Journal Article Page
European UrologyVolume 59, issue 3, pages e5-e14, March 2011
Benign Prostatic Hyperplasia
Silodosin Therapy for Lower Urinary Tract Symptoms in Men with Suspected Benign Prostatic Hyperplasia: Results of an International, Randomized, Double-Blind, Placebo- and Active-Controlled Clinical Trial Performed in Europe
Accepted 31 October 2010, Published online 10 November 2010, pages 342 - 352
Silodosin is a new selective therapy with a high pharmacologic selectivity for the α1A-adrenoreceptor.
Our aim was to test silodosin's superiority to placebo and noninferiority to tamsulosin and discuss the findings in the context of a comprehensive literature review of the new compound silodosin.
Design, setting, and participants
We conducted a multicenter double-blind, placebo- and active-controlled parallel group study. A total of 1228 men ≥50 yr of age with an International Prostate Symptom Score (IPSS) ≥13 and a urine maximum flow rate (Qmax) >4 and ≤15 ml/s were selected at 72 sites in 11 European countries. The patients were entered into a 2-wk wash-out and a 4-wk placebo run-in period. A total of 955 patients were randomized (2:2:1) to silodosin 8 mg (n = 381), tamsulosin 0.4 mg (n = 384), or placebo (n = 190) once daily for 12 wk.
We calculated the change from baseline in IPSS total score (primary), storage and voiding subscores, quality of life (QoL) due to urinary symptoms, and Qmax. Responders were defined on the basis of IPSS and Qmax by a decrease of ≥25% and an increase of ≥30% from baseline, respectively.
Results and limitations
The change from baseline in the IPSS total score with silodosin and tamsulosin was significantly superior to that with placebo (p < 0.001): difference active placebo of −2.3 (95% confidence interval [CI], −3.2, −1.4) with silodosin and −2.0 (95% CI,−2.9, −1.1) with tamsulosin. Responder rates according to total IPSS were significantly higher (p < 0.001) with silodosin (66.8%) and tamsulosin (65.4%) than with placebo (50.8%). Active treatments were also superior to placebo in the IPSS storage and voiding subscore analyses, as well as in QoL due to urinary symptoms. Of note, only silodosin significantly reduced nocturia versus placebo (the change from baseline was −0.9, −0.8, and −0.7 for silodosin, tamsulosin, and placebo, respectively; p = 0.013 for silodosin vs placebo). An increase in Qmax was observed in all groups. The adjusted mean change from baseline to end point was 3.77 ml/s for silodosin, 3.53 ml/s for tamsulosin, and 2.93 ml/s for placebo, but the change for silodosin and tamsulosin was not statistically significant versus placebo because of a particularly high placebo response (silodosin vs placebo: p = 0.089; tamsulosin vs placebo: p = 0.221). At end point, the percentage of responders by Qmax was 46.6%, 46.5%, and 40.5% in the silodosin, tamsulosin, and placebo treatment groups, respectively. This difference was not statistically significantly (p = 0.155 silodosin vs placebo and p = 0.141 tamsulosin vs placebo).
Active treatments were well tolerated, and discontinuation rates due to adverse events were low in all groups (2.1%, 1.0%, and 1.6% with silodosin, tamsulosin, and placebo, respectively). The most frequent adverse event with silodosin was a reduced or absent ejaculation during orgasm (14%), a reversible effect as a consequence of the potent and selective α1A-adrenoreceptor antagonism of the drug. The incidence was higher than that observed with tamsulosin (2%); however, only 1.3% of silodosin-treated patients discontinued treatment due to this adverse event.
Silodosin is an effective and well-tolerated treatment for the relief of both voiding and storage symptoms in patients with lower urinary tract symptoms suggestive of bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. Its overall efficacy is not inferior to tamsulosin. Only silodosin showed a significant effect on nocturia over placebo.
ClinicalTrials.gov Identifier NCT00359905.
Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate caused by cellular hyperplasia of both glandular and stromal elements . As the prostate increases in size, it may occlude the lumen of the prostatic urethra, obstructing urine flow . However, studies have shown that prostate size and urinary flow rate usually do not correlate with the severity of lower urinary tract symptoms (LUTS), which may vary from subject to subject . In clinical practice, patients are treated for LUTS suggestive of bladder outlet obstruction (BOO) due to BPH, often called “LUTS/BPH.”
Even if voiding symptoms are the most prevalent in cases of LUTS/BPH, patients usually perceive the storage symptoms as the most bothersome group of symptoms . The objective of therapy for such patients is to improve LUTS/BPH and hence quality of life (QoL). In addition, treatment is aimed at preventing complications such as acute urinary retention or upper urinary tract dilation consequent to BOO. Existing medical therapy includes α-blockers, which are currently the preferred first-line therapy for all men with moderate or severe LUTS/BPH , and 5α-reductase inhibitors (5-ARIs), which are a recommended treatment option for men with moderate or severe LUTS/BPH and an enlarged prostate. α-Blockers can be used regardless of prostate size because they act on the dynamic/neurally mediated contraction of the muscular stroma that is increased in BPH; 5-ARIs act by shrinking the stromal component of the gland. Both components are thought to contribute to the symptoms and impairment of outflow in patients with LUTS/BPH .
Nonselective α1-adrenoceptor blockers increase urinary flow rate and improve symptoms in men with symptomatic BPH; however, they may be associated with side effects related to peripheral vasodilation, such as postural hypotension, dizziness, and headache , , and . Conversely, drugs with a high affinity for α1A-adrenoceptors may be more prostate specific and may maintain the therapeutic response in the treatment of symptomatic BPH with less effect on blood pressure and fewer cardiovascular side effects  and .
Silodosin is a new agent with high selectivity for α1A-receptors, which predominate in the male bladder outflow tract relative to α1B-receptors. It has been demonstrated in vitro that silodosin's α1A-to-α1B binding ratio is extremely high (162:1), suggesting the potential to markedly reduce dynamic neurally mediated smooth muscle relaxation in the lower urinary tract while minimizing undesirable effects on blood pressure regulation . In this context, the evaluation of the uroselectivity of silodosin versus that of tamsulosin and prazosin in vivo has shown good uroselectivity (determined from the ratio of the dose-reducing intraurethral pressure as contrasted to blood pressure) in rats and dogs  and .
This paper reports the results of the first randomized placebo-controlled European study with silodosin in the treatment of patients with LUTS/BPH. The study compared silodosin with the effective and widely used drug tamsulosin .
2. Patients and methods
2.1. Study design
A multicenter double-blind, placebo- and active-controlled parallel group clinical study was conducted in 72 hospital clinics and inpatient units in 11 countries in Europe. After a wash-out phase of 14 d and a 4-wk single-blind placebo run-in period, subjects who met the selection criteria were randomly assigned (in a ratio of 2:2:1, with stratification by center, with blocks of five assigned to each center, produced and managed centrally by an international contract research organization) to a 12-wk treatment with silodosin 8 mg, tamsulosin 0.4 mg, or placebo, administered once daily. At the centers, all study personnel and participants were blinded to treatment assignment for the entire duration of the study. The ethics committee of each participating center approved the study protocol, and the study was conducted according to the Declaration of Helsinki. Each patient signed a written informed consent before beginning any investigational procedure.
Eight visits were foreseen: at day −42 (start of the wash-out period) and day −28 (start of the placebo run-in period); at baseline (pre- and postrandomization); and after 7, 14, 28, 56, and 84 d of treatment (or in the case of premature study termination).
Prerandomization procedures consisted of the collection of a medical history (including a urologic history), a check of concomitant medications, a physical examination (including a digital rectal examination), and a postvoid residual volume determination by ultrasound.
The International Prostate Symptom Score (IPSS) questionnaire (including question 8, BPH-related health status), a validated instrument widely used for the assessment of symptom severity in patients with BPH , was administered to the patients at screening, at baseline, and after 7, 14, 28, 56, and 84 d of treatment (or in the case of premature study termination). Because the study was performed in several European countries and involved patients speaking different languages, the questionnaire was linguistically validated by the MAPI Institute (an international company that specialized in linguistic validation for appropriate cross-cultural use and interpretation of patient-reported assessments) in the relevant languages.
Peak urine maximum flow rate (Qmax) was also measured once 2–6 h postdose at the same time periods as IPSS, using standard calibrated devices. A voided volume of at least 125 ml needed to be obtained for a valid assessment.
Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were measured at each visit, with the subject supine at rest for at least 5 min before measurements. A test for postural hypotension was performed at screening and pre- and postdose at baseline. Laboratory tests and a 12-lead electrocardiogram (ECG) were performed at screening, at baseline, and at study end (or in the case of premature discontinuation). Adverse events (AEs) were collected at each visit. The appearance of new unfavorable and unintended signs, symptoms, or diseases or worsening of conditions already present at baseline in the postrandomization period were considered as treatment-emergent adverse events (TEAEs).
2.2. Study population
Men ≥50 yr of age with LUTS (defined by a stable IPSS total score ≥13 points), BOO (defined by a Qmax between 4 and 15 ml/s, with a minimum voided volume of ≥125 ml), and the evidence of satisfactory compliance with study medication (80–120% during the placebo run-in period) were eligible for inclusion in the study. Principal exclusion criteria were improvement in the IPSS total score ≥25% in the run-in period, postvoid bladder residual volume ≥250 ml, intravesical obstruction from any cause other than BPH, history of any procedure considered an intervention for BPH, active urinary tract infection or history of recurrent urinary tract infections, current prostatitis or diagnosis of chronic prostatitis, history of prostate or invasive bladder cancer, significant postural hypotension, use of 5-ARIs within 6 mo, or use of an α-blocker or phytotherapy within 2 wk before entry.
2.3. Study end points and statistical analyses
The primary end point of the study was to demonstrate the superiority of silodosin to placebo and its noninferiority to tamsulosin for the relief of LUTS associated with BPH and suggestive of BOO. This was measured by a change from baseline in the total score (questions 1–7) of the IPSS questionnaire (primary efficacy parameter).
The total number of subjects to be randomized was set at 820 (328 for silodosin 8 mg, 328 for tamsulosin 0.4 mg, and 164 for placebo) to reject the null hypothesis that the two active treatments were not equivalent with the following assumptions: a standard deviation of 5.2, one sided, 90% of power, a noninferiority margin of a mean change of −1.5 IPSS points, and 20% of patients not valid for inclusion in the per-protocol (PP) population. This sample size was also adequate for a two-sided test at the 0.05 significance level, with 90% power, to detect a mean change in the IPSS total score  of −2 from baseline between each active group and placebo.
Secondary efficacy parameters were as follows: improvement in storage and voiding symptoms subscores, QoL due to urinary symptoms (question 8 of the IPSS), Qmax, and percentage of treatment responders by IPSS (decrease from baseline ≥25%) and by Qmax (increase from baseline ≥30%).
Statistical analyses were performed using the following procedures. For the analysis of the primary efficacy variable, the superiority of the active treatments (silodosin and tamsulosin) versus placebo was tested first in the intent-to-treat (ITT) population (all subjects who had a baseline IPSS assessment and at least one valid postbaseline IPSS assessment). Next, the noninferiority of silodosin versus tamsulosin was tested in the PP population (all subjects who completed the study without any major protocol violation). Last, because all the planned tests were satisfied, the superiority of silodosin versus tamsulosin was tested (ITT population). For the secondary efficacy variables, the superiority of the active treatments (silodosin and tamsulosin) versus placebo was tested first, followed by the comparison between silodosin and tamsulosin.
The overall treatment group comparisons of the change from baseline in the IPSS total score, by visit and at end point (in both ITT and PP populations), were estimated based on adjusted means obtained from the main analysis of the covariance model, which included terms for treatment, pooled center, and baseline value.
The percentage of responders to IPSS and the percentage of responders to Qmax were summarized at each visit and at end point by treatment group; comparisons between each of the active treatment groups and placebo and between silodosin and tamsulosin were made using the Cochran Mantel Haenszel test, stratified by pooled center, for both populations.
A post hoc analysis was conducted in the subgroup of patients with nocturia at baseline (defined as at least two voids per night), as assessed by question 7 of the IPSS.
In terms of safety, the safety population was defined as all subjects who were randomized and who received at least one dose of double-blind study medication. Safety was assessed primarily on the basis of TEAEs occurring in the different groups postrandomization. In addition, the change from baseline was evaluated for the following safety parameters: DBP, SBP, and HR in a supine position and after standing (orthostatic test), laboratory determinations, ECG findings, and physical examination.
3.1. Disposition of patients
A total of 1228 patients were screened, 955 of whom were randomized to receive silodosin 8 mg (381), tamsulosin 0.4 mg (384), or placebo (190), respectively. The first patient was enrolled on May 18, 2006, and the last patient completed the study on May 10, 2007. Fig. 1 shows the patient allocation. The main reasons for study discontinuation were protocol violation (2.5%) and voluntary withdrawal by the subject (2.4%). The discontinuation rate due to TEAE was low (≤2.1%) in all groups.
3.2. Demographics and other baseline characteristics
Table 1 summarizes the demographic and baseline characteristics of the safety population. No statistically significant differences were seen between the three treatment groups with respect to age, body mass index, IPSS total score, storage and voiding subscores, and QoL due to urinary symptoms. Of note, 424 patients (44.4%) were hypertensive, and many subjects were on concomitant antihypertensive medications. At baseline, many patients had a past or current history of erectile dysfunction (24.0%) or complained of ejaculation disorders. These included orgasm semen quantity reduced (8.3%), orgasm semen force reduced (6.9%), and orgasm with no semen (0.8%), with an overall 24.0% rate of pretreatment ejaculatory disorders.
|Silodosin 8 mg||Tamsulosin 0.4 mg||Placebo||Total||p value|
|(n = 381)||(n = 384)||(n = 190)||(n = 955)|
|Age, yr, n (%)|
|50–64||158 (41.5)||157 (40.9)||75 (39.5)||390 (40.8)|
|65–74||168 (44.1)||183 (47.7)||93 (48.9)||444 (46.5)|
|≥75||55 (14.4)||44 (11.5)||22 (11.6)||121 (12.7)|
|Mean ± SD||65.8 ± 7.70||65.9 ± 7.41||66.0 ± 7.37||65.8 ± 7.51|
|Race, n (%)|
|White||381 (100.0)||384 (100.0)||190 (100.0)||955 (100.0)||Not estimable|
|BMI, kg/m2, n (%)|
|<25||84 (22.0)||109 (28.4)||46 (24.2)||239 (25.0)|
|25–29||238 (62.5)||214 (55.7)||118 (62.1)||570 (59.7)|
|≥30||59 (15.5)||61 (15.9)||25 (13.2)||145 (15.2)||0.624|
|IPSS total score|
|Mean ± SD||19.1 ± 4.23||18.9 ± 4.37||19.3 ± 4.33||19.1 ± 4.30|
|IPSS storage subscore|
|Mean ± SD||7.9 ± 2.49||7.9 ± 2.51||8.0 ± 2.64||7.9 ± 2.53|
|IPSS voiding subscore|
|Mean ± SD||11.3 ± 3.13||11.0 ± 3.27||11.3 ± 3.22||11.2 ± 3.20|
|QoL due to urinary symptoms, n (%)|
|Delighted||0 (0.0)||3 (0.8)||0 (0.0)||3 (0.3)|
|Pleased||2 (0.5)||6 (1.6)||0 (0.0)||8 (0.8)|
|Mostly satisfied||27 (7.1)||23 (6.0)||12 (6.3)||62 (6.5)|
|Mixed||98 (25.7)||105 (27.3)||44 (23.2)||247 (25.9)|
|Mostly dissatisfied||140 (36.7)||135 (35.2)||65 (34.2)||340 (35.6)|
|Unhappy||98 (25.7)||95 (24.7)||57 (30.0)||250 (26.2)|
|Terrible||16 (4.2)||17 (4.4)||10 (5.3)||43 (4.5)|
|Missing||0 (0.0)||0 (0.0)||2 (1.1)||2 (0.2)|
|Mean ± SD||3.9 ± 1.01||3.9 ± 1.09||4.0 ± 1.00||3.9 ± 1.04|
|Urine Qmax, ml/s|
|Mean||10.78 ± 2.726||10.27 ± 2.726||10.32 ± 2.816||10.49 ± 2.752|
BMI = body mass index; IPSS = International Prostate Symptom Score; Qmax = maximum flow rate; QoL = quality of life; SD = standard deviation.
3.3. Efficacy results
3.3.1. Change from baseline in International Prostate Symptom Score total score (primary efficacy parameter)
|Silodosin 8 mg||Tamsulosin 0.4 mg||Placebo|
|ITT population||n = 371||n = 376||n = 185|
|Baseline, mean ± SD||19 ± 4||19 ± 4||19 ± 4|
|Change from baseline to end point, adjusted means||−7.0||−6.7||−4.7|
|Difference active vs placebo (95% CI)||−2.3 (−3.2, −1.4)*||−2.0 (−2.9, −1.1)*||–|
|Difference tamsulosin vs silodosin (95% CI)||0.3 (−0.4, 1.0)†||–||–|
|PP population||n = 346||n = 347||n = 168|
|Baseline, mean ± SD||19 ± 4||19 ± 4||19 ± 4|
|Change from baseline to week 12, adjusted means||−7.0||−6.7||−4.8|
|Difference active vs placebo (95% CI)||−2.2 (−3.2. −1.3)*||−1.9 (−2.8, −0.9)*||–|
|Difference tamsulosin vs silodosin (95% CI)||0.4 (−0.4, 1.1)†||–||–|
* p < 0.001 versus placebo.
CI = confidence interval; ITT = intention to treat; PP = per protocol; SD = standard deviation.
For all treatment groups, there was no plateau in response; however, the largest decreases in the total IPSS score occurred rapidly, within the first 2 wk of treatment. Superiority of active treatments versus placebo was observed with highly statistically significant differences at all weeks (p < 0.001) both in the ITT and PP population.
3.3.2. Responder rates according to International Prostate Symptom Score total score
In all three treatment groups, the percentage of IPSS responders progressively increased from baseline to week 12. At study end, 66.8% and 65.4% of the patients receiving silodosin or tamsulosin were responders (respectively), compared with 50.8% in the placebo group.
The differences versus placebo were highly significant (p < 0.001) for both active compounds, whereas the comparison between silodosin and tamsulosin did not show a statistically significant difference.
3.3.3. Voiding and storage subscores
Table 3 shows the mean change from baseline to end point in the IPSS subscore of voiding symptoms (questions 1, 3, 5, and 6) and of storage symptoms (questions 2, 4, and 7). The statistically significant superiority of both active treatments versus placebo on voiding and storage subscores was observed at all weeks of treatment. The comparison between silodosin and tamsulosin did not show a statistically significant difference, even if a numerical difference in favor of silodosin was observed in the voiding subscore. Of note, in the subgroup of patients with nocturia at baseline (n = 764), only silodosin significantly reduced nocturia versus placebo (change from baseline −0.9, −0.8, and −0.7 for silodosin, tamsulosin, and placebo, respectively; p = 0.013 for silodosin vs placebo, p = 0.095 for tamsulosin vs placebo, and p = 0.314 for silodosin vs tamsulosin).
|Treatment arm||IPSS storage symptoms||IPSS voiding symptoms|
|Difference (95% CI) vs placebo||Change
|Difference (95% CI) vs placebo|
|Silodosin||−2.5||−0.7† (−1.1, −0.2)||−4.5||−1.7* (−2.2, −1.1)|
|Tamsulosin||−2.4||−0.6† (−1.1, −0.2)||−4.2||−1.4* (−2.0, −0.8)|
* p < 0.001 versus placebo.
† p = 0.002 versus placebo.
CI = confidence interval; IPSS = International Prostate Symptom Score.
3.3.4. Quality of life
An improvement in the change from baseline in QoL due to urinary symptoms (question 8 of the IPSS) was reported for all treatment groups (−1.1 for silodosin, −1.1 for tamsulosin, and −0.8 for placebo). Once again, highly statistically significant differences were observed between active treatments and placebo at all weeks (at end point p = 0.002). At end point, the percentage of patients negatively affected by urinary symptoms (feeling mostly dissatisfied, unhappy, and terrible) was reduced >50% in the silodosin and tamsulosin groups (from 66.9% to 34.0% and from 64.1% to 29.0%, respectively), and about a third in the placebo group (from 69.7% to 45.4%) (Table 4).
|No. (%)||No. (%)||No. (%)|
|Delighted, pleased, or mostly satisfied||29 (7.8)||32 (8.5)||12 (6.5)|
|Mixed: about equally satisfied and dissatisfied||94 (25.3)||103 (27.4)||43 (23.2)|
|Mostly dissatisfied, unhappy, or terrible||248 (66.9)||241 (64.1)||129 (69.7)|
|Delighted, pleased, or mostly satisfied||163 (44.0)||168 (44.7)||63 (34.0)|
|Mixed: about equally satisfied and dissatisfied||82 (22.1)||99 (26.3)||38 (20.5)|
|Mostly dissatisfied, unhappy, or terrible||126 (34.0)||109 (29.0)||84 (45.4)|
* Data analysis for week 12 was based on last observation carried forward.
3.3.5. Maximum flow rate
A larger increase from baseline in Qmax (milliliters per second) was observed for both active treatment groups compared with placebo but was not statistically significant. The adjusted mean change from baseline to end point was 3.77 ml/s for silodosin (p = 0.089 vs placebo), 3.53 ml/s for tamsulosin (p = 0.221 vs placebo), and 2.93 ml/s for placebo. The percentage of Qmax responders was larger for the silodosin and the tamsulosin treatment groups compared with the placebo group; however, only sporadic statistically significant differences versus placebo were found for either active treatment group during the various follow-up visits due to a particularly high placebo response. At end point, the percentage of responders was 46.6% (p = 0.155 vs placebo) and 46.5% (p = 0.141 vs placebo) in the silodosin and the tamsulosin treatment groups, respectively, and 40.5% in the placebo group. This difference was not statistically significant.
3.4. Safety results
3.4.1. Treatment-emergent adverse events
Overall, the percentage of subjects who reported at least one TEAE was 34.9% (133 of 381) for subjects in the silodosin group, 28.9% (111 of 384) in the tamsulosin group, and 24.2% (46 of 190) in the placebo group (silodosin vs placebo: p = 0.0094; silodosin vs tamsulosin: p = 0.0749). The most frequently reported TEAEs (>2%) were a reduced or absent ejaculation during orgasm (coded by the Medical Dictionary for Regulatory Activities preferred term as “retrograde ejaculation”) and headache. The percentage of subjects reporting AEs coded as “retrograde ejaculation” was 14.2% (54 of 381) in the silodosin treatment group, which was significantly higher compared with 2.1% (8 of 384) and 1.1% (2 of 190) of subjects in the tamsulosin and placebo treatment groups, respectively. The verbatim terms reported by the investigators in the silodosin group and coded as retrograde ejaculation were orgasm with no semen, orgasm semen quantity reduced, and retrograde ejaculation. Headache was reported by a higher percentage of subjects in the tamsulosin group (5.5%; 21 of 384) compared with the silodosin group (2.9%; 11 of 381) but was similar and not significantly different than headaches reported in the placebo group (4.7%; 9 of 190).
The percentage of subjects who discontinued the study due to a TEAE was small and not statistically different in all treatment groups (silodosin 2.1%, eight subjects; tamsulosin 1.0%, four subjects; placebo 1.6%, three subjects). The most common TEAE leading to discontinuation was failure of ejaculation (five subjects in the silodosin group and one in the tamsulosin group). This TEAE was reversible after study discontinuation.
Nine subjects of 955 (0.9%) experienced a serious TEAE; of these, three were considered possibly related to the study drug by the treating investigator: prostate cancer and supraventricular arrhythmia (silodosin) and anxiety (tamsulosin). Two subjects died during the study; both deaths were unrelated to the drugs used in the study.
3.4.2. Other safety parameters
No clinically meaningful changes were recorded for any of the laboratory parameters, vital signs, or ECGs observed during the study in any of the treatment groups. Table 5 presents the supine DBP, SBP, and HR and the change from baseline in DBP, SBP, and HR observed with the silodosin, tamsulosin, and placebo groups. No clinically relevant or statistically significant differences versus placebo were observed with silodosin. An important characteristic of silodosin is the lack of clinically relevant or statistically significant changes in blood pressure or heart rate versus placebo. However, a minor but statistically significant difference versus placebo was observed with tamsulosin.
|Silodosin 8 mg (n = 381)||Tamsulosin 0.4 mg (n = 384)||Placebo (n = 190)|
|Supine systolic BP|
|Baseline (mean ± SD)||133.8 (12.61)||133.0 (13.29)||132.8 (13.57)|
|CFB at end point (adjusted means)||−1.8||−2.2||−0.4|
|Difference active vs placebo (95% CI)||−1.4 (−3.0, 0.1)||−1.8 (−3.4, −0.3)||–|
|p value vs placebo||0.075||0.022||–|
|Difference tamsulosin vs silodosin (95% CI)||−0.4 (−1.7, 0.9)||–||–|
|p value vs tamsulosin||0.536||–||–|
|Supine diastolic BP|
|Baseline (mean ± SD)||80.6 (7.47)||80.5 (7.99)||80.6 (7.70)|
|CFB at end point (adjusted means)||−1.0||−1.6||−0.6|
|Difference active vs placebo (95% CI)||−0.3 (−1.4, 0.7)||−1.0 (−2.1, 0.0)||–|
|p value vs placebo||0.515||0.060||–|
|Difference tamsulosin vs silodosin (95% CI)||−0.7 (−1.5, 0.2)||–||–|
|p value vs tamsulosin||0.132||–||–|
|Supine heart rate|
|Baseline (mean ± SD)||67.4 (8.83)||67.8 (9.10)||67.3 (8.43)|
|CFB at end point (adjusted means)||0.8||1.3||1.1|
|Difference active vs placebo (95% CI)||−0.3 (−1.6, 1.0)||0.2 (−1.1, 1.5)||–|
|p value vs placebo||0.643||0.753||–|
|Difference tamsulosin vs silodosin (95% CI)||0.5 (−0.5, 1.5)||–||–|
|p value vs tamsulosin||0.340||–||–|
BP = blood pressure; CFB = change from baseline; CI = confidence interval; SD = standard deviation.
No subject experienced a marked decrease in blood pressure when performing the postrandomization orthostatic test after the first dosing of the drug. Only a few subjects in both active treatment groups reported an increase in HR >20 beats per minute without any clinically important change in SBP or DBP.
This prospective statistically well-powered study evaluated the efficacy and safety of the new highly selective agent silodosin, an α1A-receptor, for the treatment of moderate to severe LUTS due to BPH. A population of patients with LUTS/BPH who were representative of those seen in clinical practice in terms of age, concomitant diseases, and medication was selected. In the patient group, approximately 60% were elderly, and about 57% were on concomitant antihypertensive medication.
In this study, silodosin proved to be an effective drug for the treatment of both storage and voiding LUTS associated with BPH because a statistically significant and potentially clinically relevant difference versus placebo was observed in the IPSS total score, in the storage and voiding subscores, and in QoL due to urinary symptoms. The improvement became evident soon after the initiation of therapy. The treatment effect with silodosin appeared to be at least equivalent to and numerically consistently greater than that seen with tamsulosin when considering the change from baseline in the IPSS total score, in the voiding subscore, and in the responder rates, even if the differences were not statistically significant. There was also a greater benefit seen when considering the QoL on active therapy with either silodosin or tamsulosin as compared with placebo.
It is noteworthy that the selective effect of α1A-receptor antagonism seemed to offer a clinically relevant benefit not only on voiding but also on storage symptoms. Of note, only the effect of silodosin (and not of tamsulosin) on nocturia was significantly better than that of placebo. The mechanism of this action remains to be clarified.
In this study, treatment with silodosin also showed an early and sustained increase in Qmax; however, the difference versus placebo was not statistically significant. A similar order of magnitude for the flow rate was seen with the active comparator tamsulosin, which has been clearly documented in the past to produce significant changes when compared with placebo.
The first randomized double-blind, placebo-controlled study that was conducted with silodosin in Japan recruited men ≥50 yr of age with an IPSS of ≥8 and a QoL score of ≥3. Patients were randomized to receive silodosin 4 mg twice daily, tamsulosin 0.2 mg once daily (the Japanese dosage, lower than the European dosage), or placebo for 12 wk . The primary end point was the change in IPSS from baseline. In all, 457 patients were randomized (176 to silodosin, 192 to tamsulosin, and 89 to placebo). The change in the total IPSS from baseline in the silodosin, tamsulosin, and placebo groups was −8.3, −6.8, and −5.3, respectively. There was a significant decrease in the IPSS versus placebo in the silodosin group from 1 wk, and silodosin showed a significant decrease in IPSS versus tamsulosin at 2 wk. In the subgroup of patients with severe symptoms (IPSS ≥20), silodosin also offered a significantly better improvement than placebo (−12.4 vs −8.7). The incidence rates of AEs were 88.6%, 82.3%, and 71.6%, respectively; for drug-related AEs they were 69.7%, 47.4%, and 36.4%, respectively. The most common AE in the silodosin group was abnormal ejaculation, which occurred more often in the silodosin than in the tamsulosin group (22.3% vs 1.6%). However, only five men (2.9%) discontinued treatment because of abnormal ejaculation.
Marks and colleagues assessed the efficacy and safety of silodosin 8 mg for the treatment of BPH in two randomized placebo-controlled phase 3 studies done in the United States . Of 923 patients with a mean age of 65 yr, 466 received silodosin (8 mg/d) and 457 were given placebo with breakfast for 12 wk. After 0.5 wk (3–4 d) of treatment, patients receiving silodosin showed significant improvement in IPSS subscores (difference −1.9; p < 0.0001), storage (−0.5; p = 0.0002), and voiding (−1.4; p < 0.0001) compared with the placebo group. The mean change from baseline in total IPSS was −4.2 for silodosin versus −2.3 for placebo, and differences between treatments in total IPSS and subscores increased by week 12 (p < 0.0001). Mean change from baseline in Qmax (ml/s) 2–6 h after initial dose was greater (p < 0.0001) with silodosin (2.8 ± 3.4) than placebo (1.5 ± 3.8). These differences remained significant (p < 0.001) for the 12 wk. The lack of significant difference as compared with placebo in our study could be explained by a higher than expected placebo response, supported by the similar efficacy to tamsulosin, which was also not significantly different from placebo and was at variance with the published literature .
A long-term open-label extension study of patients from these two studies was conducted over 40 wk, with all patients receiving silodosin 8 mg once daily with breakfast . The primary objective of this study was to assess safety. Of the 661 participants, 435 (65.8%) completed the study and 431 (65.2%) experienced 924 AEs. No serious AEs that the investigators considered to be drug related occurred. AEs reported most often (percentage of patients) included retrograde ejaculation (20.9%), diarrhea (4.1%), and nasopharyngitis (3.6%). Orthostatic hypotension and dizziness occurred in 2.6% and 2.9% of patients, respectively. The percentage of patients with TEAEs, stratified by preceding double-blind treatment (placebo or silodosin), was higher for de novo (previous treatment with placebo: 71.5%) than for continuing silodosin treatment (58.3%). More patients receiving de novo (7.5%) versus continuing treatment (1.9%) discontinued study participation because of retrograde ejaculation. The mean IPSS change (standard deviation) from baseline (after 12 wk of previous double-blind therapy) to week 40 (observed cases) was −4.5 (6.7) for de novo treatment (p < 0.0001) and −1.6 (6.0) for continuing treatment (p < 0.01). Silodosin was well tolerated and in particular was associated with low incidences of dizziness and orthostatic hypotension.
Because the efficacy of both tamsulosin and silodosin appear to be very similar, the question has to be posed regarding the potential additional advantage of silodosin. Studies conducted recently have suggested that silodosin as a consequence of its high subtype selectivity is less likely than tamsulosin to have significant cardiovascular side effects either when used alone or in combination with other agents, which may affect blood pressure. This is particularly important and relevant in more elderly patients.
Kobayashi et al.  provided evidence for this suggestion. They evaluated the efficacy on the urethra (intraurethral pressure) and cardiovascular system (hypotension) of silodosin (α1A-adrenoceptor antagonist) and tamsulosin (α1A+1D-adrenoceptor antagonist) in dogs with BPH altered with age. Under anesthesia, the increase in intraurethral pressure evoked by hypogastric nerve stimulation was measured, together with the level of systemic mean blood pressure. Each drug was administered intravenously in progressively increasing doses. Silodosin (0.3–300 μg/kg) dose-dependently inhibited the hypogastric nerve stimulation–induced increase in intraurethral pressure (without significant hypotensive effects) in both young and old dogs with BPH. Tamsulosin (0.3–300 μg/kg) also dose-dependently inhibited the intraurethral pressure increase in both groups, but it had a hypotensive effect that was significantly greater in old than in young dogs with BPH. The potency of silodosin on intraurethral pressure was similar between young and old dogs with BPH and was without significant hypotensive effects. The authors concluded that if one extrapolated these data to man, silodosin should be a safe and effective medication for LUTS in patients of all age groups.
In a placebo-controlled open-label clinical crossover study evaluating potential interaction with a phosphodiesterase inhibitor , 22 healthy men 45–78 yr of age received 8 mg silodosin for 21 d. On days 7, 14, and 21, subjects also received a single dose of sildenafil 100 mg, tadalafil 20 mg, or placebo in random sequence. Orthostatic tests were performed before (baseline) and 1–12 h after single-dose treatment. Coadministration of silodosin and maximum therapeutic doses of sildenafil or tadalafil in healthy men caused no clinically important orthostatic changes in blood pressure or HR and no orthostatic symptoms. The most frequent TEAE observed during silodosin therapy was ejaculatory dysfunction (EjD) consisting of one of the following group of symptoms: orgasm, semen quantity reduced; orgasm, semen force reduced; or orgasm, no semen.
Although it is a widely held view among clinicians that EjD is a consequence of an effect on the bladder neck, it is in fact not true retrograde ejaculation but rather “anejaculation” caused by an effect on the ejaculatory apparatus (prostate, seminal vesicles, and vasa) and indeed has been coded incorrectly as retrograde ejaculation in several clinical studies . It has been recognized for many years that the vas is an excellent pharmacologic model for the α1A-receptor . Although it is possible that the clinical differences between silodosin and tamsulosin as compared with other α1-adrenoceptor antagonists do not exclusively relate to their subtype selectivity , additional properties of these drugs such as a proposed insurmountable antagonism in the vas deferens  or additional effects on other receptor systems (eg, dopamine and/or serotonin ) should be considered. Finally, it has been proposed that abnormal ejaculation is not primarily regulated at the level of the vas deferens but rather at central nervous sites that control its function .
This is clearly a typical side effect of α1-adrenoreceptor antagonists, particularly those with selectivity for α1A-adrenoreceptors, because this subtype is distributed throughout the organs participating in the emission phase of ejaculation . Nonclinical studies have shown that α-adrenoreceptors, particularly α1A-adrenoreceptors, are essential for the physiologic contraction of the vas deferens and hence for sperm delivery from the testes to the urethra . Reduced ejaculation is caused by an impaired function of the vas deferens rather than by alterations in sperm formation, number, or function . This effect does not represent a safety concern because it indicates only a reduction in semen volume that is reversible (within a few days) upon discontinuation of treatment  and , and it is not perceived as particularly bothersome (in this study, the discontinuation rates were very low in all groups and were comparable with placebo).
It is now well established that EjD is commonly associated with both increasing age and the presence of LUTS , , , and . The Multinational Survey of the Aging Male-7 results confirmed the significant relationship between LUTS and EjD in aging men.
A post hoc analysis of the North American studies on silodosin  suggested that EjD may be a predictor of the efficacy of the α1-adrenoreceptor blockade. Roehrborn and colleagues found that 28.1% of patients in these studies experienced EjD and reported that these patients experienced a greater improvement in symptoms and a clinically meaningful greater improvement in flow rate than those who did not experience EjD . Homma et al.  carried out a similar analysis evaluating improvements in symptoms in the Japanese study . The silodosin subgroup with failure of ejaculation experienced a greater reduction in total IPSS than the silodosin subgroup without impairment of ejaculation and the placebo subgroup (−11.8 vs −7.2 vs −5.3, respectively). Interestingly, the dropout rates in both of the silodosin groups were very similar.
As expected for a highly uroselective drug, silodosin appears to be a safe drug that is at least equivalent to tamsulosin in efficacy. A major advantage of this drug is its lack of cardiovascular side effects. It has no clinically relevant effect on blood pressure when measured either in the supine position or during orthostatic testing. This is important because most patients treated for LUTS associated with BPH are elderly and often on concomitant antihypertensive therapy or taking agents such as phosphodiesterase inhibitors. No unfavorable effect has been observed on ECG or laboratory tests, including liver function tests and tests of creatinine and glucose levels.
This large multinational study has confirmed the results of previous studies, demonstrating silodosin to be an effective and safe treatment for the relief of both voiding and storage symptoms in patients with benign prostatic enlargement consequent upon BOO due to BPH. It may be particularly useful in more elderly patients where there is the potential for drug–drug interactions and where potential cardiovascular side effects need to be minimized.
Author contributions: Christopher R. Chapple had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chapple, Montorsi.
Acquisition of data: Chapple, Montorsi, Tammela, Wirth, Koldewijn, Fernández Fernández.
Analysis and interpretation of data: Chapple, Montorsi, Tammela, Wirth, Koldewijn, Fernández Fernández.
Drafting of the manuscript: Chapple, Montorsi, Tammela, Wirth, Koldewijn, Fernández Fernández.
Critical revision of the manuscript for important intellectual content: Chapple, Montorsi, Wirth, Koldewijn, Fernández Fernández.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Christopher R. Chapple and Francesco Montorsi are consultants and researchers for Recordati. Teuvo L.J. Tammela, Manfred Wirth, Evert Koldewijn, and Eldiberto Fernández Fernández are researchers for Recordati.
Funding/Support and role of the sponsor: Recordati Ireland Ltd, Ringaskiddy, County Cork, Ireland, was involved in the design and conduct of the study, collection of the data, management of the data, analysis, interpretation of the data, preparation, review, and approval of the manuscript.
Acknowledgement statement: The authors wish to thank Dr. Massimo Casi, senior clinical project leader, for his dedicated help and support in finalizing the manuscript.
Appendix A. Complete List of Study Participants
Finland: T. Forsell (Kotka); P. Hellström (Oys); M. Multanen (Kouvola); T.L.J. Tammela (Tampere)
France: H. Botto (Suresnes); D. Chevallier (Nice)
Germany: F. König (Berlin); M. Schulze (Markkleeberg); J. Willgerodt (Leipzig); M. Wirth (Dresden); A. Von Keitz (Marburg)
Italy: F. Gaboardi (Milan); V. Gentile (Rome); M. Motta (Catania); P. Rigatti (Milano); R.M. Scarpa (Orbassano); O. Risi (Treviglio)
The Netherlands: E. Koldewijn (Eindhoven); E. Meuleman (Amsterdam); V. Van de Walle (Geleen)
Poland: P. Chlosta (Kielce); B. Darewicz (Bialystok); A. Dobrowolski (Myslowice); W. Dudziak (Srem); A. Gajda (Warszawa); P. Wedzikowski (Lodz); R. Jarema (Warszawa); R. Szwedowski (Opole); J. Szyperski (Bydgoszcz); P. Trypens (Warszawa); M. Wyczółkowski (Krakow)
Romania: F. Bajan (Pitesti); N. Calomfirescu (Bucharest); M. Dinu (Bucharest); C. Gingu (Bucharest); V. Jinga (Bucharest); C. Nitoiu (Bucharest)
Russia: S. Al-Shukri (St. Petersburg); V.P. Avdoshin (Moscow); I.A. Gorelov (St. Petersburg); I.S. Gorelov (St. Petersburg); V.K. Kheifets (St. Petersburg); B.V. Kunin (St. Petersburg); V.I. Kuzmin (St. Petersburg); O.B. Loran (Moscow); E.B. Mazo (Moscow); L.S. Mikhailov (St. Petersburg); I. Sedavnykh (St. Petersburg); A.V. Shanava (St. Petersburg); V.N. Shirshov (Moscow); V.N. Surikov (Moscow); A. Zhivov (St. Petersburg); M. Forkampf-Laue (St. Petersburg)
Spain: J. Caballero Alcántara (Marbella); E. Leon Dueñas (Sevilla); E. Fernández Fernández (Madrid); J.M. Fernández Gómez (Oviedo); F. Jiménez Cruz (Valencia); J.A. Portillo Martín (Santander)
Ukraine: A.A. Lyulko (Zaporizhzhya); A.V. Lyulko (Dnipropetrovsk); I. Gorpynchenko (Kyiv); F. Kostyev (Odesa); V. Lesovoy (Kharkiv); S. Pasiechnikov (Kyiv); V. Pirogov (Kyiv); V. Zaytsev (Chernivtsi)
United Kingdom: C.R. Chapple (Sheffield); S. Natale (Plymouth); R. Persad (Bristol); M. Speakman (Taunton, Somerset); A. Thorpe (Newcastle upon Tyne)
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a Department of Urology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK
b Department of Urology, Università Vita Salute San Raffaele, Milan, Italy
c Department of Urology, Tampere University Hospital, Tampere, Finland
d Department of Urology, University Hospital Carl Gustav Carus, Dresden, Germany
e Department of Urology, Catharina Hospital, Eindhoven, The Netherlands
f Department of Urology, University Hospital Ramón y Cajal, Madrid, Spain
A complete list of study participants is provided in the appendix.
© 2010 European Association of Urology, Published by Elsevier B.V.
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