Clostridium Botulinum Toxin Adverse Reaction, Neurogenic Bladder, Parkinson's Disease, Urinary Incontinence
Conditions
Keywords
Parkinson's Disease, Neurogenic Bladder, Urinary Incontinence, botulinum toxin, cystoscopy, Effect of Other Parasympatholytics [Anticholinergics and Antimuscarinics] and Spasmolytics
Brief summary
The basic nerve deficit of Parkinson's disease (PD) leads to lower urinary tract symptoms of frequency, urgency and urge urinary incontinence. Lower urinary tract symptoms tend to occur at more advanced stages of PD. In the over-65 year old age group, where 1% of men suffer from this disease, they are also prone to development of benign prostatic hyperplasia (BPH) and consequent associated lower urinary tract dysfunction. Similarly the over 65-year age group develop spontaneous overactive bladder up to a prevalence of 30% of both men and women. The urologic disorder is exceedingly devastating in reducing the quality of life in these individuals due to the lower urinary tract symptoms and ultimate urinary incontinence in a high proportion of patients. While attempts at pharmacologic treatment are partially satisfactory many patients are intolerant of oral drugs. Botulinum-A neurotoxin (BTX-A) has been shown in pilot trials to be quite effective in reducing overactive bladder symptoms and is specifically beneficial for a wide-variety of neurogenic bladder causes of over activity . The treatment procedure of injecting the detrusor muscle of the bladder with BTX-A is quite simple, does not impose significant risks to the patient, and can be performed as an office urologic procedure. This pilot clinical trial intends to demonstrate the safety and efficacy of low-dose Botox-A injections into the bladder to improve urinary symptoms in 20 patients.
Detailed description
This open-label pilot study will evaluate the safety and efficacy of intra-detrusor injections of botulinum-A toxin (BTX-A) in 20 male or female patients with Parkinson's disease and neurogenic overactive bladder with or without urinary incontinence, but without evidence of significant urinary retention (\>25% of bladder capacity at void). Patients will be invited to participate based upon subjective symptoms of uncontrolled lower urinary tract urgency, frequency and urinary incontinence. Only patients who have a Hoehn and Yahr Stage IV or better (or UPDRS equivalent) will be considered. Patients must have tried anti-muscarinic agents and failed to improve or were intolerant of these pharmacologic agents. Oral anti-muscarinic medications will be discontinued two weeks prior to urodynamics testing and treatment visit. At baseline urinary symptom scores will be obtained using The King's Health Questionnaire (KHQ, a validated scoring system for urinary symptoms) and the AUA Urinary Symptom Score. In addition a 3-day fluid intake and urinary outflow timed voiding diary will be submitted at the time of testing and treatment as well as follow-up visits. After signing an informed consent and meeting all inclusion and exclusion criteria, patients will be tested with urodynamic studies to determine current lower urinary tract neurophysiologic functioning. A free-flow urinary flow rate and post-void residual urine volume test will be performed as well as filling cystometrogram and pressure/flow measurement. Patients with evidence of outlet obstruction (high pressure/low flow) will be excluded from the study. Only patients with a post-void residual urine volume less than or equal to 25% of the total bladder volume at void will be included. No catheters or other measurement devices will be attached to the body at the time of the initial free urinary flow and post-void urine volume measurement. A repeat pressure/flow determination will be performed during the urodynamics cystometrogram. After qualification to proceed, patients will then be transferred to the adjoining cystoscopy suite. Pre-procedure oral sedation and analgesia will be given. Subjects will undergo cystoscopy under topical lidocaine anesthesia and undergo 25-gauge needle injections of BTX-A. BTX-A treatment for each participant will be limited to a total dose of 100 units in a minimum of 10 to 20 locations. Any patient unable to void after the procedure will receive an indwelling catheter for 24 hours. Patients will be contacted by telephone within 24-48 hours after the procedure for safety assessment. Follow-up clinic visit evaluations will occur at 1 month, 3 months, 6 months and 9 months. A 3-day voiding diary, King's Health Questionnaire, AUA Symptom Score sheet and Global Response Assessment (GRA) Questionnaire will be collected at each follow-up visit. Incontinence will be documented on this diary. Uroflowmetry and post-void residual volume will also be assessed at each follow-up visit.
Interventions
DRUGCystoscopic injection of Botox into the urinary bladder
100 U of Botox A injected transurethrally into the urinary bladder muscle and submucosa.
Sponsors
Allergan
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
• * Male or female subjects, 50 to 85 years of age. * Patients diagnosed with Parkinson's disease prior to lower urinary tract symptoms. * Documentation of low volume desire to void and/or unstable detrusor contractions with or without incontinence on cystometrogram. Voiding diary consistent with overactive bladder * 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 has minimum to moderate severity/stage of disease, Hoehn and Yahr stage IV or less (or UPDRS equivalent) * Usual and customary medications allowed
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. * Concurrent participation in another investigational drug or device study or participation within 60 days period of time prior to study * New anticholinergic medication. Should discontinue any anti-muscarinic medication 14 days prior to injection. * Treatment with botulinum toxin of any serotype prior to enrollment in study (if applicable). * Any medical condition that may put the subject at increased risk with exposure to BTX-A including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other disorder that might interfere with neuromuscular function (if applicable). * Evidence of alcohol, drug abuse or other relevant neuropsychiatric condition (if applicable) * Urinary tract infection * Significant BPH with evidence of severe bladder trabeculation * Greater than 50% post-void residual urine volume * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Requiring Catheterization for Urinary Retention Secondary to Treatment. | zero to six months | Requirement for catheter because of urinary retention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Incontinence Episodes Per Day | 6 months | Urinary incontinence 6 months after treatment (n=16). Data are included for participants who completed all diary entries and attended the Month 6 visit |
Countries
United States
Participant flow
Recruitment details
Recruitment period extended between February 1, 2009 and September 2010. Stanford University Clinics represented location for enrollment and clinical trial.
Pre-assignment details
Patients underwent screening in the clinic and were excluded per protocol prior to enrollment. Open label study.
Participants by arm
| Arm | Count |
|---|---|
| Botulinum Toxin Treatment Injection of Botox into urinary bladder for neurogenic symptoms. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Botulinum Toxin Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 19 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 70.95 years STANDARD_DEVIATION 8.22 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
Number of Patients Requiring Catheterization for Urinary Retention Secondary to Treatment.
Requirement for catheter because of urinary retention.
Time frame: zero to six months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Urinary Leaks Per Day | Number of Patients Requiring Catheterization for Urinary Retention Secondary to Treatment. | 0 participants |
Secondary
Number of Incontinence Episodes Per Day
Urinary incontinence 6 months after treatment (n=16). Data are included for participants who completed all diary entries and attended the Month 6 visit
Time frame: 6 months
Population: Per protocol. Quantified from 3-day voiding diary at baseline and each clinical evaluation to 6 months. Mean change in daily incontinence made up analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Urinary Leaks Per Day | Number of Incontinence Episodes Per Day | Baseline urinary incontinence | 3.76 leaks/day | Standard Deviation 2.57 |
| Urinary Leaks Per Day | Number of Incontinence Episodes Per Day | Urinary incontinence 6 months after treatment | 1.40 leaks/day | Standard Deviation 1.43 |
Comparison: Paired t test comparison of baseline number of urinary leaks per day versus number of leaks per day at 6 month evaluation after treatment.p-value: 0.0087t-test, 2 sided