Injections of Botulinum Toxin A in Treatment of Patients With Detrusor Overactivity and Impaired Contractility

Comparative Study of Safety and Efficacy Between 100 U Suburothelial Injection and 50 U Suburothelial Plus 50 U Urethral Injections of Botulinum Toxin A in Treatment of Patients With Detrusor Overactivity and Impaired Contractility

The objectives of this study is to evaluate and compare the efficacy and safety between 100 U of botulinum toxin A (BoNT-A) suburothelial injections and combined 50 U of BoNT-A suburothelial injections and 50 U urethral injection for the treatment of detrusor overactivity and inadequate contractility (DHIC) refractory to antimuscarinic agents

Overactive bladder (OAB) is a symptom syndrome characterized by urgency frequency with or without urgency incontinence, usually no metabolic or anatomical disorders can be found and it may have great impact on quality of life. OAB symptoms were found to have a significant effect on the emotional well-being and productivity of those affected. Although there are several new therapeutic options with promising treatment outcome, antimuscarinic drugs remain the first line treatment and clinical effects with good tolerability have been confirmed. However, not all OAB patients can benefit from antimuscarinic agent, and this treatment has some adverse effects such as dizziness, dry mouth, blurred vision, and constipation, which are intolerable for some patients. Of these patients intravesical botulinum toxin (BoNT) injections provide an alternative treatment with a favorable efficacy.

Based on the understanding of the pathophysiology of OAB and detrusor overactivity (DO), BoNT has been enthusiastically applied in treating urinary urgency or incontinence refractory to antimuscarinics in recent years. Although promising therapeutic effects have been confirmed by several case series or clinical trials, the occurrence of adverse events are reported inconsistently. Analysis of patients demographics and urodynamic variables reveals that patients with ageing, low detrusor contractility, with chronic medical disease carry risks of adverse events. Although safety and efficacy were similar between elderly patients without frailty and younger patients, an increased risk of large post-void residual urine volume and a lower long-term success rate in frail elderly patients were noted after intravesical 100 U BoNT-A injection for refractory idiopathic DO. Therefore, careful dose and injection site adjustment and patient selection is mandatory to achieve satisfactory results using intravesical BoNT-A therapy.

This study aimed at compare the safety and efficacy between 100 U suburothelial injection and combined 50 U suburothelial and 50 U urethral sphincter injection of BoNT-A in patients with detrusor overactivity and inadequate contractility (DHIC). A total of 60 patients with DHIC will be enrolled and randomly allocated to each group and treated with either regimen. The safety and efficacy will be assessed by the Patient's Perception of Bladder Condition (PPBC) at different time points after injection. The results of this study may provide valuable evidence for the rational treatment regimen for patients with DHIC.

Estimated Total Sample Size 60 evaluable patients in total will be recruited

Method of Patient Assignment

Patients who meet all eligible requirements for entry into the study will be randomized into one of the two treatment groups in 1:1 ratio as shown below:

1. BoNT-A 100 units in normal saline 10ml, suburothelial injection at 20 sites of bladder wall in single treatment
2. BoNT-A 100 units in normal saline 10ml, suburothelial injection 50 U in 10 sites and 50 U urethral injections in 5 sites

Patient Inclusion Criteria

1. Adults with age of 20 years old or above
2. Patients with symptoms of urgency frequency and/or urge incontinence and urodynamically proven DHIC (defined by the International Continence Society (ICS) recommendation as: spontaneous detrusor contraction occurring during bladder filling phase or occurring before uninhibited detrusor contraction voiding at bladder capacity of less than 350ml in the urodynamic study, and has postvoid residual of more than 100ml but less than 250ml)
3. Free of active urinary tract infection
4. Free of bladder outlet obstruction on enrollment
5. Free of overt neurogenic bladder dysfunction
6. Having been treated with antimuscarinic agents for at least 1 months without effect or with intolerable adverse effects
7. Patient or his/her legally acceptable representative has signed the written informed consent form

Patient Exclusion Criteria

1. Use of antimuscarinic agent and effective in treatment of lower urinary tract symptoms

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

3. Patients with bladder outlet obstruction on enrollment

4. Patients with postvoid residual > 250ml

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

6. 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

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

8. Patients with any other serious disease considered by the investigator not in the condition to enter the trial

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

Data Analysis The efficacy evaluation will be performed on intention-to-treat populations (ITT) and per-protocol populations (PPP) datasets while the safety evaluation will be performed on ITT datasets. The primary conclusion will be made for the primary endpoint and secondary endpoint on the ITT population..

Efficacy Endpoint Analysis Net change of each efficacy item will be analyzed by paired t-test between baseline and post-treatment in the treatment group and controlled group. The net changes of each efficacy item will be analyzed by ANOVA test to compare between treatment group and controlled group. The global assessment by the patients will be analyzed by chi-square test between the treatment and controlled group.

All efficacy variables will be reported of respective point estimated and 95% confidence interval. Comparison tests will be reported of respective p value.

Safety Endpoints Adverse events will be reported by both controlled and treatment groups and by physiological systems as appropriate. Incidence of adverse events and the categories of adverse event severity between treatments will be analyzed by Cochran-Mantel-Haenszel test. The coding system used will be the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART).

Changes in physical examinations will be displayed for each individual system. All statistical tests used will be two-tailed with α= 0.05.

Inclusion Criteria:

• Adults with age of 20 years old or above
• Patients with symptoms of urgency frequency and/or urge incontinence and urodynamically proven DHIC (defined by the ICS recommendation as: spontaneous detrusor contraction occurring during bladder filling phase or occurring before uninhibited detrusor contraction voiding at bladder capacity of less than 350ml in the urodynamic study, and has postvoid residual of more than 100ml but less than 250ml)
• Free of active urinary tract infection
• Free of bladder outlet obstruction on enrollment
• Free of overt neurogenic bladder dysfunction
• Having been treated with antimuscarinic agents for at least 1 months without effect or with intolerable adverse effects
• Patient or his/her legally acceptable representative has signed the written informed consent form

Exclusion Criteria:

• Use of antimuscarinic agent and effective in treatment of lower urinary tract symptoms
• 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 postvoid residual > 250ml
• Patients with uncontrolled confirmed diagnosis of acute urinary tract infection
• Patients have laboratory abnormalities at screening including:

ALT> 3 x upper limit of normal range 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
• Patients with any other serious disease considered by the investigator not in the condition to enter the trial
• Patients participated investigational drug trial within 1 month before entering this study