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Botulinum Toxin Urethral Sphincter Injection for Dysfunctional Voiding

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01733290
First Posted: November 27, 2012
Last Update Posted: March 8, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Hann-Chorng Kuo, Buddhist Tzu Chi General Hospital
  Purpose
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.

Condition Intervention Phase
Dysfunctional Voiding Drug: Botulinum toxin A Drug: Normal saline instillation Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Botulinum Toxin Urethral Sphincter Injection for Dysfunctional Voiding - A Multicenter Study, Randomized, Double-Blind, Placebo Control

Resource links provided by NLM:


Further study details as provided by Hann-Chorng Kuo, Buddhist Tzu Chi General Hospital:

Primary Outcome Measures:
  • Net change of Patient Perception of Bladder Condition (PPBC) [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of Patient Perception of Bladder Condition (PPBC) at baseline and 4 weeks after the initial injection. If patients have a PPBC improved by two scales, they are considered as successfully treated, otherwise failed treatment.

    Safety:

    Systemic adverse events



Secondary Outcome Measures:
  • Net change of the quality of life score [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the quality of life score at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups. Quality of life score which are adopted from the International Prostate Symptom Score (IPSS) system.

    Safety:

    Systemic adverse events


  • Net change of the maximal urethral closure pressure (MUCP) [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the maximal urethral closure pressure (MUCP) at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events


  • Net change of the functional profile length (FPL) [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the functional profile length (FPL) at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events


  • Net change of the cystometric bladder capacity (CBC) [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of cystometric bladder capacity (CBC) at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events


  • Net change of the bladder compliance [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the bladder compliance at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events


  • Net change of the voiding detrusor pressure (Pdet) [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the voiding detrusor pressure (Pdet) at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events


  • Net change of the maximal flow rate (Qmax) [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the maximal flow rate (Qmax) at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events


  • Net change of the voided volume [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the voided volume at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events


  • Net change of the postvoid residual urine volume (PVR) [ Time Frame: Baseline and 4 weeks ]

    Efficacy:

    Efficacy measured the net change of the residual urine volume (PVR) at baseline and 4 weeks after BoNT-A injection within and between the treatment group and control groups.

    Safety:

    Systemic adverse events



Enrollment: 70
Actual Study Start Date: October 2012
Study Completion Date: February 2017
Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Botulinum toxin A
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.
Drug: Botulinum toxin A
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.
Other Name: Botulinum Toxin A (BoNT-A)
Placebo Comparator: Control arm-Normal saline instillation
Normal saline instillation
Drug: Normal saline instillation
Normal saline instillation
Other Name: N/S

  Hide Detailed Description

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01733290


Locations
Taiwan
Buddhist Tzu Chi General Hospital
Hualien, Taiwan, 970
Sponsors and Collaborators
Buddhist Tzu Chi General Hospital
Investigators
Principal Investigator: Hann-Chorng Kuo, M.D. Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University
  More Information

Publications:
Kuo HC. Effectiveness of baclofen plus terazosin treatment in patients with lower urinary tract symptoms caused by spastic urethral sphincter. Tzu Chi Med J 12:141-148, 2000.
Nitti VW, Fiske J. Cystometrogram versus cystometrogram plus voiding pressure-flow studies in women with lower urinary tract symptoms. J Urol 161(Suppl):201,1999.
Kuo HC. Videourodynamic evaluation of the pathophysiology of lower urinary tract symptoms in neurologically intact women. Tzu Chi Med J 11:203-213,1999.

Responsible Party: Hann-Chorng Kuo, Director of Urology, Buddhist Tzu Chi General Hospital
ClinicalTrials.gov Identifier: NCT01733290     History of Changes
Other Study ID Numbers: TCGHUROL006
First Submitted: November 8, 2012
First Posted: November 27, 2012
Last Update Posted: March 8, 2017
Last Verified: March 2017

Keywords provided by Hann-Chorng Kuo, Buddhist Tzu Chi General Hospital:
Botulinum Toxin A (BoNT-A)
Dysfunctional voiding

Additional relevant MeSH terms:
Botulinum Toxins
Botulinum Toxins, Type A
onabotulinumtoxinA
abobotulinumtoxinA
incobotulinumtoxinA
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents