Botulinum Toxin Urethral Sphincter Injection for Dysfunctional Voiding
Condition: Dysfunctional Voiding
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is designed and aimed at determine the clinical efficacy of BoNT-A on patients
      with dysfunctional voiding. The results of this study can provide further information for
      patient selection and therapeutic duration.
    

Detailed description: 
      This study is designed in a randomized, double-blind, placebo controlled, multicentric trial.
      A total of 60 patients will be enrolled. All patients have suffered from dysfunctional
      voiding that is refractory to conventional treatment. The enrolled patients should have
      severe dysuria or urinary retention, large residual urine and have been treated with
      medication or other therapeutic modality for over 3 months. The patients will be randomly
      assigned to allocate in the treatment and control groups in a 2:1 ratio. About 40 and 20
      patients will be enrolled in the treatment and control group, respectively.

      This study should be approved by the Institutional Review Board (IRB) and ethical committee
      of the hospital. Every patient should be thoroughly informed and written informed consent
      should be obtained before treatment.

      Patients will receive a complete urological work-up before treatment, including urinalysis,
      urine culture, cystoscopy to prove no anatomical stricture or lower urinary tract pathology,
      and videourodynamic study. All medication that may affect the lower urinary tract function
      will be stopped at least 1 week before Botulinum Toxin A (BoNT-A) injection.

      Videourodynamic study will be performed with the patient in supine position if patients
      cannot stand up or sit on the commode. A 6 Fr dual channel urethral pressure profiles (UPP)
      urethral catheter will be inserted to the urinary bladder. After evacuation of the residual
      urine, urethral pressure profilometry will be performed first. Then the bladder will be
      filled with normal saline containing 20% urografin at the filling rate of 30 ml/min. The
      filling and voiding cystourethrography will be investigated by a C-arm positioned below the
      patient. Uroflowmetry is recorded by a weighed transducer placed below the examination table.
      After the bladder is filled to the capacity, the patients are asked to urinate per urethrae.
      If patient cannot urinate per urethrae with the urethral catheter in situ, suprapubic
      puncture with a 18 Gauge needle and a 3-Fr epidural catheter will be undertaken and patients
      will urinate without the catheter in the urethra. The patients are requested to stand up and
      urinate into the commode. Pressure flow study and concomitant voiding cystourethrography are
      performed.

      The urodynamic parameters include maximal urethral closure pressure (MUCP), functional
      profile length (FPL), cystometric bladder capacity (CBC), bladder compliance, voiding
      detrusor pressure (Pdet), maximal flow rate (Qmax), voided volume, and postvoid residual
      urine volume (PVR). In the patients who have detrusor underactivity, the abdominal pressure
      to urinate and the detrusor leak point pressure will be measured. Images of voiding
      cystourethrography will be emphasized on the bladder neck opening, urethral sphincter
      relaxation, and dilatation of posterior urethra during voiding.

      Patients will be admitted and BoNT-A (treatment group) or normal saline (control group)
      injections will be performed in the operation room where complete cardiovascular monitoring
      is available during the operation. BoNT-A injections are made under cystoscopy guide in male
      patients and injecting periurethrally in female patients. The BoNT-A will be purchased from
      Allergan Company (Botox, 100 units/vial, Irvine, California, U.S.A.). Each vial of BoNT-A
      will be diluted to 5 ml by normal saline. A total of 100 units of BoNT-A will be injected
      deeply into the external sphincter at the 3, 6, 9 and 12 o'clock positions in approximate
      equal aliquot. After BoNT-A injections, a 14 Fr Foley catheter will be indwelled routinely
      for 1 day and then removed. Patients will be followed up for their voiding conditions. When
      dysuria persists, intermittent catheterization will be advised instead of indwelling Foley
      catheter. Antibiotics will not be necessary unless urinary tract infection occurs, and
      medications to reduce urethral sphincteric resistance are discontinued.

      Patients will be closely contacted and monitored by the research assistant by telephone. They
      will be followed up at out-patient clinic at 1 week, 2 weeks and 4 weeks after BoNT-A
      injections. After the first month after initial BoNT-A injection, patients will be followed
      up monthly until the therapeutic effect is gone. Videourodynamic study and UPP study will be
      performed at 4 weeks after BoNT-A injections. The subjective improvement of voiding condition
      will be assessed by the obstructive symptom scores (including hesitancy, intermittency,
      dysuria, small caliber of urine) and quality of life score which are adopted from the
      International Prostate Symptom Score (IPSS) system.

      The primary end-point is the change of Patient Perception of Bladder Condition (PPBC) at 4
      weeks after the initial injection. If patients have a PPBC improved by two scales, they are
      considered as successfully treated, otherwise failed treatment. The subjective symptom score,
      quality of life score and urodynamic parameters will be compared at baseline and 4 weeks
      after BoNT-A injection within and between the treatment group and control groups. For the
      patients who do not have significant improvement 4 weeks after BoNT-A injections, a second
      injection with 100 units of BoNT-A will be performed at 4 weeks after the initial injection
      regardless the patient's initial grouping. These patients will be followed up at the same
      interval until the return of voiding dysfunction.

      Continuous variables are presented as means ± standard deviations (SDs), and categorical data
      are presented as numbers and percentages (%). Statistical comparisons within group will be
      performed by paired t test, between the groups are tested using the chi-square test for
      categorical variables, and the Wilcoxon rank-sum test for continuous variables. Long-term
      successful results are compared using Kaplan-Meier analyses. Statistical assessments are
      considered significant when p < 0.05. Statistical analyses will be performed using SPSS 15.0
      statistical software (SPSS Inc., Chicago, IL).

      Any side effect related to the BoNT-A injections will be asked to report. There has not been
      reported to have serious side effect from local injection of BoNT-A to the urethral
      sphincter. However, the potential side effects, such as exacerbation of urinary incontinence,
      allergy and anaphylactic shock should be informed to the patients and carefully monitor the
      postoperative conditions. Urinalysis will be checked at the first follow-up 1 and 2 week
      after BoNT-A injection. Antibiotics will be given if patients have significant urinary tract
      infection.
    

Intervention name(s): Botulinum toxin A; Normal saline instillation
Intervention type(s): Drug; Drug
Intervention description(s): A total of 100 units of BoNT-A will be injected deeply into the external sphincter at the 3, 6, 9 and 12 o'clock positions in approximate equal aliquot.; Normal saline instillation
Other intervention name(s): Botulinum Toxin A (BoNT-A); N/S
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Botulinum Toxin A (BoNT-A); Dysfunctional voiding