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Efficacy and Tolerability of Botulinum Toxin Type A in Patients with Neurogenic Detrusor Overactivity and Without Concomitant Anticholinergic Therapy: Comparison of Two Doses
Philippe Grise a 
, Alain Ruffion b, Pierre Denys c, Guy Egon d, Emmanuel Chartier Kastler e.
Accepted 22 June 2010, Published online 2 July 2010
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Abstract
Background
Botulinum toxin type A (BoNTA) has been reported to be effective for treatment of patients with neurogenic detrusor overactivity (NDO) refractory to anticholinergic agents. However, in most of the studies, the efficacy was associated with concomitant use of anticholinergics.
Objective
To evaluate the efficacy and tolerability of BoNTA and compare two different doses in patients with NDO without concomitant anticholinergics.
Design, setting, and participants
Between 2004 and 2006, adults with NDO refractory to anticholinergics or discontinued anticholinergics due to adverse events or contraindications from four different French clinical centres were included in a prospective, randomised, double-blind, comparative trial. Inclusion criteria were urinary incontinence (UI) resulting from NDO that could not be managed with anticholinergics. Patients with bladder cancer, lithiasis, or urinary infection were excluded.
Intervention
Patients were randomised to receive an intradetrusor injection of 500 U or 750 U of BoNTA.
Measurements
The initial evaluation (ie, clinical and urodynamic variables and quality of life [QoL]) was repeated at days 30, 90, 180, and 360. Primary outcome was complete continence rate at day 30. Secondary outcomes were cumulative incontinence rate, reappearance of leakages, pad usage, urodynamics, and QoL.
Results and limitations
Seventy-seven patients received 500 U (n = 39) or 750 U (n = 38) of BoNTA and were included in the full analysis set for efficacy analysis. Complete continence at day 30 was observed in 22 patients (56.4%) and 28 patients (73.7%) receiving 500 U or 750 U of BoNTA, respectively (p = 0.056; one-sided χ2 test to compare to α = 0.025). The median delay in the reappearance of leakages was 168 d. Monotherapy of BoNTA significantly improved UI in patients with NDO. Although there was a trend towards a greater improvement with 750 U of BoNTA, no statistically significant differences in terms of clinical and urodynamic variables and QoL were found between the treatment groups. Tolerability was excellent and equivalent for both doses.
Conclusions
Monotherapy of BoNTA at Dysport (Ipsen, Brisbane, CA, USA) doses of 500 U or 750 U seems to be effective and well tolerated in patients with NDO.
Keywords: Botulinum toxin type A, Cholinergic antagonist, Detrusor overactivity, Neurogenic, Urinary incontinence, Urodynamics.
Article Outline
1. Introduction
Patients with detrusor overactivity (DO) resulting from neurologic disorders (eg, spinal cord injury and multiple sclerosis) often experience problems with urinary incontinence (UI), which may severely affect a patient's quality of life (QoL). Medication with oral anticholinergic agents has been widely used as a first-line treatment for patients with neurogenic DO (NDO). However, in many cases, anticholinergics are associated with limited efficacy and bothersome systemic adverse events, including dry mouth, constipation, and blurred vision [1]. The intravesical route of administration of botulinum toxin type A (BoNTA) may provide an alternative treatment to achieve profound inhibition of NDO and avoid high systemic drug levels. BoNTA injected into the detrusor muscle of patients with UI resulting from NDO refractory to anticholinergics has been reported to be effective and to improve QoL in three placebo-controlled studies [2], [3], and [4] and several open-label studies [5], [6], [7], [8], [9], [10], [11], [12], and [13]. However, in most of these studies, efficacy was demonstrated using concomitant oral anticholinergics for a variable period of time together with another type of botulinum toxin type A. Relatively few studies analysed the efficacy and tolerability of BoNTA without anticholinergics [14], [15], and [16].
The aim of this study was to evaluate the efficacy and tolerability of a single intradetrusor injection of BoNTA (Dysport, Ipsen, Brisbane, CA, USA) alone comparing two different doses (500 U or 750 U) in patients with UI resulting from NDO refractory to anticholinergics or discontinued anticholinergics due to adverse events or contraindications in a multicentre, prospective, randomised, double-blind, comparative trial. Additional use of anticholinergics was not allowed during the study period. This is the first clinical trial comparing two Dysport doses in monotherapy; previous studies allowed concomitant use of anticholinergics.
2. Patients and methods
2.1. Patients
Patients aged ≥18 yr were recruited from four clinical centres in France from March 2004 to July 2006. Patients were included if they had UI resulting from NDO and were refractory to oral anticholinergics, discontinued treatment because of adverse events, or had contraindications to anticholinergics. All patients performed clean intermittent self-catheterisation (CISC) at inclusion except one patient, who was assisted by a parent. UI was defined as the occurrence of one involuntary leakage or more of urine over a 24-h period. The use of anticholinergics was prohibited at least 15 d before the initial evaluation and during the study period. Patients with any previous BoNTA treatment, pregnancy, symptomatic urinary tract infection (UTI), bladder lithiasis, bladder cancer (BCa), myasthenia, and concomitant use of aminoglycosides were excluded from the study.
2.2. Study design
This was a multicentre, prospective, randomised, double-blind, comparative study of two different doses of BoNTA injected into the detrusor muscle of adults with NDO refractory to anticholinergics or discontinued anticholinergics because of adverse events or contraindications. As concomitant use of anticholinergics was not allowed during the study period, it was unethical to use a placebo-controlled design. Patients were followed over the course of a 360-d period, with follow-up visits at days 30, 90, 180, and 360. At the end of the study period, the patients were treated according to physician preference. The study was approved by the Local Research Ethics Committee (CCPRB Haute Normandie, 2 December 2003) and conducted in compliance with good clinical practice (GCP) guidelines and the Declaration of Helsinki. Written informed consent was obtained from all patients. The study was registered in ClinicalTrials.gov under the trial registration number NCT00213577.
2.3. Product and injection technique
At day 0, eligible patients were randomly assigned to receive a single injection of BoNTA at two different doses (500 U or 750 U). The randomisation was centralised. The treatment pack was delivered by the pharmacy of each hospital. Prophylactic antibiotics were administered 3 h before BoNTA injection. BoNTA was reconstituted with 0.9% preservative-free saline to a total volume of 5 ml. The bladder was distended with approximately 100 ml saline to enable adequate visualisation. Under cystoscopic guidance, 20 injections of 0.25 ml each were injected intramuscularly into the detrusor, sparing the trigone. Injections were performed with the patient under general, local, or no anaesthesia.
2.4. Patient assessment
Patients were evaluated before injection at day 0 (baseline) by physical examination, a 3-d bladder diary to assess clinical symptoms (frequency, number of leakages, and pad usage) and urodynamics (reflex detrusor volume [RDV], maximum cystometric capacity [MCC], and bladder compliance [BC]). A disease- and organ-specific Qualiveen questionnaire with four domains (limitations, constraints, fears, and feelings) was used to assess the Specific Impact of Urinary Problems (SIUP) on QoL [4], and [17]. The initial evaluation was repeated at days 30, 90, 180, and 360. The primary efficacy outcome was complete continence rate at day 30. Secondary outcomes referring to continence were cumulative incontinence rate and reappearance of leakages. Other secondary efficacy outcomes were pad usage, urodynamics, and QoL. Other parameters recorded were the number of CISCs. Side-effects and tolerability were registered at each visit.
2.5. Statistical analysis
A sample size calculation of 39 patients per group was based on a between-group target difference of 25% in complete continence rate at 30 d using a one-sided Fisher exact test with an α of 0.025 and 80% power, assuming 70% improvement for 500 U of Dysport and 95% improvement for 750 U of Dysport treatment. Treatment outcomes were based only on investigator experience because of an absence of placebo-controlled studies. For practical reasons, we decided to include 40 patients per group.
All efficacy analyses were performed on the full analysis set (FAS). The FAS population was defined as those patients who had received one BoNTA intradetrusor injection and who had undergone at least one postbaseline assessment of efficacy. Tolerability analysis was performed on the safety set (SS), which was defined as those patients who had received one BoNTA intradetrusor injection. A between-group comparison on primary end point was performed by a one-sided χ2 test. Incidence of reappearance of leakages was estimated using the Kaplan-Meier method, and groups were compared using the log-rank test. Patients without reappearance of leakages were censored at their last available information. A multivariate logistic regression analysis, selecting the variables on urodynamic parameters (BC, RDV, MCC) as well as on demographic parameters (gender, age, disease duration, aetiology, and level of injury), was used to determine the independent prognostic value of baseline variables for predicting urinary continence at day 30.
Between-group comparisons on secondary end points referring to continence as well as in the subgroup analyses was performed by a χ2 test or Fisher exact test (in case of an expected cell number <5). A post hoc analysis was performed to analyse the impact of severity of urinary symptoms at baseline; patients were divided into two subgroups: patients with mild incontinence (<5 leakages) and patients with moderate or severe incontinence (≥5 leakages) at baseline. Secondary outcome measures were evaluated upon change from baseline by a paired student t test or the nonparametric Wilcoxon signed-rank test (in case of a rejection of the normal distribution) or the McNemar test to compare percentages. For primary analyses, a p value <0.025 was considered statistically significant, with <0.05 for the secondary analyses.
Because of study discontinuation and missing data, analyses of secondary efficacy outcomes were made according to the last observation carried forward (LOCF) approach. The data were collected and held by the principal investigator and analysed by the company Peter Holmes Clinical in Paris, France.
3. Results
3.1. Demographic baseline characteristics and participant flow
Seventy-nine patients were enrolled in the study (Fig. 1). One patient was not treated, as a suspicious lesion was found during cystoscopy. The other 78 participants were randomly assigned to one of the two treatment groups, receiving a BoNTA dose of either 500 U (n = 40) or 750 U (n = 38). One patient who received 500 U of BoNTA dropped out of the study before the first postbaseline evaluation; a total of 77 patients were included in the FAS for efficacy analyses. There were no statistically significant differences in demographic baseline characteristics among the treatment groups (Table 1). All patients performed CISC at inclusion and during the follow-up period, except one patient who was assisted by a parent.
00594-4/assets/gr1.jpg)
Fig. 1
Overview of study design and patient flow. BoNTA = botulinum toxin type A.
Table 1
Demographic baseline characteristics
| BoNTA 500 U (n = 39) | BoNTA 750 U (n = 38) | Total (n = 77) | |
|---|---|---|---|
| Age, yr: | |||
| Mean ± SD | 42.6 ± 12.4 | 38.3 ± 12.8 | 40.5 ± 12.7 |
| Range | 18.3–71.1 | 17.6–63.7 | 17.6–71.1 |
| Gender, No. (%) | |||
| Men | 23 (59.0) | 21 (55.3) | 44 (57.1) |
| Women | 16 (41.0) | 17 (44.7) | 33 (42.9) |
| Aetiology, No. (%) | |||
| Spinal cord injury | 25 (64.1) | 24 (63.2) | 49 (63.6) |
| Multiple sclerosis | 9 (23.1) | 9 (23.7) | 18 (23.4) |
| Other causes | 5 (12.8) | 5 (13.2) | 10 (12.9) |
| Level of injury, No. (%) | |||
| Paraplegic | 25 (64.1) | 24 (63.2) | 49 (63.6) |
| Tetraplegic | 4 (10.3) | 4 (10.5) | 8 (10.4) |
| Disease duration, yr | |||
| Mean ± SD | 8.3 ± 8.0 | 8.7 ± 9.4 | 8.5 ± 8.7 |
BoNTA = botulinum toxin type A; SD = standard deviation.
3.2. Efficacy
3.2.1. Clinical variables
Complete continence at day 30 was observed in 56.4% of patients (n = 22) and 73.7% of patients (n = 28) receiving 500 U or 750 U of BoNTA, respectively (one-sided χ2 test; p = 0.056 to compare to 0.025). We observed a lower complete continence rate in the moderate to severe incontinence subgroup compared to the mild incontinence subgroup (Table 2). Cumulative incontinence rates increased over time without statistically significant differences between either group (Table 3). The reappearance of leakages was evaluated on the 50 patients who were continent at day 30. On the first 80 d after BoNTA injection, a slower reappearance of leakages in the 750 U arm was observed than in the 500 U BoNTA arm (Fig. 2). However, after this time point, no differences could be seen between the treatment groups. The median delay of reappearance of leakages was 168 d, 164.5 d for patients receiving 500 U compared to 173.5 d for patients who were treated with 750 U of BoNTA (log-rank test; p = 0.612).
Table 2
Complete continence rate after botulinum toxin type A treatment at day 30
| Total | BoNTA 500 U | BoNTA 750 U | p | |
|---|---|---|---|---|
| Total population, No. | 77 | 39 | 38 | |
| Complete continence rate, No. (%) | 50 (65.0) | 22 (56.4) | 28 (73.7) | 0.056* |
| Subpopulation at baseline | ||||
| Mild incontinence, No. | 45 | 22 | 23 | – |
| Complete continence rate, No. (%) | 34 (75.6) | 16 (69.6) | 18 (81.8) | 0.491° |
| Moderate to severe incontinence, No. | 32 | 16 | 16 | – |
| Complete continence rate, No. (%) | 16 (50) | 6 (37.5) | 10 (62.5) | 0.157# |
BoNTA = botulinum toxin type A.* One-sided χ2 test.° Fisher exact test.# χ2 test.
Table 3
Cumulative incontinence rates over time after botulinum toxin type A intradetrusor injection at two different doses
| Visit | BoNTA 500 U (n = 39) | BoNTA 750 U (n = 38) | p value (χ2 test) |
|---|---|---|---|
| Day 30, No. (%) | 17 (43.6) | 10 (26.3) | 0.112 |
| Day 90, No. (%) | 24 (61.5) | 21 (55.3) | 0.576 |
| Day 180, No. (%) | 29 (74.4) | 26 (68.4) | 0.564 |
| Day 360, No. (%) | 36 (92.3) | 35 (92.1) | 1.000* |
BoNTA = botulinum toxin type A.
*
00594-4/assets/gr2/gr2_584x415.jpg)
Fig. 2
Kaplan-Meier estimate of freedom from reappearance of leakages after botulinum toxin type A intradetrusor injection at two different doses in patients with neurogenic detrusor overactivity.
BoNTA = botulinum toxin type A.
Pad usage significantly decreased at day 30 compared with baseline in patients who were treated with 500 U of BoNTA (McNemar test; p = 0.006) or 750 U of BoNTA (McNemar test; p < 0.001). Although no statistically significant differences were found between the treatment groups during the study period, intradetrusor injection with 750 U of BoNTA showed at each time point after baseline lower pad usage compared with 500 U of BoNTA (Table 4).
Table 4
Impact of botulinum toxin type A intradetrusor injection at two different doses on pad usage during the study period (last observation carried forward)
| Visit | BoNTA 500 U (n = 38) | BoNTA 750 U (n = 38) | p value (χ2 test) |
|---|---|---|---|
| Baseline, No. (%) | 23 (60.5) | 23 (60.5) | 1.000 |
| Day 30, No. (%) | 13 (34.2) | 11 (28.9) | 0.622 |
| Day 90, No. (%) | 13 (34.2) | 8 (21.1) | 0.200 |
| Day 180, No. (%) | 15 (39.5) | 10 (26.3) | 0.222 |
| Day 360, No. (%) | 19 (50.0) | 14 (36.8) | 0.247 |
BoNTA = botulinum toxin type A.
3.2.2. Urodynamic variables
At day 30, mean RDV, MCC, and BC statistically significantly increased from baseline in patients treated with either 500 U or 750 U of BoNTA (student t test; all p < 0.001), except BC in patients who received 500 U of BoNTA (Table 5). Significant improvements in urodynamic parameters were maintained throughout the study period. Patients treated with 750 U of BoNTA demonstrated a tendency towards greater improvements in RDV, MCC, and BC than those patients treated with 500 U (Table 6). On multivariate analysis, neither urodynamic results (p = 0.096 for BC) nor demographics (p = 0.058 for BoNTA dose and p = 0.073 for aetiology) at baseline were independent prognostic factors for urinary continence at day 30 after BoNTA intradetrusor injection.
Table 5
Comparison of baseline and follow-up visits at day 30 in urodynamic variables after botulinum toxin type A intradetrusor injection (all values: mean plus or minus standard deviation)
| RDV (ml) | BoNTA 500 U | BoNTA 750 U |
|---|---|---|
| n = 27 | n = 24 | |
| Day 0 | 159.6 ± 97.3 | 120 ± 81.3 |
| Day 30 | 315.6 ± 173.9 | 271.0 ± 139.5 |
| Difference D30–D0 | 156.0 ± 203.1 | 150.6 ± 117.1 |
| p < 0.001* | p < 0.001* |
| MCC (ml) | BoNTA 500 U | BoNTA 750 U |
|---|---|---|
| n = 37 | n = 36 | |
| Day 0 | 242.4 ± 123.9 | 180.7 ± 103.5 |
| Day 30 | 434.5 ± 178.6 | 423.7 ± 211.2 |
| Difference D30–D0 | 192.1 ± 226.9 | 243.0 ± 174.8 |
| p < 0.001* | p < 0.001* |
| BC (ml/cm H2O) | BoNTA 500 U | BoNTA 750 U |
|---|---|---|
| n = 37 | n = 37 | |
| Day 0 | 32.4 ± 32.1 | 22.9 ± 21.5 |
| Day 30 | 36.9 ± 27.8 | 59.2 ± 99.1 |
| Difference D30–D0 | 4.5 ± 39.1 | 36.3 ± 95.4 |
| p = 0.487* | p < 0.001** |
RDV = reflex detrusor volume; BoNTA = botulinum toxin type A; MCC = maximum cystometric capacity; BC = bladder compliance.
*
**
Table 6
Impact of botulinum toxin type A intradetrusor injection at two different doses on urodynamic variables during the study period*
| BoNTA 500 U | BoNTA 750 U | p value (Wilcoxon) | |||
|---|---|---|---|---|---|
| n | Median percent change | n | Median percent change | ||
| RDV (ml) | |||||
| Day 30 | 27 | 81.3 (−2.3/232.0) | 24 | 130.5 (40.2/253.0) | 0.322 |
| Day 90 | 33 | 66.7 (−2.6/180.0) | 34 | 132.1 (28.8/195.0) | 0.080 |
| Day 180 | 35 | 51.4 (−11.1/130.0) | 35 | 75.5 (28.8/195.0) | 0.070 |
| Day 360 | 35 | 51.4 (−11.1/130.0) | 36 | 56.4 (19.0/190.3) | 0.190 |
| MCC (ml) | |||||
| Day 30 | 37 | 62.5 (18.6/212.6) | 36 | 130.2 (58.1/225.1) | 0.272 |
| Day 90 | 37 | 60.0 (10.0/150.0) | 38 | 109.8 (50.0/179.9) | 0.065 |
| Day 180 | 37 | 45.8 (0.0/119.0) | 38 | 86.7 (49.7/156.4) | 0.060 |
| Day 360 | 37 | 34.4 (0.0/119.0) | 38 | 75.7 (25.0/150.0) | 0.121 |
| BC (ml/cm H2O) | |||||
| Day 30 | 37 | 25.9 (−32.7/138.1) | 37 | 100.0 (17.4/257.9) | 0.056 |
| Day 90 | 37 | −2.4 (−35.1/63.6) | 38 | 55.0 (0.0/174.3) | 0.032 |
| Day 180 | 37 | 11.1 (−40.0/116.2) | 38 | 55.0 (0.0/168.4) | 0.148 |
| Day 360 | 37 | 0.0 (−50.0/129.1) | 38 | 43.8 (−32.1/275.0) | 0.107 |
BoNTA = botulinum toxin type A; RDV = reflex detrusor volume; MCC = maximum cystometric capacity; BC = bladder compliance; LOCF = last observation carried forward.
*
3.2.3. Quality of life
The QoL of patients improved after treatment with either 500 U or 750 U of BoNTA, and this enhancement was maintained throughout the study period (Fig. 3). No statistically significant differences were found between the two doses.
00594-4/assets/gr3.jpg)
Fig. 3
Median relative (percent) improvement from baseline in the Specific Impact of Urinary Problems index in patients with neurogenic detrusor overactivity treated with monotherapy of botulinum toxin type A at two different doses, as assessed by a disease- and organ-specific Qualiveen questionnaire.
SIUP = Specific Impact of Urinary Problems; BoNTA = botulinum toxin type A.
3.3. Tolerability
Patient follow-up (n = 78) was, on average, 145.6 ± 121.6 d (500 U) and 169.5 ± 121.4 d (750 U) for BoNTA. Overall, eight (10.3%) patients experienced an adverse event; two of these patients received 500 U of BoNTA (5%, 2 out of 40), and six patients received 750 U of BoNTA (15.8%, 6 out of 38; Table 7). One patient with urgency who received 750 U of BoNTA (2.6%) dropped out of the study. One patient who received 750 U of BoNTA (2.6%) presented with treatment-related fatigue of severe intensity but was not withdrawn from the study. Cardiac frequency, arterial pressure, and body temperature were stable over the study period and were not different between the treatment groups. Most of the adverse events were not related to the BoNTA treatment.
Table 7
Tolerability of botulinum toxin type A intradetrusor injection
| BoNTA, U | Adverse event | Visit, d | Intensity | Treatment related |
|---|---|---|---|---|
| 500 | Haematuria and fever | 30 | Mild | No |
| 750 | Urgency | 180 | Moderate | No |
| 750 | Pyelonephritis | 30 | Moderate | No |
| 750 | General fatigue with vertigo | 30 | Severe | Yes |
| 500 | Difficulty for transfer out of a wheelchair | 30 | Mild | No |
| 750 | Constipation | 30 | Moderate | No |
| 750 | Difficulty for CISC | 30 | Mild | ND |
| 750 | Fever | 90 | ND | No |
BoNTA = botulinum toxin type A; CISC = clean intermittent self-catheterisation; ND = not determined.
4. Discussion
According to the literature, between 42% and 87% of patients became completely continent after a single BoNTA intradetrusor injection in patients with NDO refractory to anticholinergics. Efficacy in terms of clinical and urodynamic variables decreased with time and lasted for a period of approximately 3–9 mo [10], [11], and [12]. However, most of these patients were treated with concomitant use of anticholinergics for a variable period of time.
In this study, patients with NDO refractory to anticholinergics or discontinued anticholinergics because of adverse events or contraindications received an intradetrusor injection with 500 U or 750 U of BoNTA without further anticholinergic treatment. Complete continence at day 30 was achieved in 56.4% and 73.7% of patients who received 500 U and 750 U of BoNTA, respectively. The onset of secondary incontinence was approximately 6 mo. Further evidence for a positive treatment effect was shown by improvements in bladder function. Increases in bladder capacity, as measured by MCC, demonstrated that the bladder could accommodate a larger volume of urine without involuntary losses. This finding was further supported by increases in RDV and BC, which were generally still present at the end of the study period. The reported variability of urodynamic variables, in particular BC, may be explained by the different severity of patients’ neurogenic diseases. The reported changes with BoNTA monotherapy were translated into significant improvements in QoL, which were also maintained throughout the treatment period. These results imply that the effect of a BoNTA intradetrusor injection continued during the study period, even without concomitant use of anticholinergics. When baseline demographics and urodynamic results were placed in a logistic regression model for multivariate analysis, we were unable to identify any variable that could aid in predicting which patients will achieve complete continence at day 30 after BoNTA intradetrusor injection.
Interestingly, symptom improvement with monotherapy of BoNTA may lead to a systematic decrease in the use of anticholinergic agents after BoNTA injection to minimise short- and long-term anticholinergic-related adverse events. With no concomitant anticholinergic treatment, patients were not exposed to the adverse events related to anticholinergics. In addition, the tolerability of a single BoNTA injection was very good, with only one reported treatment-related adverse event and one patient withdrawn from the study because of a non-treatment-related adverse event. This finding is generally consistent with the known profile of adverse events of BoNTA intradetrusor injections for treatment of patients with NDO, as assessed in open-label studies and one placebo-controlled trial [4], [5], [6], [13], and [18].
Although there seems to be a trend towards faster and better improvement in clinical and urodynamic variables in patients with NDO who received 750 U versus 500 U of BoNTA, it should be noted that patients in the 750 U group had less beneficial outcomes on urodynamics at baseline. Nevertheless, no statistically significant differences were observed between the treatment groups, and no definite conclusion on the dose of BoNTA required can be reached. In our study, the assumed treatment improvement was ambitious, as no references existed at the time of study construction, slightly underpowering the intergroup significance. Notwithstanding, the results on BoNTA treatment in monotherapy are promising. In line with our results, Grosse et al [18] found no clear dose-related effect of 500 U, 750 U, or 1000 U of BoNTA at a follow-up period of 3.8 mo in patients with NDO. However, Del Popolo [5] demonstrated a comparable improvement in symptoms and urodynamic parameters with 500 U and 750 U of BoNTA, and QoL improvement with 750 U seems to be better than with 500 U.
In an increasing number of clinical studies, repeated BoNTA injections have shown prolonged efficacy, indicating no evidence of drug resistance [5], [18], [19], [20], and [21]. In addition, Hori et al [7] recently showed that 90% of patients would consider continuing BoNTA injections in the long term. Although long-term studies assessing the effect of repeated injections on the bladder are necessary, repeated injections of BoNTA without concomitant use of anticholinergics may be a valuable option for rapidly controlling UI for an increased period of time in patients with NDO. One may consider an injection when symptoms reappear or with an estimation of about every 6 mo, considering the median delay of reappearances and monotherapy of BoNTA.
5. Conclusions
To our knowledge, this is the first multicentre, prospective, randomised, double-blind, comparative study showing that monotherapy of Dysport improves symptoms in patients with NDO refractory to anticholinergics or discontinued anticholinergics because of adverse events or contraindications and with good tolerability. In addition, patient QoL improved. More studies are needed to draw final conclusions on the optimal dose and indications for repeated injections of BoNTA.
Author contributions: Philippe Grise had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Grise.
Acquisition of data: Grise, Ruffion, Chartier-Kastler, Denys, Egon.
Analysis and interpretation of data: Grise, Ruffion, Chartier-Kastler, Denys, Egon.
Drafting of the manuscript: Grise, Ruffion, Chartier-Kastler.
Critical revision of the manuscript for important intellectual content: Grise, Ruffion, Chartier-Kastler.
Statistical analysis: Grise, Ruffion, Chartier-Kastler.
Obtaining funding: Grise.
Administrative, technical, or material support: Grise.
Supervision: Grise.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: P. Grise is an investigator for Ipsen, Medtronic, and CL Medical. A. Ruffion is an investigator Allergan, Astellas, AstraZeneca, Coloplast, Ipsen, Medtronic, and Takeda and a consultant for Allergan and Coloplast. E. Chartier-Kasler is an investigator for Allergan, Astellas, AstraZeneca, Coloplast, Ipsen, and Medtronic; a consultant for Allergan, Coloplast, and Zambon; and a speaker for AMS, Astellas, AstraTech, Coloplast, and GSK. P. Denys is an investigator for Allergan, Ipsen, and Medtronic.
Funding/Support and role of the sponsor: Ipsen Pharma France provided support for the design and conduct of the study as well as approval of the manuscript.
Acknowledgment statement: The authors acknowledge Ipsen Pharma France for providing drug and financial support for the extra costs related to study and Peter Holmes Clinical for statistical input and analyses.
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Footnotes
a Department of Urology, Rouen University Hospital, Rouen Cedex, France
b Department of Urology, Hospices Civils, Lyon, France
c Department of Rehabilitation, Garches Hospital, Garches, France
d Department of Rehabilitation, Centre de l’Arche, Le Mans, France
e Department of Urology, Pitié Salpêtrière Hospital, Medical School Pierre and Marie Curie, University Paris VI, Paris, France
Corresponding author. Department of Urology, Rouen University Hospital, 1 Rue de Germont, 76031 Rouen Cedex, France. Tel. +33 2 32 88 81 73, Fax: +s33 2 32 88 82 05.
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