Rapid efficacy of the highly selective α(1A)-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies.

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.

West China hospital set of measures in Chinese to evaluate back pain treatment.

OBJECTIVE: Chinese is the most commonly spoken language in the world, and back pain is as prevalent in China as it is elsewhere. Nevertheless, there is a paucity of measures in Chinese to evaluate back pain treatment. We assemble a set of Chinese measures to evaluate outcomes in diverse domains. A set of measures is necessary, because measures in one domain may vary independently from measures in another. Chinese measures are in four domains: pain intensity, global rating of improvement, physical disability, and emotional functioning. The Oswestry Disability Index (ODI) represents the domain of physical disability, and both the World Health Organization Five-Item Well-being Index (WHO-5) and the Center for Epidemiological Studies-Depression Scale (CES-D depression scale) represent the domain of emotional functioning. DESIGN: Measures were cross-culturally adapted into Chinese. The development of Chinese versions of the ODI, the WHO-5, and the CES-D entailed psychometric evaluation. Additionally, we administered the previously validated Chinese SF-36 to evaluate the validity of measures in our set. SETTING: The western-style Pain Clinic and the Acupuncture Clinic of West China Hospital (Chengdu, Sichuan Province). PATIENTS: Eighty-six patients with nonspecific back pain. RESULTS: We found no significant differences between patients from the Pain Clinic and those from the Acupuncture Clinic. For the ODI, the CES-D, and the WHO-5, we evaluated the psychometric properties of reliability, validity, and ceiling and floor effects. We found these properties to be good to excellent. CONCLUSIONS: In the Appendix (available online, in supplemental materials for this article), we present the West China Hospital set of measures in Chinese to evaluate back pain treatment.

Rapid efficacy of the highly selective alpha1A-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies.

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.

Efficacy and safety of transdermal and oral oxybutynin in children with neurogenic detrusor overactivity.

PURPOSE: We evaluated the efficacy and safety of transdermal and oral oxybutynin in children with neurogenic detrusor overactivity. MATERIALS AND METHODS: Children with neurogenic detrusor overactivity 6 to 15 years old and previously receiving oxybutynin were assigned randomly at a 3:1 ratio to treatment with transdermal or oral oxybutynin. Initial dosages (transdermal 1.3, 2.9 or 3.9 mg daily; oral 5, 10 or 15 mg daily), based on pre-study dosages, were adjusted after 2 weeks and then maintained for 12 weeks. The primary efficacy end point was change from baseline to last observation in average urine volume collected by clean intermittent catheterization. RESULTS: A total of 57 patients were randomized to receive transdermal (41) or oral (16) oxybutynin. Safety data were available for 55 patients and efficacy data were available for 52. Mean +/- SD urine volume increased from 95 +/- 64 ml to 125 +/- 74 ml (p <0.001) with transdermal oxybutynin and from 114 +/- 75 ml to 166 +/- 92 ml (p = 0.002) with oral oxybutynin. Transdermal oxybutynin resulted in significant improvement in all measured urodynamic parameters. Similar trends and a significant increase in maximal cystometric bladder capacity were observed in the smaller oral oxybutynin group. There were 12 treatment related adverse events noted with transdermal oxybutynin (mild skin reaction) and 1 with oral oxybutynin (vasodilatation). The ratio of N-desethyloxybutynin-to-oxybutynin plasma concentrations was substantially lower with transdermal (1.4) than with oral (6.7) oxybutynin. CONCLUSIONS: Transdermal oxybutynin was a well tolerated and effective alternative to oral oxybutynin in treating neurogenic detrusor overactivity in children who previously tolerated oxybutynin.

Strategy for Assessing New Drug Value in Orphan Diseases: An International Case Match Control Analysis of the PROPEL Study.

BACKGROUND: Although randomized studies are designed to assess overall survival (OS) benefit, the conduct of regulatory studies in patients with orphan diseases can be timely and costly without offering the same commercial return on the investment. The peripheral T-cell lymphomas (PTCL) represent a rare group of heterogeneous lymphoid malignancies with very poor prognosis. PROPEL was a pivotal phase II study that led to the accelerated approval of pralatrexate for patients with relapsed or refractory PTCL. METHODS: An international database of 859 patients was assembled from four institutions with an interest in PTCL, of which 386 were considered eligible for matching against the PROPEL criteria. Using a rigorous propensity score matching algorithm, a unique 1:1 case match of 80 patients was performed. RESULTS: The analysis demonstrated an OS benefit for the PROPEL population with a median OS of 4.07 and 15.24 months (hazard ratio = 0.432, 95% confidence interval = 0.298 to 0.626), respectively, for the control and PROPEL populations. Highly statistically significant improvements in OS were noted for the PROPEL population about the subtype of PTCL (save anaplastic large cell lymphoma) and all age groups, including the elderly (>65 years of age). For patients on PROPEL, there was a statistically significant prolongation in progression free survival compared with the line of prior therapy, including those with refractory disease. CONCLUSION: In the context of this case-match-control study, patients treated on PROPEL experienced an OS advantage compared with an international database of historical controls. This information can help inform critical decision-making regarding clinical studies in PTCL.

Effect of estimated prostate volume on silodosin-mediated improvements in the signs and symptoms of BPH: does prostate size matter?

OBJECTIVE: The uroselective α-blocker silodosin significantly improved International Prostate Symptom Score (IPSS) in two 12-week, double-blind (DB), placebo-controlled Phase III studies in men aged ≥ 50 years with symptoms of benign prostatic hyperplasia (BPH) and maintained symptom improvement during a 9-month open-label (OL) extension. This post-hoc analysis evaluated the effects of estimated prostate volume (EPV) on silodosin-mediated symptom improvement. METHODS: Patients were stratified by EPV (<30 mL or ≥ 30 mL) calculated from prostate-specific antigen (PSA) concentrations using a published algorithm. Group comparisons were done by analysis of covariance with last observations carried forward. RESULTS: Of 890 patients with PSA baseline data, 192 had EPV < 30 mL and 698 had EPV ≥ 30 mL. During DB treatment, silodosin was associated with significant symptom improvement (adjusted mean difference versus placebo) in men with EPV < 30 mL (-2.0; P = 0.038) and those with EPV ≥ 30 mL (-3.0; P < 0.0001). Among patients who received silodosin during DB treatment, changes from baseline in IPSS to the end of OL extension (mean ± standard deviation) were similar for EPV < 30 mL (n = 60, -7.0 ± 6.8) and EPV ≥ 30 mL (n = 242, -8.0 ± 7.1; P = 0.416). Also, among patients who received placebo as DB treatment, symptom improvement at the end of OL extension was similar for EPV < 30 mL (n = 62, -6.2 ± 8.1) and EPV ≥ 30 mL (n = 275, -6.7 ± 6.1; P = 0.339). CONCLUSION: Silodosin effectively relieved BPH-related symptoms for up to 12 months, irrespective of prostate size, including in patients with enlarged prostates.

Lack of pharmacodynamic interaction of silodosin, a highly selective alpha1a-adrenoceptor antagonist, with the phosphodiesterase-5 inhibitors sildenafil and tadalafil in healthy men.

OBJECTIVES: To evaluate the orthostatic effects and safety of coadministration of silodosin with the phosphodiesterase-5 inhibitors sildenafil and tadalafil. METHODS: In this placebo-controlled, open-label crossover study, 22 healthy men aged 45-78 years received 8 mg silodosin for 21 days. 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 hours after single-dose treatment. A positive orthostatic test was defined as decrease in systolic blood pressure (SBP) >30 mm Hg, decrease in diastolic blood pressure (DBP) >20 mm Hg, increase in heart rate (HR) >20 bpm, or presence of orthostatic symptoms. Treatment effects were compared by analysis of covariance. RESULTS: In comparison with placebo, sildenafil or tadalafil caused small but statistically significant reductions in blood pressure; however, no statistically significant orthostatic changes in SBP, DBP, or HR (P >.05) were caused. Time-matched maximum mean difference (95% confidence interval) vs placebo in 1-minute orthostatic change was -2.3 (-6.8-2.2) mm Hg for SBP, -2.2 (-5.6-1.2) mm Hg for DBP, and 1.7 (-1.5-4.9) bpm for HR. The number of postdose positive orthostatic tests was similar for all treatments (sildenafil, 57; tadalafil, 59; placebo, 53). Adverse events (in 7 subjects) were mild (26) or moderate (2). No orthostatic symptoms occurred. CONCLUSIONS: 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.

Effect of silodosin on specific urinary symptoms associated with benign prostatic hyperplasia: analysis of international prostate symptom scores in 2 phase III clinical studies.

PURPOSE: Pooled results from 2 randomized, placebo-controlled, US phase III studies (NCT00224107, NCT00224120) showed that silodosin, a uroselective α-blocker, significantly improved International Prostate Symptom Scores (IPSS) in men with symptomatic benign prostatic hyperplasia (BPH). This analysis evaluated the effect of silodosin on each symptom assessed by IPSS questionnaire. MATERIALS AND METHODS: Study participants (N = 923) were men aged ≥50 years with IPSS ≥13 and Qmax 4-15 mL/s. They received silodosin 8 mg or placebo once daily for 12 weeks. Patient responses to 7 IPSS questions were collected at weeks 0 (baseline), 0.5, 1, 2, 4, and 12 and scored on a 6-point scale. Efficacy of silodosin versus placebo was assessed by analysis of covariance. RESULTS: For each symptom, the 2 treatment groups had similar mean baseline scores. Decrease in score from baseline (mean ± standard deviation) to last observation was significantly greater with silodosin than with placebo for all symptoms (P < 0.005); symptom improvement with silodosin (versus placebo) was greatest for weak stream (silodosin, -1.1 ± 1.4 versus placebo, -0.5 ± 1.2; P < 0.0001) and smallest for nocturia (silodosin, -0.6 ± 1.1 versus placebo, -0.4 ± 1.2; P = 0.0037). Compared with placebo, silodosin significantly improved nocturia within 1 week (silodosin, -0.5 ± 1.07 versus placebo, -0.3 ± 1.05; P = 0.009) and all other symptoms within 3 to 4 days (P < 0.01). CONCLUSIONS: Silodosin significantly improved all BPH-associated symptoms assessed by IPSS questionnaire within the first week of treatment. All improvements were maintained over the 12-week study period.

Silodosin in the treatment of the signs and symptoms of benign prostatic hyperplasia: a 9-month, open-label extension study.

OBJECTIVES: To evaluate long-term safety of the highly selective alpha(1A)-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia (BPH). METHODS: Patients enrolled in this open-label extension study had completed 1 of 2 identical double-blind, placebo-controlled 12-week studies of silodosin treatment for symptomatic BPH. For 40 weeks, patients received silodosin 8 mg once daily with breakfast. Adverse events (AEs) were recorded to evaluate safety. Change in International Prostate Symptom Score was a secondary variable. RESULTS: Of the 661 participants, 435 (65.8%) completed the study; 431 patients (65.2%) experienced 924 AEs. No serious AEs that were considered drug-related by investigators occurred. AEs reported most often (percentage of patients) were 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 treatment-emergent AEs, 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%) vs continuing treatment (1.9%) discontinued study participation because of retrograde ejaculation. Mean International Prostate Symptom Score change (standard deviation) from baseline to week 40 (observed cases) was -4.5 (6.7) for de novo treatment (P <.0001) and -1.6 (6.0) for continuing treatment (P <.01). CONCLUSIONS: Silodosin was well tolerated by men with BPH-related symptoms and was associated with low incidences of dizziness and orthostatic hypotension. Discontinuation because of retrograde ejaculation was more common among patients receiving silodosin de novo than in those who continued silodosin treatment.

Back pain claim rates in Japan and the United States: framing the puzzle.

STUDY DESIGN: This is a cross-national comparison of workers' compensation claims for back pain in Japan and the United States (US). OBJECTIVES: The main objective is to juxtapose rates of back pain claims in Japan and Washington state. Because the Washington state rate closely matches rates for other US states as well as the rate for the US as a whole, it is used to represent the US rate. A puzzle is to be framed: Why are back pain claim rates in Japan and the United States so disparate? SUMMARY OF BACKGROUND DATA: Occupational back pain is common among workers in both Japan and the United States. Wage compensation for time off work is also substantial in both countries and potentially induces time off work at least as much in Japan as in the United States. Accordingly, back pain claim rates in Japan seemingly would be on the same order of magnitude as rates in the United States. METHODS: Washington state rates are based on data from its state fund. Both Japan and Washington state rates are composed of the number of workers eligible to file worker compensation claims in a given year (denominator) and the number of back pain claims accepted during that year (numerator). Because rates may fluctuate from year-to-year, 5 years of data on rates are presented, 1995-1999. Central to the comparison are Japanese and Washington state rates of workers' compensation claims for back pain with more than 3 days compensated time loss from work. RESULTS: The back pain claim rate in 1999 was 60 times higher in Washington state than in Japan. The disparity in rates for the other years in the study (1995-1998) was similar. CONCLUSION: Back pain is common among workers both in Japan and the United States, but there is no simple or necessary relationship between that symptom and how it manifests itself in one country or another. Rather, the symptom is protean in its social manifestations. As for what shapes those manifestations-or, more specifically, what causes the startling disparity in back pain claim rates between Japan and the United States-that is a puzzle. Various solutions to the puzzle are discussed, but it remains essentially unsolved.