Botulinum Toxin Urethral Sphincter Injection for Dysfunctional Voiding

March 7, 2017 updated by: Hann-Chorng Kuo, Buddhist Tzu Chi General Hospital

Botulinum Toxin Urethral Sphincter Injection for Dysfunctional Voiding - A Multicenter Study, Randomized, Double-Blind, Placebo Control

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

70

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Hualien, Taiwan, 970
        • Buddhist Tzu Chi General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • Botulinum Toxin A (BoNT-A)
Placebo Comparator: Control arm-Normal saline instillation
Normal saline instillation
Drug: Normal saline instillation
Normal saline instillation
Other Names:
  • N/S

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline and 4 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline and 4 weeks
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
Baseline and 4 weeks
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
Baseline and 4 weeks
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
Baseline and 4 weeks
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
Baseline and 4 weeks
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
Baseline and 4 weeks
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
Baseline and 4 weeks
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
Baseline and 4 weeks
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
Baseline and 4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Buddhist Tzu Chi General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2012

Primary Completion (Actual)

February 1, 2017

Study Completion (Actual)

February 1, 2017

Study Registration Dates

First Submitted

November 8, 2012

First Submitted That Met QC Criteria

November 20, 2012

First Posted (Estimate)

November 27, 2012

Study Record Updates

Last Update Posted (Actual)

March 8, 2017

Last Update Submitted That Met QC Criteria

March 7, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TCGHUROL006

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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