1. health and fitness
2. alternative medicine
3. homeopathy

Rapid Efficacy of the Highly Selective ␣1A-Adrenoceptor Antagonist
Silodosin in Men With Signs and Symptoms of Benign Prostatic
Hyperplasia: Pooled Results of 2 Phase 3 Studies
Leonard S. Marks,*,† Marc C. Gittelman,‡ Lawrence A. Hill,‡ Weining Volinn‡
and Gary Hoel‡
From the University of California at Los Angeles and Urological Sciences Research Foundation, Los Angeles, California (LSM), South Florida
Medical Research, Aventura, Florida (MCG), and Watson Laboratories, Salt Lake City, Utah (LAH, WV, GH)
Abbreviations
and Acronyms
AE ⫽ adverse event
BPH ⫽ benign prostatic
hyperplasia
I-PSS ⫽ International Prostate
Symptom Score
LOCF ⫽ last observation carried
forward
Qmax ⫽ peak urinary flow rate
QoL ⫽ quality of life
Submitted for publication November 11, 2008.
Supported by Watson Pharma, Inc.
Study received institutional review board approval.
Clinical Trial Registration NCT00224107,
NCT00224120 (www.clinicaltrials.gov).
* Correspondence: Department of Urology,
Geffen School of Medicine at UCLA, 3831 Hughes
Ave., Culver City, California 90232 (telephone: 310559-9800; FAX: 310-559-7821; e-mail: lsmarks@
ucla.edu).
† Financial interest and/or other relationship
with Allergan, American Medical Systems, Astellas,
Bayer, Beckman Coulter, Diagnostic Ultrasound,
GTX, GlaxoSmithKline, Gen-Probe, Indevus, Light
Sciences Oncology, Lilly/ICOS, Merck, Novartis,
Onconome, Pfizer, Sanofi, Solvay, Watson, National
Institutes of Health, CapCURE, Pardee Foundation
and Seder Foundation.
‡ Financial interest and/or other relationship
with Watson Pharmaceuticals.
For another article on a related
topic see page 2780.
2634
www.jurology.com
Purpose: We evaluated the efficacy and safety of silodosin for treatment of
benign prostatic hyperplasia symptoms in 2 randomized, placebo controlled,
phase 3 studies.
Materials and Methods: Men 50 years or older with an International Prostate
Symptom Score of 13 or greater and peak urinary flow rate of 4 to 15 ml per
second received placebo or 8 mg silodosin daily with breakfast for 12 weeks. The
primary end point was International Prostate Symptom Score change from baseline to last observation. Change in peak urinary flow rate was a secondary end
point. Differences in treatment efficacy were assessed by ANCOVA.
Results: Of 923 patients (mean age 65 years) 466 received silodosin and 457
placebo. After 0.5 week (range 3 to 4 days) of treatment patients receiving
silodosin vs placebo achieved significant improvement in total International
Prostate Symptom Score (difference ⫺1.9, p ⬍0.0001) and irritative (– 0.5,
p ⫽ 0.0002) and obstructive (–1.4, p ⬍0.0001) subscores. The mean ⫾ SD change
from baseline in total International Prostate Symptom Score was ⫺4.2 ⫾ 5.3 for
silodosin vs ⫺2.3 ⫾ 4.4 for placebo. Differences (silodosin vs placebo) in International Prostate Symptom Score and subscores increased by week 12 (p ⬍0.0001).
Mean change from baseline in peak urinary flow rate (ml per second) 2 to 6 hours
after initial dose was greater (p ⬍0.0001) with silodosin (2.8 ⫾ 3.4) than placebo
(1.5 ⫾ 3.8). Differences remained significant (p ⬍0.001) through week 12. The
most common treatment emergent adverse event was (mostly mild) retrograde
ejaculation (silodosin 28.1% of patients, placebo 0.9%). Few patients receiving
silodosin (2.8%) discontinued because of retrograde ejaculation. Proportions of
patients with treatment emergent orthostatic hypotension were similar for silodosin (2.6%) and placebo (1.5%).
Conclusions: Treatment with silodosin produced rapid improvement in urinary
symptoms that was sustained for 12 weeks. Silodosin was well tolerated with a
low incidence of orthostatic hypotension.
Key Words: prostatic hyperplasia, KMD 3213, signs and symptoms
BENIGN prostatic hyperplasia is a chronic
condition associated with lower urinary
tract symptoms. The prevalence of symptomatic BPH in the United States ranges
from approximately 24% in men 40 to 49
years old to approximately 44% in men
70 years old or older.1 With an aging population the number of men affected by
0022-5347/09/1816-2634/0
THE JOURNAL OF UROLOGY®
Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 181, 2634-2640, June 2009
Printed in U.S.A.
DOI:10.1016/j.juro.2009.02.034
EFFICACY AND SAFETY OF ␣-BLOCKER SILODOSIN
BPH is likely to increase.2 Although prostate enlargement is a frequent sign of BPH, the severity of BPH
related urinary symptoms generally correlates poorly
with prostate size or the extent of bladder outlet obstruction.2,3 Symptom severity appears to be dependent, at least in part, on smooth muscle tone in the
prostate and bladder neck.3,4 In vitro studies using
human prostate tissue have demonstrated that
smooth muscle tone is mediated by ␣1A-adrenoceptors,
which are abundant in the prostate and the bladder
neck.5 Consequently ␣1-adrenoceptor antagonists (␣blockers) have become the first line treatment for the
relief of BPH symptoms. First generation ␣-blockers
such as doxazosin have the potential to cause orthostatic hypotension in normotensive subjects, because
they block not only ␣1A-adrenoceptors but also ␣1Badrenoceptors, which help maintain vascular smooth
muscle tone.6,7 Concerns about the cardiovascular
safety of such agents prompted the development of
␣-blockers with increased ␣1A to ␣1B-adrenoceptor subtype selectivity.4,8 Nonclinical and clinical pharmacology data suggest that more selective ␣-blockers are
less likely than nonselective ␣-blockers to cause cardiovascular adverse effects.4,9 Preclinical studies of the
recently developed ␣-blocker silodosin indicate that
silodosin has greater ␣1A to ␣1B-adrenoceptor subtype
selectivity10,11 and greater selectivity for prostatic and
urethral tissues vs vascular tissue7,12,13 than does any
other currently available ␣-blocker. Furthermore, unlike other ␣-blockers that require a waiting period between meals and dosing, silodosin is a once daily medication taken with a meal. In this article we present
pooled results from 2 phase 3 clinical studies evaluating the efficacy and safety of silodosin in a large population of men with signs and symptoms of BPH.
MATERIALS AND METHODS
Patients and Study Design
Two 12-week, identically designed, parallel group, multicenter, randomized, double-blind, placebo controlled
phase 3 studies (SI04009, SI04010; Clinical Trials Registration Numbers NCT00224107, NCT00224120) were conducted in the United States to evaluate the efficacy and
safety of silodosin in men with signs and symptoms of
BPH. Screening of patients began for both studies in May
2005, and the last patients completed the studies in August 2006 (SI04009) and May 2006 (SI04010). Both studies were approved by central or local institutional review
boards before patient enrollment began, and were conducted in accordance with good clinical practice as described in the guidelines of the International Conference
on Harmonization (Technical Requirements for Registration of Pharmaceuticals for Human Use), the United
States Code of Federal Regulations governing the protection of human subjects and the Declaration of Helsinki.
Eligible men were at least 50 years old with an I-PSS of
13 or higher, a peak urinary flow rate of 4 to 15 ml per
2635
second and a post-void residual volume less than 250 ml.
Complete exclusion criteria are provided in the Appendix.
Concomitant medications precluding study participation
and prohibited during the trial were ␣-adrenoceptor antagonists and 5␣-reductase inhibitors. Diuretics, antispasmodics and anticholinergics were allowed only if doses
were stable during the study.
After a screening period of up to 4 weeks patients
received single-blind treatment with placebo for 4 weeks,
which was followed immediately by the 12-week doubleblind treatment period. Two weeks after the start and at
the end of the placebo run-in period, I-PSS and Qmax were
determined to assess individual responses to placebo. Patients with at least a 30% decrease in I-PSS or an increase
in Qmax of 3 ml per second or greater during the run-in
period were excluded from randomization. Eligible patients were randomly assigned (1:1) to double-blind treatment with placebo or 8 mg silodosin once daily with breakfast. Treatment assignments were made according to a
randomization schedule using PROC PLAN in SAS®, version 8.2. Randomization was performed with a permuted
block design and was not stratified by treatment center or
region. Blinding was maintained throughout the study by
the use of identical medication packaging with placebo
matching silodosin in size and external appearance.
Emergency information labels that indicated the patient’s
assigned treatment were available to the investigator should
knowledge of treatment assignment be needed to ensure the
patient’s well-being. If unblinding of the investigator, site
personnel or the patient was required in a particular case
that patient was to be discontinued from the study.
Assessments
Total I-PSS, irritative and obstructive I-PSS subscores,
and QoL related to urinary symptoms were measured at
weeks 0 (baseline), 0.5, 1, 2, 4 and 12. QoL was assessed
with use of the separately scored I-PSS question 8, “If you
were to spend the rest of your life with your urinary
condition the way it is now, how would you feel about
that?” (Responses were measured on a scale from 0 to 6,
from delighted to terrible.) Qmax was assessed at baseline,
2 to 6 hours after the first dose, and at weeks 1, 2, 4 and
12. For all patients in both studies investigators determined and reported urinary flow measurements. Subsequently all urinary flow measurements were assessed
again by a blinded central reader (MCG) and any conflicts
were resolved in discussion with the investigator. AE reports were collected at every visit except at post-randomization week 0.5. Additional safety assessments included
12-lead electrocardiograms, clinical laboratory tests and
vital sign measurements including postural hypotension
tests and physical examinations.
Statistical Analysis
Pooled data from the 2 studies were used for all analyses.
Justification for sample sizes is provided in the Appendix.
All randomized study participants who provided baseline
data for the primary efficacy variable were included in the
efficacy analyses. The primary efficacy end point was
the mean change from baseline to week 12 in total I-PSS. The
secondary efficacy end point was mean change in Qmax
from baseline to week 12. Last observations were carried
forward to impute values missing for week 12. Safety
EFFICACY AND SAFETY OF ␣-BLOCKER SILODOSIN
2636
evaluations were based on all randomized study participants who received at least 1 dose of a study drug (silodosin or placebo). Differences between treatment groups
were evaluated by ANCOVA with baseline measure used
as the covariate and treatment effect for each efficacy
variable included in the model. Results of these analyses
were calculated as adjusted means with 95% CI. A 2-sided
significance level of 5% was applied for all statistical tests.
RESULTS
Patient Disposition and Demographics
A total of 923 patients participated in the 2 studies, 457 received placebo and 466 received 8 mg
silodosin once daily (fig. 1). The 2 treatment
groups had similar demographic characteristics
(table 1). Most patients were white (89.3%). Mean
age was 65 years, 45.0% of the patients were 65
years old or older and 12.5% were 75 years old or
older. The overall proportion of patients who discontinued was slightly higher among those receiving silodosin (53 of 466, 11.4%) than among those
given placebo (38 of 457, 8.3%). Discontinuation by
patients receiving silodosin was most often attributable to AEs (6.4%), voluntary withdrawal
(1.3%), loss to followup (1.3%) and other reasons
(1.3%). Discontinuation by those receiving placebo
Assessed for eligibility 2849
Entered placebo run-in 1538
Excluded during placebo run-in
615
Adverse event
21 (3.4%)
Investigator recommendation
20 (3.3%)
Lack of efficacy
3 (0.5%)
Lost to follow-up
8 (1.3%)
Protocol violation
16 (2.6%)
Voluntary withdrawal
50 (8.1%)
Other
497 (80.8%)
Randomized 923
Placebo 457
Silodosin 466
Completed 419 (91.7%)
Completed 413 (88.6%)
Discontinued/lost to follow-up 38 (8.3%)
Discontinued/lost to follow-up 53 (11.4%)
Lost to follow-up
Lost to follow-up
3 (0.7%)
Discontinued due to
Adverse events
Protocol violation
Voluntary withdrawal
6 (1.3%)
Discontinued due to
10 (2.2%)
3 (0.7%)
14 (3.1%)
Adverse events
30 (6.4%)
Protocol violation
3 (0.6%)
Voluntary withdrawal
6 (1.3%)
Lack of efficacy
2 (0.4%)
Lack of efficacy
6 (1.3%)
Other reasons
6 (1.3%)
Other reasons
6 (1.3%)
Safety analysis 457
Efficacy analysis 457
Safety analysis 466
Efficacy analysis 466
Figure 1. Flow diagram of patient disposition
EFFICACY AND SAFETY OF ␣-BLOCKER SILODOSIN
Table 1. Patient characteristics at baseline
Silodosin
No. pts
No. race (%):
Black
Asian
White
Hispanic
Other
Age:
Mean (SD)
Range
No. age (%):
Younger than 65
65 or Older
Younger than 75
75 or Older
Mean (SD) kg wt
Mean (SD) cm ht
Mean (SD) I-PSS
Mean (SD) I-PSS irritative subscore
Mean (SD) I-PSS obstructive subscore
Mean (SD) Qmax
Placebo
466
457
14 (3.0)
5 (1.1)
425 (91.2)
20 (4.3)
2 (0.4)
22 (4.8)
6 (1.3)
399 (87.3)
25 (5.5)
5 (1.1)
64.6 (8.1)
50.2–86.1
64.7 (8.1)
44.9*–86.8
259 (55.6)
207 (44.4)
406 (87.1)
60 (12.9)
89.7 (16.2)
176.9 (7.3)
21.3 (5.1)
9.3 (2.6)
12.0 (3.6)
8.7 (2.6)
249 (54.5)
208 (45.5)
402 (88.0)
55 (12.0)
89.1 (14.7)
176.9 (7.3)
21.3 (4.9)
9.3 (2.5)
12.0 (3.5)
8.9 (2.8)
* One patient in the placebo group was 44.9 years old, which was younger than
the age range stipulated in the protocol (50 years or older).
was most often attributable to voluntary withdrawal
(3.1%), AEs (2.2%) and other reasons (1.3%).
Efficacy
Patients in the silodosin and placebo groups had
similar baseline values for total I-PSS, irritative and
obstructive I-PSS subscores, Qmax and QoL (I-PSS
question 8) (table 1). At 0.5 week (ie 3 to 4 days) after
treatment initiation (the earliest time of efficacy
assessment) patients receiving silodosin achieved
significant (p ⬍0.0005) improvement (mean change
from baseline ⫾ SD) in total I-PSS (⫺4.2 ⫾ 5.26 vs
placebo ⫺2.3 ⫾ 4.37), and in irritative (⫺1.4 ⫾ 2.35
vs placebo ⫺0.8 ⫾ 2.16) and obstructive (⫺2.8 ⫾ 3.55
vs placebo ⫺1.4 ⫾ 2.99) I-PSS subscores (table 2,
fig. 2, A to C). At week 12 including LOCF the
differences in symptom improvement between patients receiving silodosin and those receiving placebo
had further increased with highly significant (p
⬍0.0001) treatment effects noted for total I-PSS
(⫺6.4 ⫾ 6.63 vs placebo ⫺3.5 ⫾ 5.84), and irritative
(⫺2.3 ⫾ 2.93 vs placebo ⫺1.4 ⫾ 2.66) and obstructive
(⫺4.0 ⫾ 4.31 vs placebo ⫺2.1 ⫾ 3.76) subscores
(table 2, fig. 2, A to C).
Rapid onset of improvement also was observed for
Qmax. Urinary flow measurements made 2 to 6 hours
after patients received the first dose of medication
demonstrated that those receiving silodosin had a
significantly (p ⬍0.0001) higher increase from baseline in mean Qmax (2.8 ⫾ 3.44) than did those receiving placebo (1.5 ⫾ 3.76). Overall this improvement
was sustained for the duration of the 12-week study
(LOCF, silodosin 2.6 ⫾ 4.43 vs placebo 1.5 ⫾ 4.36,
2637
p ⫽ 0.0007) (table 2, fig. 2, D). During the course of
the study QoL improved to a greater extent in patients receiving silodosin than in those receiving
placebo (table 3). The percentage of patients delighted, pleased or mostly satisfied with the prospect
of living with their current urinary condition for the
rest of their lives increased from 6.9% (32 of 466) to
32.0% (149 of 466) in the silodosin group and from
7.2% (33 of 457) to 22.5% (103 of 457) in the placebo
group.
Safety and Tolerability
Of the 923 patients 168 (36.8%) who received placebo experienced 259 AEs and 257 (55.2%) who received silodosin experienced 462 AEs. Few patients
(ie 7 [1.5%] in the placebo group and 6 [1.3%] in the
silodosin group) experienced serious AEs of which 1
event was considered possibly drug (silodosin or placebo) related. This event, a case of suspected syncope, occurred in an 85-year-old patient who received silodosin and was also taking the ␣-blocker
prazosin. The use of prazosin, which usually is prescribed for hypertension and is well-known for its
potential to cause syncope, was prohibited in the
study protocol.14 The most common treatment emergent AE was retrograde ejaculation, which was reported by 28% of patients who received silodosin
(table 4). For most of these patients (79%) the events
were mild. Only 2.8% of patients who received silodosin discontinued treatment because of retrograde
ejaculation. The percentage with treatment emergent orthostatic hypotension was similar among pa-
Table 2. Summary of changes from baseline at weeks 0.5
and 12
Mean (SD) Change From
Baseline
Efficacy Variable
Total I-PSS:
Wk 0.5
Wk 12
I-PSS irritative
subscore:
Wk 0.5
Wk 12
I-PSS obstructive
subscore:
Wk 0.5
Wk 12
Qmax (ml/sec):
2–6 Hrs after
first dose
Wk 12
Difference Silodosin vs Placebo
Silodosin
Placebo
Adjusted
Mean (95% CI)
p Value
⫺4.2 (5.26)
⫺6.4 (6.63)
⫺2.3 (4.37)
⫺3.5 (5.84)
⫺1.9 (⫺2.5, ⫺1.3)
⫺2.8 (⫺3.6, ⫺2.0)
⬍0.0001
⬍0.0001
⫺1.4 (2.35)
⫺2.3 (2.93)
⫺0.8 (2.16)
⫺1.4 (2.66)
⫺0.5 (⫺0.8, ⫺0.3)
⫺1.0 (⫺1.3, ⫺0.6)
0.0002
⬍0.0001
⫺2.8 (3.55)
⫺4.0 (4.31)
⫺1.4 (2.99)
⫺2.1 (3.76)
⫺1.4 (⫺1.8, ⫺1.0)
⫺1.9 (⫺2.4, ⫺1.4)
⬍0.0001
⬍0.0001
2.8 (3.44)
1.5 (3.76)
1.3
(0.9, 1.8)
⬍0.0001
2.6 (4.43)
1.5 (4.36)
1.0
(0.4, 1.5)
0.0007
Data analysis for week 12 was based on LOCF.
EFFICACY AND SAFETY OF ␣-BLOCKER SILODOSIN
2638
A
B
Total I-PSS
I-PSS Irritative Subscore
0
Placebo
Silodosin
–2
–4
–6
–8
–10
BL 0.5 1
2
Placebo
Silodosin
Mean Change From Baseline
Mean Change From Baseline
0
4
12
–1
–2
–3
BL 0.5 1
LOCF
2
4
C
D
I-PSS Obstructive Subscore
Mean Change From Baseline
Mean Change From Baseline
Placebo
Silodosin
–1
–2
–3
–4
BL 0.5 1
LOCF
12
LOCF
Qmax
4
0
–5
12
Week
Week
2
4
12
LOCF
Placebo
Silodosin
3
2
1
0
BL 2-6h 1
2
4
Week
Week
Figure 2. Mean changes from baseline (BL) in total I-PSS (A), I-PSS irritative subscore (B), I-PSS obstructive subscore (C) and Qmax (D).
Earliest post-dose I-PSS measurements occurred at week 0.5 and earliest post-dose Qmax measurements occurred 2 to 6 hours after
initial dosing. At all times differences between silodosin and placebo were statistically significant for total I-PSS (p ⬍0.0001), irritative
subscore (p ⬍0.001), obstructive subscore (p ⬍0.0001) and Qmax (p ⬍0.005). Error bars indicate 95% confidence intervals. Measurements were based on observed cases except where indicated.
tients receiving placebo (1.5%) and those receiving
silodosin (2.6%) (table 4).
DISCUSSION
Combined data from 2 phase 3 studies enrolling
more than 900 patients with symptoms of BPH
showed that 12-week treatment with silodosin reTable 3. Summary of QoL related to urinary symptoms
Baseline:
Delighted, pleased or mostly satisfied
Mixed about equally satisfied ⫹ dissatisfied
Mostly dissatisfied, unhappy or terrible
Wk 12:
Delighted, pleased or mostly satisfied
Mixed about equally satisfied ⫹ dissatisfied
Mostly dissatisfied, unhappy or terrible
Data analysis for week 12 was based on LOCF.
No.
Silodosin (%)
No.
Placebo (%)
32 (6.9)
126 (27.0)
308 (66.1)
33 (7.2)
124 (27.1)
300 (65.6)
149 (32.0)
141 (30.3)
176 (37.8)
103 (22.5)
110 (24.1)
244 (53.4)
sulted in significant, rapid and sustained improvement in lower urinary tract symptoms as assessed
by I-PSS, including irritative and obstructive subscores, and by Qmax. The onset of silodosin associated effects was rapid. Significant improvement in
Qmax was observed 2 to 6 hours after initiation of
treatment, and significant reductions in total I-PSS,
and in irritative and obstructive I-PSS subscores
were observed by 3 to 4 days, when the first postbaseline assessment was conducted. These results
are consistent with previously published data from a
placebo controlled phase 3 study conducted in Japan,
where silodosin is currently marketed.15 In that
study patients with symptoms of BPH who were
treated with 4 mg silodosin twice daily showed significantly greater improvement in total I-PSS (vs
placebo) within 1 week. After 2 weeks of treatment
improvement in I-PSS was also significantly greater
in the silodosin group than in a comparator group
treated with the ␣1A-selective ␣-blocker tamsulosin
(0.2 mg daily).
EFFICACY AND SAFETY OF ␣-BLOCKER SILODOSIN
Silodosin
Placebo
131 (28.1)
134
4 (0.9)
4
15 (3.2)
15
5 (1.1)
6
12 (2.6)
12
7 (1.5)
9
medical therapy (including ␣-blockers) for BPH
showed that placebo responses of BPH related symptoms and Qmax are common, may last 12 months or
longer and may lower baseline values for urinary
symptoms by up to 20%.20 Although the 4-week placebo run-in period is a customary feature of clinical
studies performed to evaluate the efficacy of therapies for BPH symptoms, this interval may be too
short to allow identification of all patients who
would demonstrate a placebo response during subsequent treatment.
12 (2.6)
14
6 (1.3)
6
CONCLUSIONS
11 (2.4)
11
10 (2.2)
10
11 (2.4)
11
4 (0.9)
5
10 (2.1)
11
1 (0.2)
1
Table 4. Summary of treatment emergent AEs occurring
in more than 2% of patients receiving silodosin
Retrograde ejaculation:
No. pts (%)
No. events
Dizziness:
No. pts (%)
No. events
Orthostatic hypotension:
No. pts (%)
No. events
Diarrhea:
No. pts (%)
No. events
Nasopharyngitis:
No. pts (%)
No. events
Headache:
No. pts (%)
No. events
Nasal congestion:
No. pts (%)
No. events
2639
Preferred terms from the Medical Dictionary for Regulatory Activities.
Silodosin was safe and well tolerated. The only
serious treatment emergent AE that occurred could
have been attributable to concurrent use of another
␣-blocker that was prohibited in the study protocol.
Retrograde ejaculation was the most common silodosin related AE (28%), leading to discontinuation
in only 2.8% of patients treated with silodosin. In
the Japanese study the percentage of patients receiving silodosin who experienced abnormal ejaculation (22%) was similar to that in the present study
and the discontinuation rate due to abnormal ejaculation (2.9%) was equally low.15 Retrograde ejaculation is a characteristic adverse effect of ␣1A-selective ␣-blockers4 that has been shown to be reversible
after administration of the drug is stopped.16 In the
original phase 3 trials of tamsulosin (0.4 or 0.8 mg
daily) the percentages of patients receiving tamsulosin who experienced abnormal ejaculation were
8.4% (0.4 mg daily) and 18.1% (0.8 mg daily). It is
worth noting that adherence to treatment with tamsulosin at 1 and at 5 years was substantially greater
in patients who experienced abnormal ejaculation
than in those who did not.17
Although both of the studies reported here used a
run-in period to exclude patients with substantial
placebo response, double-blind treatment with placebo during 12 weeks improved I-PSS and Qmax. A
placebo effect also was observed for QoL related to
urinary symptoms (I-PSS question 8). Substantial
placebo effects despite the use of placebo run-in periods also have been observed in double-blind, placebo controlled studies of other ␣-blockers.18,19 A
recent systematic literature review of studies of
Silodosin, a selective ␣1A-adrenoceptor antagonist, significantly reduced signs and symptoms of BPH during
a period of 12 weeks. Significant changes were observed
at the earliest post-baseline assessments. I-PSS, including irritative and obstructive subscores, improved significantly (p ⬍0.0005) within 3 to 4 days. Moreover
significant improvement (p ⬍0.0001) in Qmax was observed 2 to 6 hours after the first dose of silodosin.
Silodosin was safe and well tolerated. Retrograde ejaculation was the most common drug related AE but it
rarely resulted in discontinuation of treatment. In addition, silodosin had a low incidence of orthostatic hypotension and was associated with few events of dizziness. The
rapid onset of clinical efficacy established for silodosin
would make it a useful option for the treatment of patients with signs and symptoms of BPH.
ACKNOWLEDGMENTS
Roland Tacke, PhD and Marsha Hall from Scientific
Connexions (Newtown, Pennsylvania) provided assistance with funding from Watson Pharma, Inc.
APPENDIX
1) Exclusion criteria included intravesical obstruction unrelated to BPH; bladder
calculi; history of or current condition affecting bladder function; prior surgical
intervention to relieve BPH or bladder neck obstruction; active urinary tract
infection or history of recurrent urinary tract infection within the past 2 years;
prostatitis within the past 3 months; BPH unrelated urinary retention within
the past 3 months; and a history of recurring prostatitis (more than 3 times
within the past year), prior or current prostate cancer or prostate specific
antigen greater than 10 ng/ml; prior invasive bladder cancer; bladder catheterization or bladder or prostate instrumentation within the past 30 days and
history of or current significant postural hypotension, including changes in systolic
(greater than 30 mm Hg) or diastolic (greater than 20 mm Hg) blood pressure or heart
rate (more than 20 beats per minute), and lightheadedness, fainting, blurred vision,
profound weakness or syncope upon change in position.
2) Sample size for each of the 2 studies was based on providing an adequate
number of patients for a safety database to meet the regulatory requirement of at
least 100 patients exposed for 1 year and 300 patients for 6 months. By using the
common standard deviation of 5.2 in change from baseline in I-PSS total score
observed in a pilot phase 2 study of silodosin in the United States (Study US021),
a sample size of 240 subjects per treatment group with 90% power and ␣ ⫽ 0.05
would detect a difference of 1.54 of mean I-PSS change from baseline between
treatment groups. Thus, this sample size would be sufficient to detect a clinically
meaningful difference in mean I-PSS of 2 to 2.5.21
2640
EFFICACY AND SAFETY OF ␣-BLOCKER SILODOSIN
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