To evaluate the effect of onabotulinumtoxinA on urodynamic outcomes in patients with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).
To evaluate the effect of onabotulinumtoxinA on urodynamic outcomes in patients with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).
Results from two pivotal Phase III trials (n = 691) were pooled. MS or SCI patients with NDO, received intradetrusor onabotulinumtoxinA 200 U (n = 227), 300 U (n = 223), or placebo (n = 241). Change from baseline in UI episodes/week (Week 6), maximum cystometric capacity (MCC), maximum detrusor pressure at first involuntary detrusor contraction (IDC) (PdetmaxIDC), volume at first IDC (VpmaxIDC), and detrusor compliance (DC) were measured.
OnabotulinumtoxinA significantly increased MCC overall (+153.6 ml with 200 U vs. +11.9 ml with placebo). Over 60% of onabotulinumtoxinA-treated patients had no IDC at Week 6; in patients with an IDC at Week 6, VpmaxIDC improved (+183.4 ml with 200 U vs. +17.5 ml with placebo), and PdetmaxIDC decreased (−32.4 cmH2O with 200 U vs. +1.1 cmH2O with placebo). OnabotulinumtoxinA-treated patients had a significant increase in DC (+59.8 ml/cmH2O with 200 U vs. −5.2 with placebo). Urodynamic improvements were comparable in patients regardless of baseline DC and corresponded with significant reductions in UI episodes/week for both onabotulinumtoxinA doses versus placebo, with no clinically relevant differences between 200 and 300 U groups. Most common adverse event was urinary tract infection (UTI); complicated UTIs were low across all treatment groups. In patients not catheterizing at baseline, a dose-dependent increase in post-void residual urine was observed at Week 2 following onabotulinumtoxinA treatment.
OnabotulinumtoxinA significantly improved urodynamic outcomes in NDO patients, even in those with low baseline DC, and corresponded with improvements in UI episodes. Both doses of onabotulinumtoxinA were well tolerated. Neurourol. Urodynam. 32:1109–1115, 2013. © 2013 Wiley Periodicals, Inc.
Neurogenic detrusor overactivity (NDO) is commonly found in patients with neurological conditions such as multiple sclerosis (MS) and spinal cord injury (SCI).[1, 2] NDO is characterized by the presence of involuntary detrusor contractions (IDC) on filling cystometry. Such IDCs may be associated with decreased urodynamic bladder capacity with resulting symptoms of urinary incontinence (UI) and impairment in patients' quality of life.
Recently, two pivotal, multicenter, placebo-controlled, Phase III studies have demonstrated that onabotulinumtoxinA (BOTOX®, Allergan, Inc., Irvine, CA) significantly reduced UI episodes and improved maximum cystometric capacity (MCC), maximum detrusor pressure (MDP) during first IDC, and quality of life in patients with MS and SCI with UI due to NDO.[3, 4] Pooling the results from these two Phase III trials provides a larger dataset for further analysis of urodynamic outcomes, including subgroup analyses of patients with low detrusor compliance (DC) at baseline. We evaluated the effect of onabotulinumtoxinA 200 and 300 U on urodynamic outcomes in pooled Week 6 results from the two Phase III trials conducted in patients with NDO due to SCI or MS.[3, 4]
Details regarding study design and patient selection for the individual studies have been described previously.[3, 4] Briefly, the Phase III studies, called the DIGNITY (Double-blind InvestiGation of purified Neurotoxin complex In neurogenic deTrusor overactivitY) studies (ClinicalTrials.gov NCT00311376 and NCT00461292), were multicenter, randomized, double-blind, placebo-controlled trials. The studies included patients with NDO due to SCI (T1 or below, with injury ≥6 months before screening) or MS (clinically stable for ≥3 months before screening and an Expanded Disability Status Score [EDSS] ≤6.5), with ≥14 UI episodes per week, who were not adequately managed by anticholinergics (i.e., inadequate efficacy or intolerable side effects). Patients taking anticholinergics at baseline had to maintain their use throughout the study (dosage to remain stable), and those not using anticholinergics at baseline were to remain off them for the duration of the study. Patients were either using clean intermittent catheterization (CIC) prior to study entry or, if they were not, had to be willing to initiate CIC if necessary. Patients who micturated spontaneously were required to have a post-void residual (PVR) volume of <200 ml to be included in the study.
Patients were randomized 1:1:1 to receive 30 intradetrusor injections of placebo, onabotulinumtoxinA 200 U, or onabotulinumtoxinA 300 U1 administered cystoscopically, avoiding the trigone. Patients were followed up for 52 weeks and evaluated post-treatment at Weeks 2, 6, and 12 and every 6 weeks thereafter. Patients could request one additional treatment starting at 12 weeks after the first treatment. Patients could qualify for retreatment if they reported either a <30% reduction or <50% reduction from baseline in weekly UI episodes.
A standardized procedure for urodynamic assessments was used across all participating study centers according to the International Continence Society (ICS) guidelines, and the values were interpreted by a single central reader. Urodynamic assessments included MCC, MDP only at first IDC (PdetmaxIDC), percentage of patients with no IDC on post-treatment urodynamics at 6 weeks, volume at first IDC (VpmaxIDC), and DC (change in volume/change in Pdet, where change in volume = MCC and change in Pdet = end fill pressure). The definition of MCC did not change during the study; the upper limit of bladder filling was always 500 ml. The term DC is used throughout the manuscript and corresponds to bladder compliance as per the ICS terminology. In this NDO population, MDP was assessed at first IDC and not at the end of the filling phase. Urodynamic analyses were also performed in a subgroup of patients with low DC at baseline (≤20 ml/cmH2O). A 7-day bladder diary was used to collect several parameters, including the primary efficacy variable of the number of weekly UI episodes and the volume voided per micturition. The time to patient request for retreatment was captured for the assessment of duration of effect.
Adverse events (AEs) were recorded throughout the study. The AE of urinary tract infection (UTI) did not distinguish between symptomatic and asymptomatic UTIs and were reported per the investigator's clinical assessment. The PVR urine volume was assessed in those patients who did not use CIC, and urinary retention was recorded as an AE based on the investigators' clinical judgment.
Efficacy analyses were conducted using the intent-to-treat (ITT; all randomized patients) population and the primary time point was Week 6. Analysis of covariance (ANCOVA) was used to compare changes from baseline in urodynamic endpoints between onabotulinumtoxinA and placebo groups, with baseline value as covariate, and treatment arm, etiology, concurrent use/nonuse of anticholinergics, and investigator site as factors. For the assessment of change from baseline at Week 6 in volume at first IDC, MCC was imputed for those patients who did not exhibit an IDC post-treatment. The change from baseline in UI episodes between the treatment groups was assessed using the same ANCOVA model, and the duration of treatment effect was estimated using Kaplan–Meier analysis. Safety analyses were performed on the safety population (all patients who received study drug).
The pooled ITT population (n = 691) was comprised of patients with MS (55.1%) and SCI (44.9%), with 241, 227, and 223 patients randomized to placebo, onabotulinumtoxinA 200 U, or onabotulinumtoxinA 300 U, respectively (Table I).
|Placebo (n = 241)||OnabotA 200 U (n = 227)||OnabotA 300 U (n = 223)|
|Age, years, mean (SD)||46.2 (13.3)||45.9 (13.3)||45.6 (13.0)|
|Gender, male, n (%)||116 (48.1)||93 (41.0)||82 (36.8)|
|Use of anticholinergic therapy, n (%)||140 (58.1)||120 (52.9)||119 (53.4)|
|Use of CIC, n (%)||139 (57.7)||119 (52.4)||117 (52.5)|
|Low DC at baseline (≤20 ml/cmH2O), n (%)||77 (32.0)||77 (33.9)||87 (39.0)|
|Patients with MS||34 (44.2)||33 (42.9)||36 (41.4)|
|Patients with SCI||43 (55.8)||44 (57.1)||51 (58.6)|
|Disease characteristics, mean (SD)|
|Duration of NDO (years)||7.7 (6.9)||7.3 (6.6)||7.9 (7.4)|
|UI episodes per week||31.5 (23.0)||32.4 (21.1)||31.1 (17.5)|
|Volume per void (ml)||153.2 (91.7)||156.3 (102.7)||159.7 (101.6)|
|Pooled ITT||253.5 (141.9)||250.2 (151.4)||252.2 (146.4)|
|Subgroup with low DC at baseline||190.0 (135.2)||190.4 (150.9)||183.9 (121.3)|
|MDP during 1st IDC (cmH2O)|
|Pooled ITT||47.3 (35.8)||51.5 (37.3)||45.0 (35.1)|
|Subgroup with low DC at baseline||56.1 (42.0)||66.2 (38.4)||52.7 (38.1)|
|Volume at 1st IDC (ml)|
|Pooled ITT||209.3 (130.5)||204.4 (136.6)||192.9 (125.9)|
|Subgroup with low DC at baseline||149.9 (111.9)||170.9 (149.6)||134.1 (92.9)|
|Pooled ITT||64.2 (92.6)||55.7 (81.4)||54.4 (80.5)|
|Subgroup with low DC at baseline||9.7 (5.0)||11.0 (5.1)||10.4 (5.0)|
Baseline demographics and disease characteristics were similar across the treatment groups in the pooled ITT population (Table I). Mean age was 45.9 years, mean duration of NDO was 7.7 years, 54.8% of patients were on anticholinergic therapy, and 54.3% were using CIC. Baseline urodynamic parameters were also comparable across treatment groups (Table I), with a mean MCC of 252 ml, mean PdetmaxIDC of 47.9 cmH2O, and mean VpmaxIDC of 186.3 ml. Of the 691 patients in the pooled ITT population, 241 patients (34.9%) had low DC (≤20 ml/cmH2O) at baseline, of whom 103 (42.7%) had MS and 138 (57.3%) had SCI. In this subgroup of patients with low DC, the baseline urodynamic parameters were comparable across the treatment groups; however, mean baseline MCC and VpmaxIDC values were lower, and mean PdetmaxIDC values were slightly higher compared with the respective baseline values in the pooled ITT population (Table I).
Nearly two-thirds of patients treated with onabotulinumtoxinA did not have an IDC at the urodynamic investigation at Week 6 (64.1% and 65.1% in the onabotulinumtoxinA 200 and 300 U groups, respectively) compared with 18.4% in the placebo group (Fig. 1A). In the subset of patients who did have an IDC at Week 6, mean PdetmaxIDC was significantly decreased in both onabotulinumtoxinA dose groups (−32.4 and −30.1 cmH2O in the 200 and 300 U groups, respectively) compared with a small increase in the placebo group (+1.1 cmH2O; P < 0.001) (Fig. 1B). A significant mean increase in DC was also seen with onabotulinumtoxinA treatment (+59.8 and +50.4 ml/cmH2O in the 200 and 300 U groups, respectively) compared with a small decrease in the placebo group (−5.2 ml/cmH2O; P < 0.001) (Fig. 1C).
Patients treated with either dose of onabotulinumtoxinA showed statistically significant increases from baseline in MCC at Week 6 versus placebo (P < 0.001) (Fig. 1D), with no clinically relevant differences between the 200 and 300 U dose groups. Mean increases were +153.6 and +163.1 ml in the 200 and 300 U groups compared with +11.9 ml in the placebo group.
Volume at first IDC was significantly increased with onabotulinumtoxinA treatment, compared with placebo (P < 0.001); mean increases were +183.4 and +202.4 ml in the 200 and 300 U groups, compared with +17.5 ml in the placebo group (Fig. 1E). There were no clinically relevant differences between the onabotulinumtoxinA dose groups for any of the urodynamic parameters.
As noted previously, 241 of the 691 patients (34.9%) in the pooled ITT population had low DC at baseline. Approximately 60% of patients in this subgroup who were treated with either 200 or 300 U onabotulinumtoxinA did not have an IDC at Week 6 (59.7% and 62.7% in 200 and 300 U onabotulinumtoxinA groups, respectively, vs. 13.7% in the placebo group) (Fig. 1A). In those patients who did have an IDC, mean PdetmaxIDC was significantly decreased in both dose groups (−39.5 and −30.3 cmH2O in the 200 and 300 U groups, respectively), compared with placebo (−5.6 cmH2O; P < 0.001) (Fig. 1B). A significant mean increase in DC was also seen with onabotulinumtoxinA (+75.2 and +66.9 ml/cmH2O in the 200 and 300 U groups, respectively), compared with placebo (+15.7 ml/cmH2O; P < 0.001) (Fig. 1C). The magnitude of treatment effect in PdetmaxIDC and DC was slightly higher than the pooled ITT population for the 200 U group and similar for the 300 U group. Furthermore, in this low baseline DC subgroup, only 6.6% of onabotulinumtoxinA-treated patients in both dose groups had no improvement in DC (i.e., a change of ±1 ml/cmH2O from baseline) at Week 6, compared with 19.7% in the placebo group. OnabotulinumtoxinA treatment significantly increased MCC in patients with low DC at baseline, compared with placebo (P < 0.001) (Fig. 1D). Mean increases were +171.1 and +206.6 ml in the 200 and 300 U groups, compared with +13.5 ml in the placebo group.
As in the ITT population, volume at first IDC was significantly increased with onabotulinumtoxinA, compared with placebo (P < 0.001); mean increases were +175.2 and +235.9 ml in the 200 and 300 U groups, compared with +25.1 ml with placebo (Fig. 1E). The magnitude of the increases in MCC and volume at first IDC in the low baseline DC subgroup were similar to the pooled ITT population for the 200 U group and slightly higher for the 300 U group. Overall, there were no clinically relevant differences in the urodynamic improvements between the subgroup with low DC at baseline and the pooled ITT population.
Weekly UI episodes were significantly reduced from baseline in both onabotulinumtoxinA dose groups, compared with placebo. The mean decreases at the primary time point of Week 6 were −21.3 UI episodes for both onabotulinumtoxinA groups, compared with −10.5 for placebo (P < 0.001) (Fig. 2A). This corresponded to a mean percent reduction from baseline in UI episodes at Week 6 of −69% and −68% in the onabotulinumtoxinA 200 and 300 U groups versus −32.1% with placebo. The proportion of patients who achieved a 100% reduction from baseline in UI episodes at Week 6 was significantly higher in the onabotulinumtoxinA groups versus placebo (37.0% and 40.4% in 200 and 300 U groups vs. 9.1% in placebo group; P < 0.001).
Both doses of onabotulinumtoxinA significantly increased the volume per void at Week 6 versus placebo (P < 0.001), with mean increases from baseline of +108.4 and +121.2 ml in the onabotulinumtoxinA 200 and 300 U groups versus +15.6 ml in placebo group (Fig. 2B).
Duration of treatment effect (time to retreatment request) was median 269 days (38.4 weeks) and 265 days (37.9 weeks) following onabotulinumtoxinA 200 and 300 U, respectively, versus 92 days for placebo (13.1 weeks). There were no clinically relevant differences between the 200 and 300 U dose groups in any of these clinical outcomes.
In patients with low DC (≤20 ml/cmH2O) at baseline, weekly UI episodes were significantly decreased in both onabotulinumtoxinA groups, compared with placebo. The mean decreases from baseline in UI episodes at Week 6 were −21.6 and −21.4 in the 200 and 300 U groups, compared with −9.7 in the placebo group (P < 0.05) (Fig. 2C). Similar clinical outcomes were observed in patients with high DC (>20 ml/cmH2O) at baseline, with significant mean decreases of −21.6 and −21.7 UI episodes at Week 6 in the onabotulinumtoxinA 200 and 300 U groups respectively, compared with −11.2 in the placebo group (P < 0.001) (Fig. 2D).
Overall, there were no relevant differences in the clinical outcomes between the subgroups with low and high DC at baseline.
In the pooled safety population (n = 677), the most common AEs across treatment cycle 1 were UTI and urinary retention. The incidence of both was higher in onabotulinumtoxinA-treated patients versus placebo, with the highest incidence in the 300 U group (Table II); the study objective was not to detect statistical differences in AEs between the treatment groups. In this study, complicated UTIs (pyelonephritis or urosepsis) were reported in five patients: three cases of pyelonephritis (two in the placebo group; one in the 300 U group) and two cases of urosepsis (both in the placebo group). The overall rate of discontinuation due to AEs was low (1.5% [10/677]) and occurred in 1 (0.4%), 3 (1.3%), and 6 (2.8%) patients treated with placebo, onabotulinumtoxinA 200 and 300 U, respectively (Table II).
|Adverse event, n (%)||Placebo (n = 235)||OnabotA 200 U (n = 226)||OnabotA 300 U (n = 216)|
|Overall AEs||174 (74.0)||192 (85.0)||181 (83.8)|
|Serious AEs||27 (11.5)||28 (12.4)||36 (16.7)|
|AEs with incidence ≥5%|
|UTI||85 (36.2)||117 (51.8)||121 (56.0)|
|Urinary retention||8 (3.4)||45 (19.9)||50 (23.1)|
|Hematuria||8 (3.4)||12 (5.3)||15 (6.9)|
|Diarrhoea||10 (4.3)||11 (4.9)||13 (6.0)|
|Fatigue||7 (3.0)||16 (7.1)||7 (3.2)|
|Pyrexia||8 (3.4)||16 (7.1)||5 (2.3)|
|Constipation||7 (3.0)||11 (4.9)||11 (5.1)|
|Nasopharyngitis||7 (3.0)||10 (4.4)||12 (5.6)|
|Muscular weakness||5 (2.1)||10 (4.4)||13 (6.0)|
|Nausea||3 (1.3)||9 (4.0)||11 (5.1)|
|MS relapse||6 (2.6)||4 (1.8)||12 (5.6)|
|Vulvovaginal mycotic infectiona||3 (2.5)||7 (5.3)||5 (3.6)|
|AEs leading to study discontinuation||1 (0.4)||3 (1.3)||6 (2.8)|
In patients not using CIC at baseline (44.8% [303/677], most of whom had MS), a dose-dependent increase in PVR was observed at Week 2 following treatment with onabotulinumtoxinA (Table III). The percentage of patients with a PVR ≥200 ml was highest in the 300 U dose group, as was the proportion of patients who initiated CIC for urinary retention in treatment cycle 1 (7.1%, 30.8%, and 44.0% in the placebo, onabotulinumtoxinA 200, and 300 U groups, respectively) (Table III).
|Parameter||Placebo (n = 99)||OnabotA 200 U (n = 104)||OnabotA 300 U (n = 100)|
|Baseline PVR (ml), mean (SD)||57.2 (56.4)||62.6 (52.2)||57.9 (50.5)|
|Change from baseline in PVR at Week 2 (ml), mean (SD)||3.1 (56.5)||98.3 (173.1)*||176.0 (256.9)*|
|Patients (%) with PVR (≥200 ml) at Week 2||3.5||30.5||44.2|
|Patients initiating CIC due to urinary retention, n (%)||7 (7.1)||32 (30.8)||44 (44.0)|
The analysis of these pooled data demonstrates that onabotulinumtoxinA at doses of both 200 and 300 U significantly improved urodynamic parameters in patients with UI due to NDO, with no clinically relevant differences between the two doses. These data corresponded well to the reductions in UI episodes as measured by 7-day voiding diaries. The parallel improvements in the objective outcomes of urodynamic assessments and patient-reported UI episodes are in line with the individual Phase III trials[3, 4] and further confirm that there are no clinically relevant differences in efficacy between onabotulinumtoxinA 200 and 300 U dose groups. Furthermore, the duration of effect (time to retreatment request) was significantly longer with onabotulinumtoxinA, compared with placebo (approximately 9 months vs. 3 months, respectively). There appears to be no difference in the duration of effect between the two onabotulinumtoxinA dose groups evaluated in this pooled study.
Approximately 60–65% of patients in both the pooled ITT population and the subgroup with low DC at baseline showed no evidence of an IDC following treatment with onabotulinumtoxinA, and in those patients who did have an IDC, PdetmaxIDC was significantly decreased. This is important in patients with a neurogenic bladder in whom frequent detrusor contractions, particularly against a closed bladder outlet, could have a negative impact on upper urinary tract function over time. Treatment with onabotulinumtoxinA significantly increased DC in NDO patients, regardless of the DC value at baseline, a parameter that is also important in these patients in whom low DC is a risk factor for renal damage or other urological complications.[7, 8] Findings with anticholinergic therapy in NDO patients have shown improvements in bladder pressures, but using high doses is frequently associated with intolerable side effects and may lead to early discontinuation of therapy.
As reflected by the increase from baseline in MCC, onabotulinumtoxinA-treated patients, both in the pooled ITT population and the subgroup with low baseline DC, experienced significant increases in bladder storage capacity. Improvements in the ability of the bladder to store urine were also reflected by the significant increases in volume at first IDC and volume per void after treatment with onabotulinumtoxinA; the mean increases in volume per void were +108.4 and +121.2 ml with the 200 and 300 U doses, respectively, in the pooled ITT population.
Studies that have previously reported clinical and urodynamic improvements with onabotulinumtoxinA in patients with NDO have not included those with low baseline bladder compliance,[10, 11] who are also known to be at high risk for renal failure.[7, 8] This pooled analysis provided a larger sample size to evaluate the urodynamic efficacy of onabotulinumtoxinA in a subgroup of patients with low DC at baseline. Improvements in urodynamic storage parameters and decreases in detrusor pressures, comparable to the overall pooled ITT population, were observed in onabotulinumtoxinA-treated patients with a mean baseline DC of 10.4 ml/cmH2O, which was threefold lower than the values reported in previous studies.[10, 11] To our knowledge, this is the first randomized, placebo-controlled, pooled study to demonstrate the urodynamic efficacy of onabotulinumtoxinA in patients with NDO with low baseline DC. It is unclear whether these improvements in DC can translate into upper urinary tract improvements and lead to a reduced risk for renal failure.
Both doses of onabotulinumtoxinA were well tolerated. Consistent with previous trials,[3, 4] the most commonly reported AE in all treatment groups was UTI, with a low rate of complicated UTIs across all treatment groups. Reports of decreased UTI rates in the NDO population in small single-center studies[12, 13] could not be confirmed in this pooled dataset from pivotal studies, which were large, placebo-controlled, multicenter trials.
OnabotulinumtoxinA-treated patients who were not catheterizing at baseline showed an increased risk of urinary retention and elevated PVR, in line with previous studies that have reported a risk of urinary retention after onabotulinumtoxinA injection.[14-16]
One limitation of this analysis was that the MDP was measured only at first IDC and not at the end of the filling phase, and it is possible that the MDP may have been higher in some patients at the end of the filling phase. Therefore, the effect of treatment on detrusor pressure may have been underestimated. Urodynamic evaluation in the subgroup of patients with low DC at baseline was post hoc; however, pooled data from the Phase III trials[3, 4] provided a larger sample size for a meaningful analysis.
OnabotulinumtoxinA significantly improved urodynamic outcomes in patients with NDO due to MS and SCI, including those with low DC at baseline. The improvements in urodynamic parameters with onabotulinumtoxinA corresponded with the patient-reported clinical outcomes of reductions in UI episodes and increases in volume per void. OnabotulinumtoxinA was well tolerated at both doses, with no increased efficacy of the 300 U over the 200 U dose.
Assistance with the writing and development of the manuscript was provided by Jaya Kolipaka, MS, and Jennifer Giel, PhD, CMPP, of Evidence Scientific Solutions, Philadelphia, PA, and funded by Allergan, Inc. The authors acknowledge all the participating investigators in the individual studies listed in references.[3, 4]
Units of biological activity of onabotulinumtoxinA cannot be compared with or converted into units of any other botulinum toxin product, and onabotulinumtoxinA is not interchangeable with other botulinum toxin preparations.