of incontinence on HRQoL.28,31 No MCID has been reported for non-stress incontinence, while the between-treatment MCID for the total I-QOL score in stress incontinence has been reported to be 2.5 points.32 (See APPENDIX 5: VALIDITY OF OUTCOME MEASURES for additional information regarding the description and validation of the I-QOL.)
The SF-12 consists of 12 items from the SF-36, which are scored and weighted to obtain two summary scores: one for physical health (the physical component summary [PCS]) and one for mental health (the mental component summary [MCS]).33,34 However, no published MCIDs could be found for the SF-12 (or 36-item health survey, the SF-36) for OAB or urinary incontinence. (See APPENDIX 5: VALIDITY OF OUTCOME MEASURES for additional information regarding the description and validation of the SF-12.)
The EQ-VAS is a 20 cm visual analog scale that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.” Respondents are asked to rate their health by drawing a line from an anchor box to the point on the EQ-VAS that best represents their health on that day. No published MCIDs could be found for OAB or urinary incontinence for the EQ-VAS. (See APPENDIX 5: VALIDITY OF OUTCOME MEASURES for additional information regarding the description and validation of the EQ-VAS.)
For studies 095, 520, and 077, adverse events were defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether related to the investigational product or not. Serious adverse events were events that were fatal, life-threatening, or required hospitalization or prolonged an existing hospitalization, resulted in persistent or significant disability or a congenital anomaly or birth defect, or were an important medical event. For studies 095, 520, safety data were presented for the 12-week double-blind treatment phase only; long-term safety and tolerability data are presented from the open-label extension phase in APPENDIX 6: SUMMARY OF OPEN-LABEL EXTENSION STUDY. For study P030438, safety and tolerability data were evaluated at each visit; no definition for harms outcomes was provided.
3.2.5. Statistical Analysis
Trials 095 and 520 had a power of 82% to detect a between-group difference (Ona A 100 U versus placebo) of 2.3 episodes per day in change from baseline in the number of incontinence episodes at a significance level of 0.05. In addition, the number of patients included per treatment group provided the trials with 89% power to detect a difference of 3.6 episodes in change from baseline in micturition. Trial 077 had a power of 61% to 92% to detect a between-group difference of four to six episodes in change from baseline in weekly frequency of urge-incontinence episodes at a significance level of 0.05. Study P030438 had a power of 62% to detect a reduction of greater than 50% compared with baseline of both urgency and urge-incontinence episodes at month three at a significance level of 0.05.
In studies 095 and 520, all efficacy outcomes were analyzed using an analysis of covariance (ANCOVA). The statistical model included treatment group as the main effect, with baseline value and site as covariates. The treatment effect on incontinence and urge incontinence was also analyzed as the proportion of patients with a ≥ 30%, 50%, 75%, and 100% decrease from baseline in the number of incontinence or urge-incontinence episodes per day using the Cochran–Mantel–Haenszel method. The time to request re-treatment was estimated using the Kaplan–Meier survival method, and between-group comparisons were performed using a log-rank test.
To adjust for multiple comparisons in studies 095 and 520, a hierarchical testing strategy was used that started with the primary efficacy end point followed by testing of the secondary end points, in which the test of any lower-ranked secondary end point was not considered statistically significant if the P value of a higher-ranked secondary end point was > 0.05. The hierarchical order of the secondary end points was frequency of incontinence episodes, treatment benefit scale, frequency of micturition episodes, I-QOL total score, KHQ domain scores, and frequency of urgency episodes.
For all other efficacy analyses, a two-sided test with P value ≤ 0.05, unadjusted for multiplicity, was considered by the manufacturer to be statistically significant. Missing values on the episodes of incontinence were imputed using the last observation carried forward (LOCF) approach. Missing values for I-QOL total scores were imputed if three or fewer items were missing, using the mean value of the non-missing items within the same domain. Missing items for I-QOL domain scores and multi-item domains of the KHQ were imputed if at least half of the items in the domain had non-missing responses, by using the mean value of responses to other items within the same domain. Missing values for single-item domains of the KHQ and other efficacy outcomes were not imputed.
For study 077, all efficacy outcomes were analyzed using an ANCOVA. The statistical model included treatment group and investigator as factors, and baseline outcome value as covariates. Unlike the phase 3 studies, no adjustment for multiplicity was made in this study. Missing values for urge incontinence were imputed using the last observation adjusted by the ratio of means for the previous and current visit over all non-missing values for all patients. Missing values for health outcome data were adjusted in a manner similar to the adjustments made for health outcomes in studies 095 and 520. Missing values for other efficacy outcomes were not imputed.
Between-treatment comparisons in study P030438 were performed using the Kruskal–Wallis test (for quantitative variables) and the χ2 test (for qualitative variables). Missing values were imputed using the LOCF approach. No adjustment for multiplicity was made in this study.
The CDR protocol included a subgroup by age (< 65 years of age versus ≥ 65 years of age); however, such analysis was undertaken only in studies 095 and 520 for the co-primary end points.
a. Analysis Populations
For studies 095, 520, and 077, the primary analysis population used for efficacy and health outcomes was the intention-to-treat (ITT) analysis set. The various analyses populations are defined below.
ITT analysis set: patients were analyzed according to the randomization assignment, regardless of actual treatment received. Missing values were imputed for the primary efficacy analyses as described previously.
Per-protocol (PP) analysis set: PP population included all randomized patients with no major protocol violations. The PP analyses were based on observed data with no imputation for missing values. The PP population was used for confirmatory analyses of primary efficacy analyses.
Safety analysis set: safety analyses were based on the treatment actually received by each patient and were performed using the safety population, consisting of all patients who received the study treatment at Day 0.
For study P030438, analysis populations were not defined; however, it seems that patients with a protocol violation were excluded from the analyses.
3.6. Efficacy
Only those efficacy outcomes identified in the review protocol are reported in this section (see Section 2.2, Table 2). See APPENDIX 4: DETAILED OUTCOME DATA for detailed efficacy data.
3.6.1. Micturition Episodes
At baseline, the mean number of micturitions per 24 hours in studies 095 and 520 ranged from 11.2 to 12.0 and was similar within and between studies ( and Appendix 4, Table 8). All treatment groups reported a reduction in the mean daily frequency of micturition episodes at week 12 (placebo 0.63 to 0.98; Ona A 2.01 to 2.35). Compared with placebo, patients treated with Ona A had a statistically significantly greater reduction from baseline in daily frequency of micturition episodes at week 12, with a mean difference of −1.04 (95% confidence interval [CI], −1.48 to −0.59) in study 095, and −1.72 (95% CI, −2.19 to −1.26) in study 520. P values for between-group differences at week 12 were < 0.001 in both studies (Appendix 4, Table 8).
Micturition Frequency. Ona A = onabotulinumtoxinA. a Daily frequency of micturition episodes for study 077 were calculated by CADTH from the reported mean weekly frequency of the micturition episodes.
At baseline, the mean weekly frequency of micturition episodes in study 077 was 73.3 for placebo and 80.3 for Ona A ( and Appendix 4, Table 8). Both treatment groups reported a reduction in the mean weekly frequency of micturition episodes at week 12 (8.3 for placebo versus 21.7 for Ona A) and week 36 (9.3 for placebo versus 22.9 for Ona A). Mean changes from baseline were not statistically significantly different between Ona A and placebo at week 12 (P = 0.053), but were statistically significantly different at week 36 (P = 0.05).
Frequency of micturition episodes was not reported for study P030438 at baseline or at 90- or 180-day end points. However, the P value for the between-group difference indicated that, compared with placebo, patients treated with Ona A had a statistically significantly greater reduction from baseline in number of micturitions per 24 hours after 90 days of receiving the treatment (P < 0.001) but not at 180 days.
3.6.2. Incontinence Episodes
At baseline, the mean number of daily incontinence episodes in studies 095 and 520 ranged from 5.1 to 5.7 and was similar within and between studies ( and Appendix 4, Table 9). All treatment groups reported a reduction in the mean daily frequency of incontinence episodes at week 12 (placebo 0.87 to 1.05; Ona A 2.52 to 2.96). Patients treated with Ona A had a statistically significantly greater reduction from baseline in daily frequency of incontinence episodes at week 12, with a mean difference of −1.65 (95% CI, −2.13 to −1.17) in study 095, and −1.91 (95% CI, −2.43 to −1.39) in study 520. P values for between-group differences were < 0.001 in both studies (Appendix 4, Table 9).
Incontinence Episodes. UI = urinary incontinence.
Subgroup data by age (< 65 versus ≥ 65) were available for studies 095 and 520 (Appendix 4, Table 10). The difference between Ona A and placebo was statistically significantly different for both subgroups, and results were generally consistent with the results for the entire population.
No results for incontinence episodes were reported for studies 077 and P030438.
The percentage of patients with ≥ 50%, ≥ 75%, or a 100% reduction from baseline in daily incontinence episodes at week 12 was also reported for studies 095 and 520. In both studies, compared with the placebo group, there was a significantly higher percentage of patients in the Ona A group who achieved a reduction of ≥ 50%, ≥ 75%, or 100% from baseline in incontinence episodes ( and Appendix 4, Table 9).
Percentage of Patients With a ≥ 50%, ≥ 75%, or 100% Reduction in Incontinence Episodes
at Week 12. UI = urinary incontinence.
3.6.3. Urge-Incontinence Episodes
The results for urge incontinence in studies 095 and 520 were similar to those for incontinence episodes, showing statistically significant between-treatment differences favouring Ona A over placebo (Appendix 4, Table 11).
At baseline, the mean weekly frequency of urge-incontinence episodes in study 077 was 27.8 for placebo and 32.5 for Ona A (Appendix 4, Table 11). Mean changes from baseline were not statistically significantly different between Ona A and placebo at week 12 nor at week 36. The percentage of patients with ≥ 50%, ≥ 75%, or a 100% reduction from baseline in weekly urge-incontinence episodes at week 12 were also reported for study 077. A statistically significantly higher percentage of patients achieved a reduction of ≥ 50% and ≥ 75% from baseline in urge-incontinence episodes in the Ona A group compared with the placebo group at week 36, but not at week 12. Compared with placebo, a statistically significantly higher percentage of patients achieved a 100% reduction in urge incontinence in the Ona A group at week 12 and week 36 (Appendix 4, Table 11).
At baseline, the mean daily frequency of urge-incontinence episodes in study P030438 was 5.9 for both the placebo and Ona A groups. The percentage of patients with ≥ 50% (primary end point) and ≥ 75% improvement from baseline of both urgency and urge-incontinence episodes at month three were reported. No statistically significant difference was found between Ona A 100 U and placebo for either ≥ 50% or ≥ 75% improvement of urgency and urge-incontinence episodes at month three.
3.6.4. Nocturia Episodes
At baseline, the mean number of nocturia episodes per 24 hours in studies 095 and 520 ranged from 2 to 2.2 and was similar within and between studies ( and Appendix 4, Table 12). All treatment groups reported a reduction in the mean daily frequency of nocturia episodes at week 12 (placebo 0.18 to 0.25; Ona A 0.45 to 0.46). Patients treated with Ona A had a statistically significantly greater reduction from baseline in daily frequency of nocturia episodes at week 12, with a mean difference of −0.20 (95% CI, −0.38 to −0.02) in study 095, and −0.27 (95% CI, −0.47 to −0.08) in study 520. P values for between-group differences at week 12 were 0.029 and 0.007 for studies 095 and 520, respectively (Appendix 4, Table 12).
Nocturia Episodes. Ona A = onabotulinumtoxinA. a Daily frequency of nocturia episodes for study 077 were calculated by CADTH from the reported mean weekly frequency of the nocturia episodes.
At baseline, the mean weekly frequency of nocturia episodes in study 077 was 12.3 for placebo and 13.9 for Ona A ( and Appendix 4, Table 12). Both treatment groups reported a reduction in the mean weekly frequency of nocturia episodes at week 12 (0.3 for placebo versus 4.1 for Ona A), but only Ona A group reported reduction in weekly frequency of nocturia episodes at week 36. Mean changes from baseline were not statistically significantly different between Ona A and placebo at week 12 or week 36.
No results for nocturia episodes were reported for study P030438.
3.6.5. Urgency Episodes
In studies 095 and 520, the number of urgency episodes was based on a “yes” response to the diary question, “Was this episode associated with a sudden and urgent need to urinate?”, while in study 077 it was based on a “yes” response to a question asking if urgency was associated with micturition or nocturia episodes. In study P030438, it was unclear how urgency, a subjective outcome, was defined and measured.
At baseline, the mean number of urgency episodes per 24 hours in studies 095 and 520 ranged from 7.9 to 9.1 ( and Appendix 4, Table 13). All treatment groups reported a reduction in the mean daily frequency of urgency episodes at week 12 (placebo 0.95 to 1.26; Ona A 2.76 to 3.39). Patients treated with Ona A had a statistically significantly greater reduction from baseline in daily frequency of urgency episodes at week 12, with a mean difference of −1.51 (95% CI, −2.14 to −0.87) in study 095, and −2.44 (95% CI, −3.09 to −1.79) in study 520. P values for between-group differences were < 0.001 in both studies (Appendix 4, Table 13).
Urgency Episodes. Ona A = onabotulinumtoxinA. a Daily frequency of nocturia episodes for study 077 were calculated by CADTH from the reported mean weekly frequency of the nocturia episodes.
At baseline, the mean weekly frequency of urgency episodes in study 077 was 62.0 for placebo and 69.9 for Ona A 100 U ( and Appendix 4, Table 13). Both treatment groups reported a reduction in the mean weekly frequency of urgency episodes at week 12 (14.1 for placebo versus 30.9 for Ona A 100 U), and week 36 (15.1 for placebo versus 30.1 for Ona A 100 U). Mean changes from baseline were statistically significantly different between Ona A 100 U and placebo at week 12 (P = 0.043), but not statistically significantly different at week 36 (P = 0.109).
At baseline, the mean number of urgency episodes per 24 hours in study P030438 was 7.0 for placebo and 8.7 for Ona A 100 U. Data findings and specific P values for between-treatment testing at 90 and 180 days were not reported. However, it was reported that there were no statistically significant between-treatment differences in urgency frequency at either time points (90 or 180 days) (Appendix 4, Table 13).
3.6.6. Time to Request Re-treatment and Proportion of Patients who Requested Re-treatment
In study 095, 81% of patients in the placebo group versus 62% of patients in the Ona A group requested re-treatment (Appendix 4, Table 14). The median time to patient request for re-treatment was statistically significantly longer in the Ona A group (21.1 weeks) compared with the placebo group (12.4 weeks; P < 0.001). In study 520, 85% of patients in the placebo group versus 63% of patients in the Ona A group requested re-treatment (Appendix 4, Table 14). The median time to patient request for re-treatment was statistically significantly longer in the Ona A group (19.1 weeks) compared with the placebo group (13.1 weeks; P < 0.001).
As per the protocol of studies 095 and 520, patients qualified for re-treatment if they met specific criteria (See Section 1.1.1). The number of patients who received re-treatment was 150 (53.6%) versus 222 (80.1%) for Ona A versus placebo in study 095, and 170 (61.4%) versus 227 (83.8%) for Ona A versus placebo in study 520. The median time to re-treatment was 24 weeks (range: 20.4 to 25.1) versus 12.6 (range: 12.3 to 13.1) for Ona A versus placebo in study 095, and 19.1 weeks (range: 18.1 to 24) versus 13.1 (range: 12.6 to 13.3) for Ona A versus placebo in study 520 (Appendix 4, Table 14).
3.6.7. Health-Related Quality of Life
a. King’s Health Questionnaire
The KHQ, a validated OAB-specific HRQoL instrument, was used in studies 095, 520, and 077 (symptoms component only). Each domain on the KHQ is scored from 0 to 100 (worst). An MCID of 5 points has been identified for each domain in patients with OAB.28,29 Data for all the domains were abstracted from the trials for studies 095 and 520 and from the symptoms component for study 077 (Appendix 4, Table 15).
In study 095, all domains except the general health perception domain showed a statistically significant between-treatment difference favouring Ona A over placebo. Patients who received Ona A treatment had a mean change from baseline scores that exceeded the established MCID of 5 points for all domains except for general health perception, while patients receiving placebo did exceed the above-mentioned MCID for the physical limitations domain only.
In study 520, all domains showed a statistically significant between-treatment difference favouring Ona A over placebo. Patients who received Ona A treatment had a mean change from baseline scores that exceeded the established MCID of 5 points for all nine domains, while patients receiving placebo did exceed the above-mentioned MCID for the incontinence impact, role limitations, physical limitations, and sleep and energy domains only.
Utility scores were derived from the KHQ in studies 095 and 520. Improvements in utility scores were statistically significantly greater for Ona A compared with placebo; however, between-treatment differences appear minimal: 0.0 (95% CI, 0.0 to 0.0) and 0.01 (95% CI, 0.01 to 0.02) in studies 095 and 520, respectively.
In study 077, the symptoms component domain showed a statistically significant between-treatment difference favouring Ona A over placebo at week 12, but not at week 36. The observed differences from baseline met or exceeded the reported MCID for both treatment groups at weeks 12 and 36 (Appendix 4, Table 15).
b. Incontinence Quality of Life Questionnaire
I-QOL is a disease-specific, quality of life questionnaire designed to measure the impacts of incontinence. I-QOL is scored as four variables: total I-QOL summary score and its three domains (avoidance and limiting behaviour, psychosocial impacts, and social embarrassment). I-QOL was used in studies 095, 520, 077, and P030438.
Compared with placebo, Ona A significantly increased (improved) I-QOL total scores from baseline at week 12 by 14.9 (95% CI, 11.1 to 18.7) in study 095, and by 16.9 (95% CI, 13.2 to 20.6) in study 520 (Appendix 4, Table 16). These improvements exceeded the reported MCID of 2.5 points. Statistically significant increases from baseline in total I-QOL were observed in study 077 at week 12 and week 36, and in study P030438 at 90 days and 180 days.
Statistically significant increases from baseline in I-QOL individual domain scores (avoidance and limiting behaviour, psychosocial impact, and social embarrassment) were observed at week 12 in studies 095 and 520 with improvements being statistically significantly higher for Ona A treatment groups compared with the placebo groups. Similarly statistically significantly higher scores in all I-QOL individual domain scores for Ona A treatment groups compared with the placebo groups were observed in study 077 at weeks 12 and 36, and in study P030438 at 90 days and 180 days, except for the social embarrassment domain in study P030438 at 90 days.
c. Twelve-Item Short-Form Health Survey
The SF-12 summary scores (PCS, MCS) and utility scores were reported for studies 095 and 520; however, no published MCIDs could be found for the SF-12 (or SF-36) in OAB or urinary incontinence.
No statistically significant difference between Ona A and placebo was found for the change from baseline at week 12 in PCS scores for both studies. Compared with placebo, Ona A produced statistically significantly increased MCS scores from baseline at week 12: 2.6 (95% CI, 0.9 to 4.3) in study 095, and 3.6 (95% CI, 2.0, 5.1) in study 520. Similarly, compared with placebo, Ona A statistically significantly increased utility scores from baseline at week 12; however, the between-treatment difference was minimal: 0.0 (95% CI, 0.0 to 0.0) in study 095, and 0.04 (95% CI, 0.02 to 0.05) in study 520 (Appendix 4, Table 17).
d. EQ-VAS
EQ-VAS was used in studies 077 and P030438. The EQ-VAS is a 20 cm visual analog scale that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.” No published MCIDs could be found for OAB or urinary incontinence for the EQ-VAS.
In study 077, the mean changes from baseline in EQ-VAS scores were not statistically significantly different in patients treated with Ona A 100 U compared with placebo. In study P030438, the mean change from baseline in the EQ-VAS score was statistically significantly higher in Ona A 100 U compared with placebo at 90 days, but not at 180 days post-treatment (Appendix 4, Table 18).
3.7. Harms
3.7.1. Adverse Events
The proportion of patients who experienced at least one adverse event was higher in the Ona A group (61.5% in study 095, 51.8% in study 520, and 80% in study 077) than in the placebo group (52.9% in study 095, 34.1% in study 520, and 76.7% in study 077) (). Study P030438 did not report the incidence of adverse events.
The most frequent adverse events after initial treatment reported in all the included studies were UTI, urinary retention, and dysuria. In studies 095 and 520, UTI, urinary retention, and dysuria occurred more frequently in the Ona A 100 U group than in the placebo group. The percentage of patients who experienced UTI was 15.5% and 20% in the Ona A groups compared with 5.9% and 5.2% in the placebo groups in studies 095 and 520, respectively. The proportion of patients who experienced urinary retention was 5.4% and 5.8% in the Ona A groups compared with 0.4% in both placebo groups. The proportions of patients who experienced dysuria were 12.2% and 5.8% in the Ona A groups, compared with 9.6% and 3.7% in the placebo groups. Similarly, in study 077, UTI and urinary retention were reported by 36.4% and 18.2% of patients in the Ona A 100 U groups, respectively, compared with 16.3% and 2.3% of patients in the placebo groups, whereas dysuria occurred in 11.6 % of patients in the placebo group compared with 1.8% in the Ona A group.
Other adverse events that occurred in studies 095 and 520 at a higher frequency in the Ona A–treated patients when compared with placebo were bacteriuria, residual urine volume (based on the investigator’s opinion and defined as the raised PVR being clinically significant but not fulfilling the definition for urinary retention), leukocyturia, sinusitis, and pollakiuria.
The incidences of anticholinergic adverse events other than urinary retention were either lower than 1% or never experienced by the patients included in the trials.
3.7.2. Serious Adverse Events
In studies 095 and 520, the proportion of patients receiving Ona A 100 U who reported at least one serious adverse event was 3.2% and 4.7% compared with 2.9% and 3.7% of patients receiving placebo (). Study 077 reported serious adverse events in 9.1% and 11.6% of patients in the Ona A 100 U and placebo groups, respectively. Study P030438 did not report serious adverse events, but they reported that 9.1% of patients in the Ona A 100 U group and 0% in the placebo group experienced at least one severe adverse event.
3.7.3. Withdrawals Due to Adverse Events
Withdrawals due to adverse events in studies 095, 520 and 077 were 1.4%, 0.7%, and 0% in Ona A–treated patients compared with 0.7%, 0.4%, and 2.3% of placebo-treated patients, respectively (). Study P030438 did not report the incidence of withdrawal due to adverse events.
3.7.4. Mortality
In studies 095 and 520, no deaths were reported during the first 12 weeks. However, in study 095, two deaths occurred after week 12 (one in the placebo group during treatment cycle 1 due to due to diverticulitis and pneumothorax, and another death in the placebo/Ona A 100 U group during treatment cycle 2 due to myocardial infarction, ventricular fibrillation, and pulmonary embolism). None of these serious adverse events were considered to be related to study treatment. In study 520, one death in the Ona A group occurred during treatment cycle 1 due to acute myocardial infarction, which was not considered to be related to study treatment. There were no deaths reported in trial 077.
3.7.5. Notable Harms
As outlined in the protocol, anaphylaxis or hypersensitivity reactions, use of CIC for urinary retention, UTI, and cardiac events were of interest for this review. Anaphylaxis or hypersensitivity reactions occurred in one patient in study 095 and one patient in study 520; both patients were in the placebo group. In studies 095, 520, 077, and P030438, the proportion of patients receiving Ona A 100 U who reported the use of CIC for urinary retention was 6.1%, 6.9%, 10.9%, and 4.5%, compared with 0%, 0.7%, 2.3% and 3.4% of patients receiving placebo.
In studies 095, 520, and 077, the proportion of patients receiving Ona A 100 U who experienced cardiac events was 0.4%, 1.1%, and 5.5%, compared with 0.7%, 0.4%, and 2.3% of patients receiving placebo. UTI events are summarized in Section 3.7.1.
