Effectiveness of onaBoNT-A vs Oral Tamsulosin in Men With Benign Prostatic Hyperplasia and Lower Urinary Track Symptoms (BPH)

This proposed intervention is the first randomized clinical trial comparing the effects of
onaBoNT-A prostate injection versus alpha adrenergic antagonist medication for LUTS
associated with BPH. Up to this point, clinical studies using onaBoNT-A in the prostate has
been limited to patient's refractory to -1 adrenoceptor blocker therapy. The study will
directly compare onaBoNT-A against -1 adrenoceptor blockers as frontline therapy in a male
Veteran cohort suffering from moderate to severe LUTS. Besides its obvious efficacy in
patients' refractory to -1 adrenoceptor blocker therapy, onaBoNTA injection has several
potential advantages over oral agents. Focal prostate injection has been shown to be safe and
obviates the systemic side effects observed with -1 adrenoceptor blockers (i.e. orthostatic
hypotension, sexual dysfunction). In addition, most clinical studies demonstrate a durable
response to onaBoNT-A treatment exceeding 12 months. Although this study is of modest length
(i.e. total 4 years), significant results could drive paradigm shifts in how LUTS associated
with BPH is treated, even with regards to frontline therapy.

Although sophisticated molecular techniques (i.e. LCM with Microarray Analysis) have been
used by other investigators to characterize gene profile changes with BPH and LUTS, this will
be the first study examining gene profile changes in drug na ve BPH View Protocol Record
patients following treatment with the -1 adrenoceptor blocker Tamsulosin or onaBoNT-A. This
study is important because scant knowledge exists on the true mechanisms by which -1
adrenoceptor blockers like Tamsulosin or onaBoNT-A improve patient urinary tract symptoms and
quality of life. It is clear, however, that nerves not only regulate prostate growth and
function but also account for LUTS that drive patients to seek therapy. This investigation
will utilize onaBoNT-A as a biological tool to identify potential novel mechanistic pathways
for future investigation that will push the development of targeted therapy to benefit those
patients refractory to all pharmacologic treatment. Potential inflammatory pathways or neural
sensory signaling alterations induced by BPH, which are modified by onaBoNT-A or Tamsulosin
to improve symptoms via gene profile changes, can be explored by expert laboratories in the
Texas Medical Center. This is a highly collaborative project utilizing expertise across
departments that will foster translational work from the laboratory to the patient. Although
not the primary goal of this study, the investigators will also search for possible
biological markers with prognostic value that could be confirmed in a future multi-center
trial.

The primary objective of this Phase 2 clinical research study is to compare the efficacy of
200 U onaBoNT-A injected into the prostate versus oral tamsulosin for the treatment of lower
urinary tract symptoms caused by BPH in male Veteran volunteers at the MEDVAMC. The secondary
objective is to determine the impact of tamsulosin and onaBoNT-A on the pathologic parameters
and RNA profiles of epithelium and stroma in BPH tissues.

Volunteers will be randomized into two groups with one receiving ona-BoNT-A injection into
the prostate and an oral placebo pill taken once daily and the other group will receive a
placebo injection and an oral tamsulosin pill once daily.

Volunteers will make five clinic visits and be contacted by telephone twice.

Inclusion Criteria:

- Males at least 50 years of age

- American Urological Association Symptom Score greater than 8

- Voided volume greater than 125 ml

- Maximum urinary flowrate less than 15 ml/sec.

- Must agree to all procedures and willfully consented

Exclusion Criteria:

- Any prior surgical intervention or use of 5-alpha-reductase medical intervention for
BPH

- Current diagnosis of acute or chronic prostatitis (which may cause LUTS that mimic
BPH)

- Previous exposure to onabotulinumtoxinA

- Overactive bladder without obstructive symptoms (i.e. decrease in force of stream,
hesitancy, intermittency, post-void dribbling)

- Active urinary tract disease or biopsy of the prostate within the past 6 weeks;

- Two documented urinary tract infections of any type in the past year (UTI defined as
greater than 100,000 colonies per ml urine from midstream clean catch or catheterized
specimen)

- Uncontrolled diabetes

- History of bladder calculi (stones)

- Penile prosthesis or artificial urinary sphincter [placement]

- Documented bacterial or acute prostatitis within the past year

- Episode of unstable angina pectoris, myocardial infarction, transient ischemic attack,
or cerebrovascular accident (stroke) within the past 6 months

- Known primary neurologic conditions such as multiple sclerosis, myasthenia gravis or
Parkinson's disease, or other neurological diseases known to affect bladder function

- History or current evidence of carcinoma of the prostate or bladder, pelvic radiation
or surgery, urethral stricture, or bladder neck obstruction

- 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 that is likely to impede successful completion of the
study, such as certain mental disorders, hypersensitivity to onabotulinumtoxinA or
anesthetics used in the study, syncope

- Daily use of a pad or device for incontinence required

- Interested in future fertility

- Postvoid Residual (PVR) greater than 350 ml

- Serum prostate specific antigen (PSA) level greater than 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 (transrectal ultrasound) biopsy, percent free PSA, or other clinical
estimations in keeping with sound urologic care

- Has taken phenylephrine, pseudoephedrine, imipramine, an anticholinergic, or
cholinergic medication within the past 2 weeks

- Has taken estrogen, androgen, any drug producing androgen suppression, or anabolic
steroids within the past 4 months

- Taking aminoglycosides or any drug that interfere with neuromuscular transmission.
Eaton-Lambert syndrome, hemophilia, hereditary clotting factors deficiency, or
bleeding diathesis

- Must be off aspirin, NSAIDS, and Coumadin for 7 or more days prior to
onabotulinumtoxinA injection

- Enrolled in another treatment trial for any disease within the past 30 days