Botulinum Toxin Urethral Sphincter Injection for Dysfunctional Voiding
Botulinum Toxin Urethral Sphincter Injection for Dysfunctional Voiding
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.
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.
Inclusion Criteria:

 -  Adults with age of 20 years old or above.

 -  Free of active urinary tract infection.

 -  Free of bladder outlet obstruction on enrollment.

 -  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.

 Exclusion Criteria:

 -  Patients with severe cardiopulmonary disease and such as congestive heart failure,
 arrhythmia, poorly controlled hypertension, not able to receive regular follow-up.

 -  Patients with bladder outlet obstruction on enrollment.

 -  Patients with uncontrolled confirmed diagnosis of acute urinary tract infection.

 -  Patients have laboratory abnormalities at screening including: Alanine
 aminotransferase (ALT) > 3 x upper limit of normal range aspartate aminotransferase
 (AST) > 3 x upper limit of normal range.

 -  Patients have abnormal serum creatinine level > 2 x upper limit of normal range.

 -  Patients with any contraindication to be urethral catheterization during treatment.

 -  Female patients who is pregnant, lactating, or with child-bearing potential without
 contraception.

 -  Patients with any other serious disease considered by the investigator not suitable
 for general anesthesia or in the condition to enter the trial.

 -  Patients participated investigational drug trial within 1 month before entering this
 study.

 -  Written informed consent has been obtained.