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

Condition(s) targeted: Neurogenic Detrusor Overactivity

Intervention: onabotulinumtoxin A (Drug); Oxybutynin ER (Drug)

Phase: Phase 3

Status: Not yet recruiting

Sponsored by: Baylor College of Medicine

Official(s) and/or principal investigator(s):
Christopher P. Smith, MD, Study Director, Affiliation: Baylor College of Medicine

Overall contact:
Sebrina Tello, Phone: 713-798-8106, Email: stello@bcm.edu

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.

Official title: A Multicenter, Double-Blind, Randomized Study of the Safety and Efficacy of Botulinum Toxin Type A (BoNT-A) Versus Oral Oxybutynin in Spinal Cord Injured Patients With Neurogenic Detrusor Overactivity (Protocol Number 11-09-10-04)

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

Primary outcome: The primary endpoint of the study will be a 50% greater reduction in mean daily incontinent episodes in the BoNT-A treated group compared to the oxybutynin ER treated group.

Secondary outcome: The utility of urinary inflammatory markers as statistically significant predictors of treatment response.

Detailed 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).

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- male or female, aged 18 to 80 years old, weighing 110 pounds or more.

- a veteran of the United States military service who has suffered a spinal cord

injury.

- urinary incontinence as a result of neurogenic detrusor overactivity for a period of

at least 3 months prior to screening as a result of spinal cord injury

- must have a stable neurological injury occurring at least 6 months or more.

- has detrusor overactivity

- has a negative pregnancy result if female and of childbearing potential.

The following criteria are also required for entry into the study at Randomization/Day 1:

- experiences at least 14 episodes or more of urinary incontinence per week with no

more than 2 incontinent-free days.

- currently uses or is willing to use clean intermittent catheterization (CIC) to empty

the bladder (indwelling catheter is not permitted).

- Volunteers with a negative urine culture result must take an antibiotic medication

for 3 days immediately prior to Randomization/Day 1 and agree to continue antibiotic medication for at least 3 days following treatment. Volunteers with a positive urine culture result indicating urinary tract infection (UTI), must take an antibiotic to which the identified organism is sensitive for at least 3 days immediately prior to Randomization/Day 1, on Randomization/Day 1, and continue for 3 days following the procedure (or longer as needed).

Exclusion Criteria:

- has history or evidence of any pelvic or urological abnormalities including but not

limited to the following:

1. elevated serum creatinine more than 2 times the upper limit of normal (reference range)

2. current or history of hematuria, 1) if the hematuria is determined to be a pathologic condition or 2) is uninvestigated

3. interstitial cystitis in the opinion of the investigator bladder stones within 6 months of screening

4. surgery or bladder disease other than detrusor overactivity that may impact bladder function with the exception of surgeries for bladder stones (more than 6 months) and stress incontinence, uterine prolapse, rectocele, or cystocele (more than1year) from screening.

- has had previous or current botulinum toxin therapy within 3 months.

- has been immunized for any botulinum toxin serotype.

- discontinued anticholinergic medication for overactive bladder less than 14 days

prior to Randomization/Day 1.

- has a history or current diagnosis of bladder cancer.

- male with previous or current diagnosis of prostate cancer or has a PSA level greater

than 10. 0 ng/mL.

- has 24 hour total volume voided more than 3000 mL of urine

- has a post void residual volume above 200 mL.

- has an active genital infection, other than genital warts, either concurrently or

within 4 weeks prior to screening.

- uses any anti-platelet or anticoagulant therapy or is using medications with

anticoagulative effects within 3 days prior to treatment.

- has hemophilia or other clotting factor deficiencies or disorders that cause bleeding

diatheses.

- has had concurrent treatment or treatment within 6 months of Randomization/Day 1 with

capsaicin or resiniferatoxin.

- currently using or plans to use an implanted or non-implantable electrostimulation/

neuromodulation device for treatment of overactive bladder.

- has a known allergy or sensitivity to any components of the study medication,

anesthetics or antibiotics or any other products associated with the treatment and general study procedures.

- has any medical condition that may put the volunteer at increased risk with exposure

to BoNT-A including diagnosed myasthenia gravis, Eaton-Lambert syndrome or amyotrophic lateral sclerosis.

- female and pregnant, nursing or planning a pregnancy during the study, or of

childbearing potential and unable or unwilling to use a reliable form of contraception during the study.

- currently or has previously participated in another therapeutic drug or device study

within 30 days of screening.

Sebrina Tello, Phone: 713-798-8106, Email: stello@bcm.edu

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

Related publications:

O'Leary M, Erickson JR, Smith CP, McDermott C, Horton J, Chancellor MB. Effect of controlled-release oxybutynin on neurogenic bladder function in spinal cord injury. J Spinal Cord Med. 2003 Summer;26(2):159-62.

Smith CP, Chancellor MB. Emerging role of botulinum toxin in the management of voiding dysfunction. J Urol. 2004 Jun;171(6 Pt 1):2128-37. Review.

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.

Liu HT, Tyagi P, Chancellor MB, Kuo HC. Urinary nerve growth factor but not prostaglandin E2 increases in patients with interstitial cystitis/bladder pain syndrome and detrusor overactivity. BJU Int. 2009 Sep 14; [Epub ahead of print]

Tyagi P, Barclay D, Zamora R, Yoshimura N, Peters K, Vodovotz Y, Chancellor M. Urine cytokines suggest an inflammatory response in the overactive bladder: a pilot study. Int Urol Nephrol. 2009 Sep 26; [Epub ahead of print]

Starting date: October 2010
Last updated: January 14, 2010