Benign Prostatic Hyperplasia
Conditions
Keywords
benign prostatic hyperplasia, BPH, botulinum toxin, BoNT/A
Brief summary
This is a double-blind randomized phase II trial to determine whether two different doses of BoNT/A injection into the prostate gland demonstrate sufficient improvement in the management of lower urinary symptoms due to BPH to warrant more extensive research. Subjects will receive either a 100U or 300U dose. Participation will last 1 year.
Interventions
DRUGbotulinum toxin type A (BoNT/A)
100 unit and 300 unit dosages: Dilute each 100 U vial with 1.3 ml of normal saline. Each reconstituted vial is then drawn up into a single syringe with a total of 4 ml = 300 U. The instrument used to inject the botulinum toxin is an ultrasound device with a transrectal ultrasound probe specially designed for prostate biopsies which has a special canal to introduce and direct a needle in to the selected prostatic area.
Sponsors
George Washington University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male at least 50 years of age. * Voided volume =\> 125 ml. * Maximum urinary flow \< 15 ml/sec. * AUA symptom severity score =\> 8. * Patient signed informed consent prior to the performance of any study procedures. * Patient able to complete the study protocol in the opinion of the investigator.
Exclusion criteria
* Any prior surgical intervention for BPH. * Current diagnosis of acute or chronic prostatitis (which may cause LUTS that mimic BPH). * Overactive bladder without bladder outlet obstruction. * Enrolled in another treatment trial for any disease within the past 30 days. * Men interested in future fertility. * Previous exposure to botulinum toxin. * On alpha-blocker within the past 48 hours. * On any 5-alpha-reductase inhibitor within the past month. * Post void residual \> 350 ml. * On phenylephrine, pseudoephedrine, imipramine, an anticholinergic, or cholinergic medication within the past 2 weeks. * On estrogen, androgen, any drug producing androgen suppression, or anabolic steroids within the past 4 months. * Clinically significant renal or hepatic impairment as determined by abnormal creatinine or AST levels (based on local institutional values). * Serum prostate specific antigen level \> 8 ng/ml (Hybritech). For those with a PSA between 4-8 ng/ml, the PSA elevation must be considered to be from a benign cause in the opinion of the PI. This decision can be based on PSA velocity, previous TRUS biopsy, percent free PSA, or other clinical estimations in keeping with sound urologic care. * Active urinary tract disease or biopsy of the prostate within the past 6 weeks. * Daily use of a pad or device for incontinence required. * Episode of unstable angina pectoris, myocardial infarction, transient ischemic attack, or cerebrovascular accident (stroke) within the past 6 months. * On aminoglycosides or any drug that interfere with neuromuscular transmission. * Eaton-Lambert syndrome, hemophilia, hereditary clotting factors deficiency, or bleeding diathesis. * Penile prosthesis or artificial urinary sphincter. * History or current evidence of carcinoma of the prostate or bladder, pelvic radiation or surgery, urethral stricture, or bladder neck obstruction. * Known primary neurologic conditions such as multiple sclerosis, myasthenia gravis or Parkinson's disease, or other neurological diseases known to affect bladder function. * Documented bacterial or acute prostatitis within the past year. * Two documented urinary tract infections of any type in the past year (UTI defined as \> 100,000 colonies per ml urine from midstream clean catch or catheterized specimen). * History of bladder calculi. * Patients must be off aspirin, NSAIDS, and Coumadin for 7 or more days prior to botulinum toxin injection. * Cancer that is not considered cured, except basal cell or squamous cell carcinoma of the skin (cured defined as no evidence of cancer within the past 5 years). * Any serious medical condition likely to impede successful completion of the study, such as certain mental disorders, hypersensitivity to botulinum toxin or anesthetics used in the study, syncope, uncontrolled diabetes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in the AUA Symptom Score Index by 30% From Baseline Within the First 12 Weeks After Injection. | 12 weeks | The primary outcome was treatment success at 3 months post-treatment, defined as (1) improvement in the AUASI by at least 30% and/or (2) Qmax improvement of more than 30%, each determined from baseline to 3 months after injection. In addition, two safety criteria also had to be met; a dose failed if (1) any reported event was determined to be related to the onabotulinum toxin A injection and was considered life threatening, disabling, or fatal or (2) \>=40% of the participants reported a moderate or severe side effect related to the botulinum toxin injection. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at the 7 clinical centers (Baylor College of Medicine, Houston TX; Cornell University, New York NY; Mayo Clinic, Rochester MN; Medical College of Wisconsin, Milwaukee WI; Northwestern University, Chicago IL; University of Colorado Denver, Aurora CO; University of Texas Southwestern Medical Center, Dallas TX).
Pre-assignment details
Screening for eligibility: male, 50+ years old, signed informed consent, no prior surgical treatment for BPH and no prior use of botulinum toxin, appropriate washout period for medical therapy, American Urological Association Symptom Index (AUASI) \>=8, voided volume \>=125 ml, maximum urinary flow rate \<15 ml/sec.
Participants by arm
| Arm | Count |
|---|---|
| 100 Units Botulinum Toxin Type A botulinum toxin type A (BoNT/A) : 100 unit and 300 unit dosages: Dilute each 100 U vial with 1.3 ml of normal saline. Each reconstituted vial is then drawn up into a single syringe with a total of 4 ml = 300 U. The instrument used to inject the botulinum toxin is an ultrasound device with a transrectal ultrasound probe specially designed for prostate biopsies which has a special canal to introduce and direct a needle in to the selected prostatic area. | 68 |
| 300 Units Botulinum Toxin Type A botulinum toxin type A (BoNT/A) : 100 unit and 300 unit dosages: Dilute each 100 U vial with 1.3 ml of normal saline. Each reconstituted vial is then drawn up into a single syringe with a total of 4 ml = 300 U. The instrument used to inject the botulinum toxin is an ultrasound device with a transrectal ultrasound probe specially designed for prostate biopsies which has a special canal to introduce and direct a needle in to the selected prostatic area. | 66 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | withdrawal or received alternate tx | 15 | 11 |
Baseline characteristics
| Characteristic | 100 Units Botulinum Toxin Type A | 300 Units Botulinum Toxin Type A | Total |
|---|---|---|---|
| Age, Customized <50 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >=50 years | 68 participants | 66 participants | 134 participants |
| Region of Enrollment United States | 68 participants | 66 participants | 134 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 68 Participants | 66 Participants | 134 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 68 | 41 / 66 |
| serious Total, serious adverse events | 7 / 68 | 5 / 66 |
Outcome results
Primary
Improvement in the AUA Symptom Score Index by 30% From Baseline Within the First 12 Weeks After Injection.
The primary outcome was treatment success at 3 months post-treatment, defined as (1) improvement in the AUASI by at least 30% and/or (2) Qmax improvement of more than 30%, each determined from baseline to 3 months after injection. In addition, two safety criteria also had to be met; a dose failed if (1) any reported event was determined to be related to the onabotulinum toxin A injection and was considered life threatening, disabling, or fatal or (2) \>=40% of the participants reported a moderate or severe side effect related to the botulinum toxin injection.
Time frame: 12 weeks
Population: By the last 12-month follow-up visit, 15 men (22%) in the 100 U dose arm and 11 (17%) in the 300 U dose arm had withdrawn due to dissatisfaction with treatment results or continued to attend study follow-up but received additional alternate treatment prior to 12 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 100 Units Botulinum Toxin Type A | Improvement in the AUA Symptom Score Index by 30% From Baseline Within the First 12 Weeks After Injection. | 46 participants |
| 300 Units Botulinum Toxin Type A | Improvement in the AUA Symptom Score Index by 30% From Baseline Within the First 12 Weeks After Injection. | 50 participants |
Comparison: Simon's optimal two-stage design was applied to determine whether there was sufficient activity at either of the two dose levels to warrant further investigation. Each patient was considered either a successful or failed response. The response rate or proportion of patients treated successfully was examined in two stages. At both stages, the two dose levels were compared to pre-determined critical cut-off values. Sample size was based on significance level α=0.05 and power 90%.p-value: <0.05Simon's optimal two-stage design