Efficacy of Botulinum Toxin Type A for the Treatment of Non-neurogenic Urinary Urge Incontinence

Urinary Urge Incontinence Clinical Trial

Official title:

Efficacy of Botulinum Toxin A Intradetrusor Injections for the Treatment of Non-neurogenic Urinary Urge Incontinence- A Randomized Double-Blind Control Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01226706
• Other study ID #: REB-08-04
• Secondary ID: 120486
• Status: Completed
• Phase: N/A
• First received: October 18, 2010
• Last updated: May 4, 2015
• Start date: June 2008
• Est. completion date: October 2012

Study information

• Verified date: May 2015
• Source: Regina Qu'Appelle Health Region
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaCanada: Ethics Review Committee
• Study type: Interventional

Clinical Trial Summary

Non-neurogenic urinary urge incontinence (UUI) is a common quality of life disorder that causes people to feel an "urgent" need to urinate. Standard treatment for UUI includes behavior modification, pelvic floor exercises, anticholinergic medication, and less commonly, sacral neuromodulation. Unfortunately anticholinergic therapy is only moderately effective.

Botulinum toxin A (BTA or Botox©) may be a useful treatment in patients that do not respond to standard therapy. Botulinum toxin A has been used in other studies to improve symptoms in neurogenic urinary incontinence, and a variety of lower urinary tract disorders. BTA has been used in other studies to improve the symptoms in urinary incontinence, migraines, spinal cord injuries and a variety of lower urinary tract disorders. However, the treatment of non-neurogenic urinary urge incontinence has not been examined in a well-controlled study.

The primary purpose of this study is to determine the efficacy of botulinum toxin A (BTA) in the treatment of non-neurogenic urinary urge incontinence (UUI). The secondary objectives are to examine the side effects associated with BTA treatment and the impact this treatment has on patients' quality of life.

Description:

Introduction:

Non-neurogenic urinary urge incontinence (UUI) is a common quality of life disorder that becomes more prevalent with age. It is described as a condition that causes people to feel an "urgent" need to urinate due to muscle spasms in the bladder. Factors such as infection, inflammation, strokes, and dementia can stimulate the bladder to create spasms and cause urine loss. Overactive bladder refers to the symptom complex of urinary frequency, urgency and or nocturia with or without incontinence. Overactive bladder is a disorder of the storage phase of the bladder affecting approximately 16.9% of the US women, increasing to 31% after age 75. Standard treatment for UUI includes behavior modification, pelvic floor exercises, anticholinergic medication, and less commonly, sacral neuromodulation. Unfortunately anticholinergic therapy is only moderately effective and causes bothersome side effects, particularly at higher doses. Sacral neuromodulation therapy is currently unavailable in Saskatchewan with the closest treatment centre being located in Calgary.

Botulinum toxin A (BTA or Botox©) may be a useful treatment in patients that do not respond to standard therapy. Botulinum toxin A has been used in other studies to improve symptoms in neurogenic urinary incontinence, migraines following spinal cord injuries, and a variety of lower urinary tract disorders. This product has been approved by FDA for treatments of the following conditions: two eye muscle disorders (blepharospasm and strabismus in December 1989), severe underarm sweating (primary axillary hyperhydrosis), brow furrow and frown lines (April 2002) and other cosmetic purposes (July 2004). For the treatment of UUI, BTA is injected into the detrusor muscle of the bladder which is the muscle of the bladder that squeezes urine towards the outlet. BTA has been used in other studies to improve the symptoms in urinary incontinence and a variety of lower urinary tract disorders, however, the treatment for non-neurogenic urinary urge incontinence has not been examined in a well-controlled study.

Research Purpose and Objectives:

The primary purpose of this study is to determine the efficacy of BTA in the treatment of non-neurogenic UUI. The secondary objectives are to examine the side effects associated with BTA treatment and the impact this treatment has on patients' quality of life.

Research Methods:

This study employs a 12 month, double-blinded, randomized, partial cross-over design. The first 6 months of the study, subjects will be randomized to receive either detrusor injection of BTA or a placebo injection. In the remaining six months, subjects in the control group will be offered the detrusor injection of BTA. All 36 subjects will be followed for the remaining 6 months.

Study Procedures and Protocol

Pre-injection Assessment:

The pre-injection and assessment stage includes an evaluation of the medical history and physical exam. Previous therapy and medication will be disclosed to the physician. The investigator will ensure the subject meets the inclusion criteria, has had urinalysis and a pregnancy test if under 50 years old.

Day of the Procedure:

On the day of the surgery, the study pharmacist will randomize subjects using a random numbers table. The study doctor, nurses, and subjects will be blinded to treatment allocation. Ancef 1gm, or in the case of penicillin allergy, cipro 400 mg, will be given by intravenous.

A local anaesthetic will be instilled at the end of the cystoscopy (40 ml 1% lidocaine) and sedation will be provided as required. Fifteen minutes will lapse before beginning the procedure.

Using a 30 degree rigid scope and minimally invasive cystoscopic technique, 10 injections at 10 U/ml per injection (altogether 100 U of BTA) will be injected into the bladder wall, sparing the trigone.3,4 Subjects assigned to the placebo condition will receive injections of a saline at a similar frequency as the BTA injections.

Subjects will be observed for 60 minutes post procedure and then discharged home. This is the standard protocol for other BTA procedures performed on an outpatient basis in the RQHR. Catheter supplies will be provided upon discharge.

Follow-up Schedule:

1. Four to Six Weeks Post-Procedure: The primary and secondary measures will be assessed.

2. Three Months post-procedure: The same procedures will be repeated as at the four-to-six week assessment.

3. Six Months post-procedure: The four-to-six week assessment will be performed, and symptoms of retention or residual since the last visit will be discussed. A cystoscopy will be performed to study culture/urinalysis, measure desire and capacity, and show incontinence. Study allocation will be revealed at six months, and BTA injection will be offered to subjects that had received the placebo.

4. Nine Months: The four-to-six week procedures are repeated.

5. Twelve Months: The four-to-six week procedures are repeated.

Potential Significance:

Current anticholinergic therapy for non neurogenic UUI has limitations. In addition to significant systemic side effects, studies have shown that only 50% of patients improve with anticholinergic therapy, and that improvement does not always involve continence. Thus, detrusor injection of BTA may be a safe and efficacious therapy for patients who have failed standard therapy with anticholinergic medication and allow for an improved quality of life.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: October 2012
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 17 Years to 80 Years

Eligibility

Inclusion Criteria:

• Female subjects, greater than 17 years of age

• Written informed consent has been obtained

• Ability to follow study instructions and likely to complete all required visits

• Written authorization for Use and Release of Health and Research Study Information has been obtained

• Subject meets the following criteria: clinical diagnosis of urinary urge incontinence with resistance to or intolerance of anticholinergic medication

• Anticholinergic medications allowed

• Willingness and ability to use self-catheterization if necessary

Exclusion Criteria:

• Uncontrolled clinically significant medical condition other than the condition under evaluation

• Known allergy or sensitivity to any of the components in the study medication

• Females with a positive pregnancy test, or who are breast-feeding, planning a pregnancy during the study, who think that they may be pregnant at the start of the study

• Concurrent participation in another investigational drug or device study

• Treatment with botulinum toxin of any serotype for urological condition prior to enrolment in study (if applicable)

• Any medical condition that may put the subject at increased risk with exposure to botulinum toxin A including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other disorder that might interfere with neuromuscular function

• Any condition or situation that, in the investigator's opinion, may put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study

• Symptomatic urinary retention or post-void residual of >200ml

• Anticoagulation therapy within 3 days of injection procedure

• Familial bleeding disorder

• UUI secondary to neurologic disease

• Myasthenia gravis

• Previous bladder pathology (e.g. transitional cell carcinoma)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Non-neurogenic
• Urinary Incontinence, Urge
• Urinary Urge Incontinence

Intervention

Drug:
• botulinum toxin Type A
Botulinum toxin Type A 100U injected into the detrusor at Day 1
• Placebo
Placebo injected into the detrusor at Day 1, followed by injection of botulinum toxin Type A 100U after 24 weeks has elapsed from previous treatment, if requested/qualified.

Locations

Country	Name	City	State
Canada	Regina General Hospital	Regina	Saskatchewan

Sponsors (1)

Lead Sponsor	Collaborator
Regina Qu'Appelle Health Region

Country where clinical trial is conducted

Canada, 

References & Publications (12)

Coyne KS, Matza LS, Kopp Z, Abrams P. The validation of the patient perception of bladder condition (PPBC): a single-item global measure for patients with overactive bladder. Eur Urol. 2006 Jun;49(6):1079-86. Epub 2006 Jan 24. — View Citation

Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ, Dasgupta P. Quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injections of botulinum neurotoxin type A and correlations with lower urinary tract symptoms and urodynamic changes. Eur Urol. 2006 Mar;49(3):528-35. Epub 2006 Jan 6. — View Citation

Nixon A, Colman S, Sabounjian L, Sandage B, Schwiderski UE, Staskin DR, Zinner N. A validated patient reported measure of urinary urgency severity in overactive bladder for use in clinical trials. J Urol. 2005 Aug;174(2):604-7. — View Citation

Patki PS, Hamid R, Arumugam K, Shah PJ, Craggs M. Botulinum toxin-type A in the treatment of drug-resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. BJU Int. 2006 Jul;98(1):77-82. — View Citation

Rajkumar GN, Small DR, Mustafa AW, Conn G. A prospective study to evaluate the safety, tolerability, efficacy and durability of response of intravesical injection of botulinum toxin type A into detrusor muscle in patients with refractory idiopathic detrusor overactivity. BJU Int. 2005 Oct;96(6):848-52. — View Citation

Sahai A, Kalsi V, Khan MS, Fowler CJ. Techniques for the intradetrusor administration of botulinum toxin. BJU Int. 2006 Apr;97(4):675-8. — View Citation

Sahai A, Khan MS, Dasgupta P. Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol. 2007 Jun;177(6):2231-6. — View Citation

Schurch B, de Sèze M, Denys P, Chartier-Kastler E, Haab F, Everaert K, Plante P, Perrouin-Verbe B, Kumar C, Fraczek S, Brin MF; Botox Detrusor Hyperreflexia Study Team. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol. 2005 Jul;174(1):196-200. — View Citation

Smith CP, Nishiguchi J, O'Leary M, Yoshimura N, Chancellor MB. Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology. 2005 Jan;65(1):37-41. — View Citation

Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, Wein AJ. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003 May;20(6):327-36. Epub 2002 Nov 15. — View Citation

Uebersax JS, Wyman JF, Shumaker SA, McClish DK, Fantl JA. Short forms to assess life quality and symptom distress for urinary incontinence in women: the Incontinence Impact Questionnaire and the Urogenital Distress Inventory. Continence Program for Women Research Group. Neurourol Urodyn. 1995;14(2):131-9. — View Citation

Vo AH, Satori R, Jabbari B, Green J, Killgore WD, Labutta R, Campbell WW. Botulinum toxin type-a in the prevention of migraine: a double-blind controlled trial. Aviat Space Environ Med. 2007 May;78(5 Suppl):B113-8. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum capacity at cystoscopy (MCC)	Cystoscopy is a test performed with a cystoscope, a narrow tube with a tiny camera at its tip, inserted into the urethra and bladder to see the inside of the bladder and urethra.; Maximum bladder capacity--the amount of liquid or gas the bladder can hold under anesthesia. Without anesthesia, capacity is limited by either pain or a severe urge to urinate.	12 months	No
Secondary	Incontinence Episodes	Incontinence- involuntary leakage of urine	12 months	No
Secondary	Number of daytime and night time voids	Frequency of daily and nightly urination	12 months	No
Secondary	Patient Perception of Bladder Condition	Disease specific validated quality of life measures. A single-item global measure for patients with overactive bladder	12 months	No
Secondary	Incontinence Impact Questionnaire	Disease specific validated quality of life measure. Health-related quality of life measures for women with urinary incontinence.	12 months	No
Secondary	Urogenital Distress Inventory	Disease specific quality of life measure. Health-related quality of life measures for women with urinary incontinence.	12 months	No
Secondary	Indevus Urgency Severity Scale	A disease specific quality of life measure. A self reported measure that assesses urinary urgency severity associated with overactive bladder	12 months	No
Secondary	Subjective benefit assessment	Self assessed description of how well they believed the Botulinum Toxin type A was working, ranging from no change to dry/complete response	12 months	No
Secondary	Adverse effects	Documented adverse effects to Botulinum Toxin type A	12 months	Yes
Secondary	Urinary Tract Infections	Documented urinary track infections	12 months	Yes
Secondary	Need for self-catheterization		12 months	Yes
Secondary	24-hour pad test	measures a pad before and after wear to get an indication of urine lost	12 months	No