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Botulinum Toxin Type A Versus Oral Oxybutynin ER in Spinal Cord Injured Patients With Neurogenic Detrusor Overactivity

2014-07-23 21:11:05 | BioPortfolio

Summary

Overactive bladder is a condition associated with symptoms of feeling the urge to urinate, urinating often, and may or may not be accompanied by leakage of urine. A patient who has a spinal cord injury (SCI) often suffers from an overactive bladder which often leads to urinary incontinence (UI - an unwanted leakage of urine).

Current treatment for incontinence in some SCI patients is clean intermittent self-catheterization (CIC). This is a procedure done by inserting a catheter (a soft, hollow tube) into the urethra into the bladder in order to empty the bladder. However, CIC can be associated with infection, which can make the urinary incontinence worse and can lead to kidney damage. There are drugs that may help with the incontinence but they are likely to cause dry mouth, constipation, and blurred vision.

BoNT-A bladder injections have been studied in clinical research trials. The results have shown an improvement in urinary symptoms by reducing how often urine leakage occurs and by increasing the amount of urine the bladder can hold.

This purpose of this clinical trial is to see if BoNT-A is safe and effective when injected into the bladder for the treatment of UI and if it works better than a drug that is taken by mouth. A second purpose of the study is to perform research tests on the urine samples provided by the volunteers. Urine presents a rich source of information for bladder diseases and the biomarkers (the chemical make-up of the urine cells) will be examined to learn if there are yet undiscovered reasons for urinary diseases. These tests would be very beneficial because the results would lead to better treatment of the urinary diseases.

Volunteers will be randomized to one of two treatments. The treatment is determined by chance like the toss of a coin. There will be a 50-50 chance of receiving either treatment. The treatments are BoNT-A bladder injection and a placebo oral capsule once a day or placebo bladder injection and oxybutynin ER (like Ditropan) capsule once a day. Placebo contains no active medicine. Participation in this study will be about 2 years and involve 10 visits to the clinic. The risks of bladder BoNT-A injection are very small but include bleeding, infection, and the rare risk of spread of BoNT-A to other muscles causing weakness. Side effects of oxybutynin ER include dry mouth, constipation, and blurred vision. The potential benefits to the volunteer include improvement in the urinary incontinence symptoms, decrease in the number of required catheterizations, and an ease of the financial burden of buying protective garments.

Description

Current treatment of neurogenic bladder dysfunction (NGB) is limited by the suboptimal results achieved using standard antimuscarinic agents. A prominent role for the actions of alternative transmitters/growth factors in peripheral micturition pathways is emerging from the growing number of pharmacologic and localization studies in humans. For example, recently published data demonstrates a significant increased expression of Nerve Growth Factor and chemokine/cytokine levels in patients with detrusor overactivity and NGB. Treatment with botulinum toxin A (BoNT-A) not only was shown to reduce detrusor overactivity and improve urinary symptoms but also significantly reduced tissue and urine levels of factors such as NGF. Up to this point, no study has directly compared the effects of front-line therapy of antimuscarinic agents versus BoNT-A on urinary symptoms in patients with NGB resulting from spinal cord injury (SCI). In addition, no investigation has examined the effects that antimuscarinic agents or BoNT-A have on urinary levels of NGF and chemokines/cytokines, whether changes in urinary levels predict a clinical response or a return in symptoms, and if changes in urinary levels predate changes in clinical response.

Dr. Smith and colleagues are ideally positioned to test these two agents in a multicenter, Veterans Affairs based SCI population with NGB and urinary incontinence. Access to selective and reliable urine testing of NGF and chemokines/cytokines gives them the unique opportunity to assess the impact that modulating these agents has on bladder function. The main purpose of this proposal is to incorporate novel urine biomarker testing into existing clinical methodologies in order to: 1) evaluate the safety and efficacy of 200 U BoNT-A injected into the detrusor versus oral oxybutynin for the treatment of urinary incontinence (UI) caused by neurogenic detrusor overactivity (NDO) in spinal cord injured patients and 2) to determine the potential role of urine biomarkers in guiding the process of patient selection and identify surrogate predictors of treatment outcomes.

This will be a multicenter, double-blind, randomized, placebo-controlled, parallel-group study to assess the safety and efficacy of BoNT-A or 10 mg per day of oral oxybutynin hydrocholoride in spinal cord injured patients diagnosed with neurogenic detrusor overactivity.

Volunteers will include both males and females with spinal cord injuries who are 18 to 80 years of age. Each will be randomized on a 1:1 assignment by the data coordinating center to one of two treatment arms. One randomization number will be assigned to each patient prior to the first treatment and will be associated with one of the following treatment sequences:

1. BoNT-A 200 U (treatment 1)/ BoNT-A 200 U (treatment 2)/ BoNT-A 200 U (treatment 3) and placebo oral capsule daily

2. Placebo injection (treatment 1)/ BoNT-A 200 U (treatment 2)/ BoNT-A 200 U (treatment 3) and oxybutynin ER 10 mg capsule daily

There will be ten study visits over a twenty-four month period.

The significance of these experiments begins with the fact that our proposed intervention is the first randomized clinical trial comparing the effects of BoNT-A (botulinum toxin A) bladder injection versus anticholinergic medication for detrusor hyperreflexia (DH). In addition, this is the first study profiling urine levels of the signaling protein nerve growth factor (NGF) and chemokines/cytokines as possible bio-markers of bladder overactivity in patients with neurogenic detrusor overactivity. Finally, this is the only study to date comparing the effects that BoNT-A or anticholinergic medications have on urine NGF and chemokine/cytokine levels. If our hypotheses prove to be correct, the significance to treating patients with spinal cord injury with botulinum toxin A will be less incontinence, the requirement of lower doses or avoidance of anticholinergic medication and its associated side effects, and the ability to prevent the complications of DH/DESD (Detrusor-External Sphincter Dyssynergia) including urinary tract infections, decubiti, and impairment of quality of life. Although this study as written is of moderate length (i.e. total 4 years), we hope that by finding significant results, we will be able to capture a longitudinal history of this population by extending follow-up to a longer duration (i.e. over 10 years).

Study Design

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

Conditions

Neurogenic Detrusor Overactivity

Intervention

onabotulinumtoxin A, Oxybutynin ER

Location

VA Palo Alto Health Care System
Palo Alto
California
United States
94304

Status

Not yet recruiting

Source

Baylor College of Medicine

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-07-23T21:11:05-0400

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Medical and Biotech [MESH] Definitions

Involuntary discharge of URINE that is associated with an abrupt and strong desire to void. It is usually related to the involuntary contractions of the detrusor muscle of the bladder (detrusor hyperreflexia or detrusor instability).

A disorder characterized by CONFUSION; inattentiveness; disorientation; ILLUSIONS; HALLUCINATIONS; agitation; and in some instances autonomic nervous system overactivity. It may result from toxic/metabolic conditions or structural brain lesions. (From Adams et al., Principles of Neurology, 6th ed, pp411-2)

A region in the mesencephalon which is dorsomedial to the substantia nigra and ventral to the red nucleus. The mesocortical and mesolimbic dopaminergic systems originate here, including an important projection to the nucleus accumbens. Overactivity of the cells in this area has been suspected to contribute to the positive symptoms of schizophrenia.

Loss or absence of normal intestinal function due to nerve damage or birth defects. It is characterized by the inability to control the elimination of stool from the body.

Inflammation caused by an injurious stimulus of peripheral neurons and resulting in release of neuropeptides which affect vascular permeability and help initiate proinflammatory and immune reactions at the site of injury.

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