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Thursday, 31 May 2018 20:17

Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study

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We determined the safety and efficacy of each of 2 doses of botulinum toxin type A (BTX-A) (200 or 300 U BOTOX®) injected into the detrusor for urinary incontinence caused by neurogenic detrusor overactivity of predominantly spinal cord origin.

Materials and Methods:

A total of 59 patients with urinary incontinence caused by neurogenic detrusor overactivity (due to spinal cord injury in 53 and multiple sclerosis in 6) requiring clean intermittent self-catheterization were randomized to receive a single dose into the detrusor of BTX-A (200 U or 300 U) or placebo. Changes in daily frequency of urinary incontinence episodes were monitored via a patient bladder diary during 24 weeks. Key urodynamic assessments (maximum cystometric capacity, reflex detrusor volume and maximum detrusor pressure during bladder contraction) were used to provide objective measures of the treatment effect on bladder function. The impact of treatment on quality of life was assessed using the Incontinence Quality of Life questionnaire.


There were significant posttreatment decreases in incontinence episodes from baseline in the 2 BTX-A groups (p ≤0.05) but not in the placebo group. In addition, more patients who received BTX-A reported no incontinence episodes during at least 1 posttreatment evaluation period. Positive treatment effects were also reflected by significant improvements in bladder function in the BTX-A groups, as assessed by urodynamics and in patient quality of life. Benefits were observed from the first evaluation at week 2 to the end of the 24-week study. No safety concerns were raised.


Intramuscular injections of BTX-A into the detrusor can provide rapid, well tolerated, clinically significant decreases in the signs and symptoms of urinary incontinence caused by neurogenic detrusor overactivity during a 24-week study period.

Urinary incontinence due to neurogenic detrusor overactivity (NDO)1 is a common problem in patients with neurological pathology, such as multiple sclerosis (MS) and spinal cord injury (SCI), with significant impact on quality of life (QOL).2 Patients with NDO commonly use clean intermittent self-catheterization (CIC) to drain the bladder. Typically when incontinence episodes occur between catheterizations, oral anticholinergic agents are used to decrease bladder contractility and improve continence. However, troublesome side effects can occur, frequently affecting patient compliance and decreasing treatment efficacy.3

Research into bladder dysfunction has identified central and peripheral receptors, representing potential targets for pharmacotherapy.4 In addition to botulinum toxin type A (BTX-A), another investigational treatment for this indication is intravesical administration of capsaicin and resiniferatoxin.4 Surgery, such as bladder augmentation, is also an option with good long-term results and acceptable complications but it is a permanent treatment.5

The effectiveness and safety of the local administration of BTX-A into the bladder has been suggested in previously reported, open label and retrospective studies done in neurogenic cases.6, 7, 8 BTX-A blocks neuromuscular activity in skeletal muscle by preventing peripheral neurotransmitter release at presynaptic cholinergic nerve terminals.9 BTX-A may inhibit acetylcholine mediated detrusor contraction and potentially inhibit other vesical bound neurotransmitters in the afferent and efferent pathways of the bladder wall, urothelium or lamina propria.10, 11

In this double-blind, placebo controlled study we determined the safety and efficacy of local intradetrusor injection of 200 and 300 U doses of BTX-A in patients with incontinence caused by NDO in whom oral therapy had failed.




This double-blind, randomized, placebo controlled, parallel group study was performed during a 26-week period. Patients from 8 centers in Belgium, France and Switzerland participated from October 2001 to December 2002. The study was done in accordance with Independent Ethics Committee regulations in each country with approval obtained prior to study initiation, in compliance with Good Clinical Practice and the Declaration of Helsinki, 1996. Written informed consent was obtained from all patients.


A total of 59 patients 18 years or older were enrolled who had urinary incontinence caused by NDO, as demonstrated by urodynamics. The condition resulted from SCI in 53 patients and MS in 6. Patients were included if they had experienced urinary incontinence for at least 6 weeks, had been inadequately treated with oral anticholinergics, although use was permitted during the study, and performed regular CIC. Main exclusion criteria were previous or current botulinum therapy for any urological condition, any endovesical pharmacological agent treatment within the previous 6 months, symptomatic urinary tract infection (UTI), any suspicious finding during cystoscopy and any clotting factor disorder.



Following a screening visit at week −2 eligible patients were randomized in a 1:1:1 ratio to a single treatment of 300 U BTX-A, 200 U BTX-A or placebo at day 0. Randomization block size6 was not divulged to maintain blinding. Followup visits occurred at weeks 2, 6, 12, 18 and 24.



The BTX-A formulation used was BOTOX® (Clostridium botulinum toxin type A). Each patient was allocated a unique randomization number, which was present on all study medication. According to the treatment group randomization patients received 3 vials of active treatment or placebo. It was advised that patients should discontinue oral anticoagulant medication at least 10 days prior to treatment and prophylactic antibiotics were administered for an appropriate period. Study medication was reconstituted with 0.9% preservative-free saline to a total volume of 30 ml. The bladder was distended with approximately 100 ml saline to enable adequate visualization. Under cystoscopic guidance 30 injections of 1.0 ml each were injected intramuscularly into the detrusor, avoiding the base and trigone, as previously reported.7 Injections were done with the patient under general, spinal, local or no anesthesia, as determined by the injecting physician. Following treatment patients were monitored for 30 minutes for adverse events (AEs) or observed for 6 hours if general anesthesia was administered.


Efficacy and safety evaluations.

The primary efficacy variable was incontinence episodes daily from week −2 to day 0 (baseline) and for 1 week prior to each study visit at weeks 2, 6, 12, 18 and 24, as recorded by patients in the bladder diary. Other parameters recorded were the number of catheterizations daily and fluid intake volume for 72 hours prior to each visit. Urodynamic measurements were performed at weeks −2, 2, 6 and 24 by cystometry or videourodynamics according to standard guidelines.12 The key measurements were maximum cystometric capacity (MCC), reflex detrusor volume (RDV) and maximum detrusor pressure during bladder contraction (MDP), using the standard International Continence Society definitions at the time of protocol writing.13

Safety evaluations included spontaneous reports of AEs, vital signs, hematology and chemistry parameters, cystography and ultrasound of the urinary tract. Serum antibody assays for neutralizing antibodies to BTX-A were also performed using the mouse protection assay14 on samples before injection and at study exit. QOL was assessed using the Incontinence Quality of Life (I-QOL) Questionnaire.15


Statistical methods.

The sample size of 18 patients per group was based on a between-group target difference of 3 episodes in change from baseline in daily incontinence episodes, assuming the baseline of 6 episodes suggested by empirical data, a 2-sided α of 0.05, 80% power and an assumed SD of 3 episodes. Between-group comparisons of each BTX-A dose group vs placebo were performed using an ANOVA model with factors for treatment and investigator together with the appropriate pairwise contrasts. Within-group changes from baseline in the frequency of daily incontinence episodes were analyzed using the paired t test. The intent to treat population was used for all analyses. Missing values of the primary efficacy variable were imputed using the mean of all nonmissing values. I-QOL data were summarized and compared among all treatments using nonparametric methods. No significance level adjustment was made for multiplicity. Data analyses were performed elsewhere.




Study population.

A total of 59 patients were recruited from the existing patient lists at each site and randomized into the 300 U BTX-A (19), 200 U BTX-A (19) and placebo (21) groups. Only 2 patients (200 U BTX-A group) did not complete the study because of withdrawal due to an AE event at day 0 and a lack of efficacy after week 6, respectively. However, the latter patient was in protocol violation due to an indwelling catheter at study entry.

There were no statistically significant differences among the 3 treatment groups for any demographic or baseline characteristics. Mean patient age was 41 years (range 20 to 72). There were more males than females (36 of 59 patients or 61.0%) and the majority were white (55 of 59 or 93.2%). The cause of NDO was primarily SCI (53 of 59 patients or 89.8%). Of these patients American Spinal Injury Association class was A to E in 33, 10, 5, 4 and 1, respectively. A total of 48 patients (81.4%) were wheelchair bound. Mean NDO history was 63 months (range 3 months to 24 years). Anesthesia was not performed before injection in 22% of patients, while 39.0% required general, 35.6% required local and 3.4% required spinal anesthesia.


Efficacy results.

In the 2 BTX-A groups improvements were demonstrated in the daily frequency of incontinence episodes and urodynamic parameters. Improvements occurred from the first posttreatment evaluation visit at week 2 and were generally maintained for the duration of the 24-week study. No evidence of a treatment by site interaction effect was observed.


Daily frequency of incontinence episodes.

At baseline the mean daily frequency of incontinence episodes was not significantly different among the 300 U BTX-A, 200 U BTX-A and placebo treatment groups (2.8, 1.9 and 3.0, respectively). Following treatment there were significant decreases in incontinence episodes at all time points in the 2 BTX-A groups, except weeks 12 and 18 in the 200 U BTX-A group, and there were none in the placebo group (fig. 1 and table 1). The decreases in the 2 BTX-A groups represented a reduction in incontinence episodes of approximately 50% despite a lower baseline than anticipated. Compared with placebo the difference between treatment groups was significant in favor of the 300 U BTX-A group at weeks 2 (p = 0.015) and 6 (p = 0.047), and in the 200 U BTX-A group at week 24 (p = 0.019).

 Opens large image

Fig. 1

Mean change from baseline in daily frequency of incontinence episodes.


Table 1Values and change from baseline in patient bladder diary parameters at each scheduled visit
Time Point Mean Daily Value (mean change from baseline)
  300 U BTX-A 200 U BTX-A Placebo
No. pts 19   19   21  
Involuntary urine loss frequency:
  Baseline 2.8 (1.86) 1.9 (1.78) 3.0 (3.29)
  Wk 2 -1.3 (1.39)* -1.0 (1.67) -0.2 (1.02)
  Wk 6 -1.5 (2.33)* -0.9 (1.84) -0.2 (1.45)
  Wk 12 -1.2 (1.66) -0.9 (2.14) -0.3 (1.46)
  Wk 18 -1.2 (1.16) -0.8 (2.75) -0.3 (1.59)
  Wk 24 -0.9 (1.34) -1.1 (1.92)* -0.1 (1.09)
Catheterization frequency:
  Baseline 4.9 (1.04) 5.5 (2.06) 4.8 (1.24)
  Wk 2 -0.1 (1.08) -0.7 (0.71)* -0.0 (0.79)
  Wk 6 0.1 (1.20) -1.2 (2.10) -0.1 (0.87)
  Wk 12 -0.1 (1.16) -1.1 (2.07) -0.1 (0.81)
  Wk 18 0.4 (1.20) -1.1 (2.34) -0.1 (0.86)
  Wk 24 0.2 (1.17) -0.7 (2.39) -0.1 (0.89)
Fluid intake vol (ml):
  Baseline 1,439 (704.44) 1,177 (491.90) 1,299 (529.58)
  Wk 1 37.6 (371.71) 34.1 (366.45) 30.5 (491.62)
  Wk 6 -121 (347.49) -123 (505.74) -97.6 (479.08)
  Wk 12 -43.4 (430.32) 137.7 (417.30) -148 (519.23)
  Wk 18 -108 (498.75) -54.7 (309.20) -52.7 (458.01)
  Wk 24 -217 (525.98) 4.1 (348.80) -96.5 (501.51)
View Table in HTML

Change from baseline represents SD.

*At each visit within-group changes from baseline paired t test and pairwise contrasts of BTX-A vs placebo single 2-way ANOVA model p <0.05.
At each visit pairwise contrasts of BTX-A vs placebo single 2-way ANOVA model p <0.05.

Overall 29 patients (49.2%) reported no incontinence episodes for at least 1, 1-week posttreatment period, of whom 24 (82.8%) were in a BTX-A treatment group, that is 10 in the 300 U and 14 in the 200 U group. Catheterization frequency and fluid intake volume remained generally constant throughout the study with no significant differences in the treatment groups or when compared with placebo, except for catheterization frequency at week 2 in the 200 U BTX-A group) (table 1). Additionally, anticholinergic use remained similar throughout the study.



There were significant increases from baseline in mean MCC in each BTX-A treatment group at all posttreatment time points (p ≤0.020), although there were no significant changes in the placebo group (table 2). Mean changes from baseline in the 2 BTX-A treatment groups were significantly higher compared with placebo at every time point except at week 24 in the 300 U BTX-A group.

Table 2Values and change from baseline in urodynamic parameters at each scheduled visit
Time Point Mean Value (mean change from baseline)
  300 U BTX-A 200 U BTX-A Placebo
No. pts 19 19 21
MCC (ml):
  Baseline 293.6 260.2 254.6
  Wk 2 479.6 (186.1)*, 482.5 (215.8)*, 282.0 (27.4)
  Wk 6 462.7 (169.1)*, 448.8 (182.1)* 299.6 (45.0)
  Wk 24 398.2 (92.9) 440.9 (174.2)*, 301.0 (41.6)
RDV (ml):
  Baseline 254.8 169.1 202.4
  Wk 2 198.1 (8.6) 306.9 (135.3) 206.7 (4.3)
  Wk 6 268.5 (96.0) 234.2 (47.3) 244.6 (42.6)
  Wk 24 305.4 (72.4) 327.4 (144.6)*, 226.4 (23.5)
MDP (cm H2O):
  Baseline 92.6 77.0 79.1
  Wk 2 41.0 (-66.3)*, 31.6 (-52.9)*, 71.4 (-7.7)
  Wk 6 45.9 (-62.2) 40.1 (-44.4)*, 69.0 (-10.1)
  Wk 24 55.2 (-35.5)*, 48.8 (-38.7)*, 80.6 (-1.4)
View Table in HTML
*At each visit within-group changes from baseline paired t test p <0.05.
At each visit pairwise contrasts between BTX-A vs placebo single 2-way ANOVA model p <0.05.


Mean RDV was recorded at baseline in all patients. After treatment 23 patients did not experience a hyperreflexive detrusor contraction for at least 1 followup visit and, therefore, no RDV was recorded. Of these 23 patients 21 (91.3%) were in a BTX-A treatment group (table 3).

Table 3Patients with no RDV by visit
Time Point No. 300 U BTX-A (%) No. 200 U BTX-A (%) No. Placebo (%)
Overall 19 19 21
Baseline 1 (5.2) 1 (5.2) 0
Wk 2 10 (52.6) 9 (47.4) 0
Wk 6 9 (47.4) 8 (42.1) 1 (4.8)
Wk 24 3 (15.8) 6 (31.6) 2 (9.5)
No RDV at 1 visit or more 11 (57.9) 10 (52.6) 2 (9.5)
View Table in HTML

Following analysis of patients with a posttreatment RDV an increase in mean RDV was significant at week 6 in the 300 U BTX-A group and at week 24 in the 200 U BTX-A group (p ≤0.021, table 2). Compared with placebo the increases in mean RDV were greater in the BTX-A groups and significant in the 200 U BTX-A group at weeks 2 and 24.



There were significant decreases from baseline in MDP at all BTX-A posttreatment time points (p ≤0.023), although there were no significant changes for placebo (table 2). Mean decreases in MDP were significantly greater in the BTX-A groups compared with placebo at all posttreatment visits.


Safety results.

The overall incidence of patients experiencing at least 1 AE was not significantly different among the treatment groups and no AEs were considered to be related to the study drug. The only AEs that occurred in more than 1 patient per treatment group were UTI and injection site pain. UTIs were reported by 4 (21.1%), 6 (31.6%) and 3 patients (14.3%) in the 300 U BTX-A, 200 U BTX-A and placebo groups, respectively. Injection site pain reported to be less than 1 hour in duration was reported by 2 (10.5%) and 1 patients (4.8%) in the 300 U BTX-A and placebo groups, respectively (table 4).

Table 4Patients with AEs
Body System Preferred Term* No. 300 U BTX-A No. 200 U BTX-A No. Placebo Among Group p Value
Overall 19 19 21  
Body as whole:
  Injection site pain 2 (10.5) 0 1 (4.8) 0.521
  Fever 1 (5.3) 0 0 0.644
  Pain 0 1 (5.3) 0 0.644
  Influenza syndrome 0 0 1 (4.8) >0.999
Digestive system:
  Gastroenteritis 1 (5.3) 0 0 0.644
  Abnormal liver function tests 0 0 1 (4.8) >0.999
Metabolic + nutritional disorders (peripheral edema) 0 1 (5.3) 0 0.644
Musculoskeletal system (arthralgia) 1 (5.3) 0 0 0.644
Nervous system:
  Neuritis 1 (5.3) 0 0 0.644
  Confusion 0 1 (5.3) 0 0.644
  MS 0 1 (5.3) 0 0.644
  Neuralgia 0 1 (5.3) 0 0.644
  Anxiety 0 0 1 (4.8) >0.999
Respiratory system:
  Sinusitis 0 1 (5.3) 0 0.644
  Pharyngitis 0 0 1 (4.8) >0.999
Skin + appendages:
  Skin ulcer 0 1 (5.3) 1 (4.8) >0.999
  Herpes zoster 0 0 1 (4.8) >0.999
  Cutaneous inflammation 0 0 1 (4.8) >0.999
  Skin disorder 0 0 1 (4.8) >0.999
Urogenital system:
  Urinary tract infection 4 (21.1) 6 (31.6) 3 (14.3) 0.455
  Hematuria 1 (5.3) 1 (5.3) 0 0.534
  Prostatic disorder 0 0 1 (4.8) >0.999
View Table in HTML
*From Allergan modified COSTART dictionary.
Based on Pearson's chi-square test but if 25% or more of cells had expected counts of less than 5, Fisher's exact test was used.

It is of note that no cases of autonomic dysreflexia or systemic effects were seen. There were no clinically relevant changes in vital signs, hematology or chemistry parameters, ultrasound or cystography observations during the study.

One patient in the BTX-A 200 U group discontinued the study during the study injection procedure prior to the administration of study drug due to urethral stricture. Two serious AEs were reported. One patient in the 200 U BTX-A group experienced confusion and 1 in the placebo group reported a skin ulcer. These AEs were not treatment related and they did not prevent study completion. All serum samples analyzed for antibodies were negative at baseline and at week 24.



There were robust improvements in the mean change from baseline in I-QOL total scores in patients treated with BTX-A at all time points (p ≤0.002), which were maintained throughout the 24 study weeks. They were statistically significant compared with placebo at all time points (fig. 2).

 Opens large image

Fig. 2

Mean total I-QOL scores at each scheduled visit




To our knowledge this is the first controlled study of the use of BTX-A (2 doses) in patients with NDO. It demonstrates that a single session of intramuscular administration of 300 or 200 U BTX-A into the detrusor is effective for improving incontinence, bladder function and QOL from the first posttreatment assessment at week 2 to the end of the 24-week study period. Mean incontinence episodes were decreased from baseline by approximately 50% in the BTX-A groups and more BTX-A treated patients reported at least 1 posttreatment incontinence-free period, which is considered the key treatment objective in clinical practice.

Further evidence for a rapid, positive treatment effect was shown by improvements in bladder function by week 2, including increases in bladder capacity, as measured by MCC, demonstrating that the bladder could accommodate a larger volume of urine without involuntary losses. This was further supported by changes in RDV after treatment. Approximately 55% of BTX-A treated patients compared with approximately 10% of placebo treated patients did not experience a hyperreflexive detrusor contraction for at least 1 posttreatment time point. When an RDV measurement was obtained, increases in mean RDV were observed, representing the bladder ability to store increased volumes before a hyperreflexive detrusor contraction occurs, potentially inducing involuntary voiding. Significant decreases in MDP following BTX-A treatment could result in a decreased risk of vesicoureteral reflux, therefore, preventing upper urinary tract deterioration and possible kidney damage.16 These results strengthen those of previous uncontrolled studies of BTX-A treatment in this patient population with NDO.6, 7, 8

A major factor in the failure of oral anticholinergic treatments is the occurrence of distressing side effects, such as dry mouth, constipation, blurred vision and somnolence, which limit doses or lead to the discontinuation of therapy.3 The safety profile of locally acting BTX-A treatment was excellent with no drug related AEs reported and no injected patients withdrawing from the study due to an AE. Theoretical risks associated with BTX-A treatment for this indication could include risk due to anesthesia, hematuria, perforation and urosepsis. However, these events, in addition to those that are not indication specific, eg influenza-like symptoms, were not observed in more than 1 patient per treatment group, although it is acknowledged that sample size was small. This may have been due to the safeguards used to minimize patient risk, that is excluding patients with any history or medical therapy for clotting disorders or symptomatic UTI, appropriate prophylactic antibiotics administered before treatment and the injection procedure, which was done using standard sterile procedures.

The most common AE in this study was UTI, which was seen in approximately a quarter of all patients. This is similar to the rate reported previously in conjunction with urodynamic procedures or CIC.17 Observed changes with BTX-A administration in incontinence episodes and bladder function combined with a low incidence of side effects were apparently translated into patient benefit with significant improvements in I-QOL scores observed throughout the 24-week study period. There is a theoretical risk of antibody formation with BTX-A administration. Although only a single treatment was administered, the lack of antibody formation in this study is consistent with previous reports evaluating the immunogenic profile of this BTX-A formulation.18

The study did not demonstrate a clear dose difference in clinical effect between the 200 and 300 U BTX-A groups, which may have been due to small sample size. Therefore, further evaluation in longer studies would be required, not only to assess the duration of effect, but also to determine whether the duration is dose related. BTX-A effectiveness for significantly decreasing incontinence episodes combined with the excellent safety profile indicates that this agent may also benefit patients with urinary incontinence of nonneurogenic origin, which is supported by preliminary results in this population.19



To our knowledge we report the first controlled study in patients with urinary incontinence caused by NDO. It demonstrates that a single administration of 300 or 200 U BTX-A into the detrusor was well tolerated and more effective than placebo for decreasing the frequency of incontinence episodes, enhancing bladder function and improving QOL. The rapid clinical benefit and sustained positive treatment effect of BTX-A observed by week 2 coupled with the reassuring safety profile seen in this study suggests that this treatment is a potential candidate for the management of neurogenic urinary incontinence.

Data analyses were performed at Allergan.



The Detrusor Hyperreflexia Study Team includes the authors and the following investigators: Dr. Andre Reitz, Spinal Cord Injury Centre, University Hospital Balgrist, Zurich, Switzerland; Professor Pierre-Alain Joseph, Service de Medecine Physique et de Readaptation, Hôpital Pellegrin and Dr. Luc Soyeur, Service d’Urologie, Hôpital Pellegrin, Bordeaux, Dr. Loïc le Normand and Dr. Jean-Jacques Labat, Clinique Urologique, Centre Hospitalier Universitaire Nantes, Hotel-Dieu, Nantes, Professor Gérard Amarenco, Dr. Samer Ismael and Dr. Béatrice Bayle, Service de Rééducation Neurologique et d’Explorations, Hôpital de Rothschild and Dr. Calin Ciofu, Service Urologie, Hôpital Tenon, Paris and Dr. Soler, Centre Dr. Bouffard-Vercelli, Cap Peyrefite, Cerbere and Cecile Laroche, Allergan SAS, Mougins, France; and Dr. Veroniqué Keppenne, Service Urologie, Centre Hospitalier Universitaire Sart Tilman, Liege, Belgium.




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Read 3854 times Last modified on Friday, 01 June 2018 18:40
Prof Karel Everaert


Karel Everaert currently works at the Department of Uro-gynaecology, Ghent University. Karel and his NOPIA research group do research in Functional Urology with a special interest in nocturia and nocturnal polyuria, sacral neuromodulation, the overactive bladder and luts in older people.

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