Long-term efficacy and tolerability of abdominal once-yearly histrelin acetate subcutaneous implants in patients with advanced prostate cancer.

Objectives. Long-term assessment of the efficacy and tolerability of subcutaneous abdominal histrelin acetate implants that have been inserted for more than two years. Materials and Methods. Retrospective data collected over a six-year period at a single center from charts of 113 patients who received the subcutaneous abdominal histrelin acetate implant. Results. Following insertion of the first implant, 92.1% and 91.8% of patients had a serum testosterone level of ≤30 ng/dL at 24 and 48 weeks, respectively. Serum testosterone levels remained at <30 ng/dL for 96% of patients at two years and for 100% of patients at 3, 4, and 5 years. The testosterone levels remained significantly less than baseline (P < 0.05). Six patients (5.3%) had androgen-independent progression when followed up on the long term, increasing the mean serum PSA at 3, 4, and 5 years to 35.0 µg/L (n = 22), 30.7 µg/L (n = 13), and 132.9 µg/L (n = 8), respectively. The mean serum PSA was significantly greater than baseline during these years (P < 0.05). Eight patients (7.1%) experienced minor, but not serious, adverse events from the histrelin acetate. Conclusion. Subcutaneous abdominal histrelin acetate implants are an effective long-term and well-tolerated administration method for treating patients with advanced prostate cancer.

Comparison of the response to treatment between Asian and Caucasian men with benign prostatic hyperplasia: long-term results from the combination of dutasteride and tamsulosin study.

The Combination of Avodart and Tamsulosin study was a 4-year, randomized, double-blind study of the efficacy and safety of dutasteride and tamsulosin, alone or in combination, in men with moderate-to-severe benign prostatic hyperplasia. In this post-hoc investigation, we analyzed primary and secondary end-points from the Combination of Avodart and Tamsulosin study in Asian (n = 325) and Caucasian men (n = 4259). The incidence of acute urinary retention or benign prostatic hyperplasia-related surgery did not differ significantly between treatment groups in the Asian subpopulation. In Caucasian men, the incidence of acute urinary retention/benign prostatic hyperplasia-related surgery was significantly lower in the combination therapy group compared with the tamsulosin monotherapy group (P < 0.001), but not compared with dutasteride monotherapy. Combination therapy significantly increased the time to benign prostatic hyperplasia clinical progression and resulted in improved International Prostate Symptom Score, maximum urinary flow rate, quality of life, and reduced prostate volume in Asian and Caucasian men who received combination therapy compared with tamsulosin monotherapy. Combination therapy also significantly improved (P < 0.05) time to benign prostatic hyperplasia clinical progression, International Prostate Symptom Score, maximum urinary flow rate and quality of life versus dutasteride in the Caucasian subpopulation. The adverse-event profile was comparable between subpopulations. In conclusion, Asian and Caucasian men respond similarly to these treatments, despite apparent racial differences in 5α-reductase activity.

Once-daily trospium chloride 60 mg extended-release provides effective, long-term relief of overactive bladder syndrome symptoms.

AIMS: Once-daily extended-release (XR) trospium chloride has been evaluated for the treatment of overactive bladder syndrome (OAB) in two 12-week randomized, double-blind, placebo-controlled studies. This pooled analysis of the 9-month open-label extensions to these studies evaluated the long-term efficacy and tolerability of trospium XR. METHODS: Following double-blind treatment, subjects with OAB could enter the open-label period, during which they received trospium 60 mg XR once daily for 36 weeks. The primary efficacy variables were changes from baseline in the number of toilet voids and urgency urinary incontinence (UUI) episodes per day at Week 48. Adverse events (AEs) were also recorded. RESULTS: Of the 1,027 subjects who completed double-blind treatment, 944 (92%) continued into the open-label period (placebo-to-trospium, N = 483; trospium-to-trospium, N = 461); 332 (68.7%) and 335 (72.7%), respectively, completed the open-label period. At Week 48, the mean change from baseline in the number of toilet voids/day was -3.21 in the placebo-to-trospium group and -3.35 in the trospium-to-trospium group, and the median change from baseline in the number of UUI episodes/day was -2.33 in both groups. Efficacy was maintained relative to Week 12 in trospium-to-trospium subjects, while improvement was seen following trospium initiation in placebo-to-trospium subjects. Improvement from baseline was also observed on secondary efficacy parameters at Week 48. Trospium was well tolerated; dry mouth and constipation were the most common class treatment-emergent AEs. Central nervous system AEs were rare and did not increase with long-term treatment. CONCLUSIONS: Long-term treatment of OAB with once-daily trospium 60 mg XR is effective and well tolerated.

Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial.

OBJECTIVE: • To investigate the influence of baseline variables on the 4-year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)-related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both. PATIENTS AND METHODS: • The 4-year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double-blind, parallel-group study of clinical outcomes in men aged ≥ 50 years with symptomatic (International Prostate Symptom Score [IPSS]≥ 12) BPH, with prostate-specific antigen (PSA) levels of ≥ 1.5 ng/mL and ≤ 10 ng/mL, and a prostate volume (PV) of ≥ 30 mL. • Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. • The primary endpoint was time to first AUR or BPH-related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health-related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Q(max) ] and body-mass index [BMI]) on the incidence of AUR or BPH-related surgery, clinical progression of BPH, and symptoms were performed. RESULTS: • There were 4844 men in the intent-to-treat population. Overall baseline characteristics were similar across all patient groups. • Regardless of baseline subgroup, the incidence of AUR or BPH-related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. • Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH-related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P ≤ 0.001). • Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of < 20 or IPSS HRQL score of < 4. The incidence of clinical progression was also higher in men receiving tamsulosin than dutasteride or combined therapy in all baseline subgroups, except for men with a baseline PV of < 40 mL. Combined therapy reduced the relative risk (RR) of clinical progression compared with tamsulosin across all baseline subgroups and compared with dutasteride across most baseline subgroups. • Symptom deterioration was the most common progression event in each treatment group regardless of baseline subgroup, except in those men with an IPSS of ≥ 20 at baseline. Combined therapy reduced the RR of symptom deterioration compared with tamsulosin across all but one baseline subgroup (the reduction was not significant for men with a baseline PV of < 40 mL) and compared with dutasteride in most subgroups. CONCLUSIONS: • Men with a baseline PV of ≥ 40 mL and any baseline PSA level of ≥1.5 ng/mL had greater reductions in the RR of AUR or BPH-related surgery and greater reductions in the RR of clinical progression and symptom deterioration on combined therapy or dutasteride monotherapy than on tamsulosin monotherapy. • These analyses support the long-term use of combined therapy with dutasteride plus tamsulosin in men with moderate-to-severe BPH symptoms and a slightly enlarged prostate.

Randomized, double-blind, placebo-controlled trial of flexible-dose fesoterodine in subjects with overactive bladder.

OBJECTIVES: To evaluate the efficacy and tolerability of flexible-dose fesoterodine vs placebo in subjects with overactive bladder (OAB). METHODS: In a 12-week double-blind trial, subjects were randomized to fesoterodine 4 mg or placebo once daily, taken within 4 hours of bedtime. At week 2, subjects could increase the fesoterodine dose to 8 mg (sham escalation for placebo). Subjects completed 3-day bladder diaries, Patient Perception of Bladder Condition, and Urgency Perception Scale at baseline and weeks 2, 6, and 12 as well as OAB Questionnaire at baseline and week 12. RESULTS: Of 883 subjects, 63% and 73% of the fesoterodine (n = 438) and placebo (n = 445) groups, respectively, opted for dose escalation. Week 12 improvements from baseline in total micturitions, urgency episodes, urgency urinary incontinence episodes, frequency-urgency sum, and all OAB Questionnaire scales and domains, but not nocturnal micturitions or nocturnal urgency episodes, were significantly greater with fesoterodine than placebo (all P <.05). Treatment differences in micturitions and frequency-urgency sum were significant by week 2 and in urgency urinary incontinence and urgency episodes by week 6. Significantly greater percentages of subjects taking fesoterodine had improved Patient Perception of Bladder Condition and Urgency Perception Scale scores at weeks 2, 6, and 12 (P <.05). Dry mouth (fesoterodine, 26%; placebo, 8%) and constipation (fesoterodine, 11%; placebo, 6%) were the most common adverse events. In both groups, 87% of the subjects completed the trial; 8% and 5% of the fesoterodine and placebo groups, respectively, discontinued because of an adverse event. CONCLUSIONS: Flexible-dose fesoterodine was efficacious and generally well tolerated for treatment of OAB symptoms.

The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study.

BACKGROUND: Combination therapy with dutasteride and tamsulosin provides significantly greater benefit than either monotherapy for various patient-reported outcomes in men with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and prostatic enlargement. OBJECTIVE: To investigate whether combination therapy is more effective than either monotherapy in reducing the relative risk for acute urinary retention (AUR), BPH-related surgery, and BPH clinical progression over 4 yr in men at increased risk of progression. DESIGN, SETTING, AND PARTICIPANTS: The Combination of Avodart and Tamsulosin (CombAT) study was a 4-yr, multicenter, randomised, double-blind, parallel-group study in 4844 men > or =50 yr of age with a clinical diagnosis of BPH, International Prostate Symptom Score > or =12, prostate volume > or =30 cm(3), prostate-specific antigen 1.5-10 ng/ml, and maximum urinary flow rate (Q(max)) >5 and < or =15 ml/s with minimum voided volume > or =125 ml. INTERVENTION: Oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. MEASUREMENTS: The 4-yr primary end point was time to first AUR or BPH-related surgery. Secondary end points included BPH clinical progression, symptoms, Q(max), prostate volume, safety, and tolerability. RESULTS AND LIMITATIONS: Combination therapy was significantly superior to tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery. Combination therapy was also significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression. Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr. Safety and tolerability of combination therapy was consistent with previous experience with dutasteride and tamsulosin monotherapies, with the exception of an imbalance in the composite term of cardiac failure among the three study arms. The lack of placebo control is a study limitation. CONCLUSIONS: The 4-yr CombAT data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe LUTS due to BPH and prostatic enlargement. CLINICALTRIALS.GOV IDENTIFIER: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103).

Diary and patient-reported outcomes in patients with severe overactive bladder switching from tolterodine extended release 4 mg/day to solifenacin treatment: An open-label, flexible-dosing, multicentre study.

OBJECTIVE: We report outcomes from the VERSUS (VESIcare Efficacy and Research Study US) study in a cohort with severe overactive bladder (OAB), defined as patients with a score >or=5 on the Patient Perception of Bladder Condition (PPBC) scale at baseline (on tolterodine extended release [ER] 4 mg/day) who remained severe at post-washout (on no drug). METHODS: VERSUS was a 12-week, open-label, flexible-dosing study assessing the efficacy, tolerability and effects on health-related quality of life (HRQOL) of solifenacin in patients with OAB. The current study is a post hoc analysis of a severely affected subgroup, as self-defined using the PPBC scale. Patients had received tolterodine ER 4 mg/day for >or=4 weeks but wished to switch therapy because of a lack of sufficient subjective improvement in urgency. They had to have continued to have three or more urgency episodes/24 hours at baseline (pre-washout, i.e. while taking tolterodine ER 4 mg/day). After >or=14 days' washout, patients received oral solifenacin 5 mg/day, with the option of continuing/adjusting the dose to 5 or 10 mg/day at weeks 4 and 8. Diary-documented improvements in urgency, urge incontinence, frequency, nocturia and nocturnal voids were compared with pre-washout (on tolterodine) and post-washout (on no drug) diary entries. The PPBC scale and Overactive Bladder Questionnaire (OAB-q) assessed patient-reported outcomes. Tolerability was evaluated based on the nature, frequency and severity of observed or reported adverse events (AEs). RESULTS: In this severe OAB cohort, the mean number of urgency episodes/24 hours decreased by 3.95 (95% CI -4.81, -3.08; p < 0.0001) from pre-washout (7.38) to study end (3.26). All other diary variables were also significantly reduced (p < 0.0001). Patients had a mean PPBC score of 5.3 at pre-washout and 3.6 at study end, representing an improvement of 1.7 (95% CI -2.0, -1.5; p < 0.0001). Patients also reported significant improvements for all OAB-q scales and domains (p < 0.0001). Treatment-emergent AEs were mostly mild/moderate, and resulted in few discontinuations (5/116, 4.3%). CONCLUSION: In patients with severe OAB symptoms, solifenacin was effective and well tolerated. Solifenacin improved urgency, incontinence, micturition frequency, nocturia and nocturnal voids in patients continuing to experience urgency episodes on tolterodine ER 4 mg/day. Patients experienced improvements in HRQOL and perceived bother from OAB.

Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 2-year data from the CombAT trial.

OBJECTIVE: To investigate the effect of dutasteride and tamsulosin as combined therapy compared with each monotherapy for improving patient-reported health outcomes in men with moderate-to-severe urinary symptoms and prostate enlargement, reporting the pre-planned 2-year analyses from the CombAT trial. PATIENTS AND METHODS: The CombAT study is an ongoing, international, double-blind, randomized, parallel-group trial. Men aged >or=50 years with a clinical diagnosis of benign prostatic hyperplasia (BPH), an International Prostate Symptom Score (IPSS) of >or=12 units, a prostate volume of >or=30 mL, a total serum prostate-specific antigen level of 1.5-10 ng/mL and a peak urinary flow of >5 and or=125 mL, were randomized to receive 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination once daily for 4 years. Symptoms were assessed every 3 months. The primary endpoint at 2 years was the change in IPSS from baseline. Secondary endpoints included various measures of health outcomes, which included the BPH Impact Index (BII), IPSS Question 8 (Q8), and the Patient Perception of Study Medication (PPSM) questionnaire. RESULTS: Combined therapy resulted in significantly greater improvements in BII and IPSS Q8 from baseline than did dutasteride from 3 months and compared with tamsulosin from 9 months (BII) or 12 months (IPSS Q8). Assessments using the PPSM questionnaire showed that a significantly higher proportion of patients were satisfied with and would request dutasteride and tamsulosin combined therapy than with each monotherapy at 24 months. CONCLUSIONS: Dutasteride and tamsulosin combined therapy provides significantly greater improvements in patient-reported quality of life and treatment satisfaction than both monotherapies at 2 years, following the trends for clinical improvements in symptom scores and peak urinary flow rates, in men with moderate-to-severe BPH symptoms.

The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT study.

BACKGROUND: Knowledge of baseline factors that influence outcomes for men with benign prostatic hyperplasia (BPH) receiving medical therapy may help to improve outcomes and cost effectiveness. OBJECTIVES: To examine the influence of baseline parameters on changes in International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Q(max)) in men with BPH receiving dutasteride, tamsulosin, or a combination of the two using 2-yr Combination of Avodart and Tamsulosin (CombAT) study data. DESIGN, SETTING, AND PARTICIPANTS: CombAT is an ongoing, 4-yr, multicentre, randomised, double-blind study in 4844 men aged >or=50 yr with clinical diagnosis of BPH, IPSS >or=12, prostate volume >or=30 cm(3), prostate-specific antigen (PSA) 1.5-10 ng/ml, and Q(max) >5 and or=125 ml. INTERVENTION: Daily tamsulosin 0.4 mg, dutasteride 0.5 mg, or the combination. MEASUREMENTS: Post hoc analyses of mean IPSS and Q(max) changes from baseline by treatment group and by baseline prostate volume, PSA, age, body mass index (BMI), IPSS, IPSS quality of life (QoL) score, BPH Impact Index score, Q(max), and previous BPH medical therapy. RESULTS AND LIMITATIONS: Combination therapy was more effective than either monotherapy after 24 mo in improving IPSS in all baseline subgroups, with benefit onset varying by baseline prostate volume. Combination therapy was also more effective in improving Q(max) versus tamsulosin in all subgroups and versus dutasteride in 10 of 18 subgroups. At 24 mo, dutasteride monotherapy resulted in significantly greater IPSS improvements versus tamsulosin in men with lower age, worse symptoms, worse QoL, less bother, higher BMI, greater Q(max), higher prostate volume, and higher PSA at baseline. Post hoc analyses, the lack of placebo control, and the exclusion of men with unsuccessful medical BPH treatment are study limitations. CONCLUSIONS: Combination therapy with tamsulosin and dutasteride affords the greatest and the most rapid symptomatic benefit among men with higher baseline prostate volume and is effective regardless of previous BPH medical therapy. Dutasteride monotherapy is more effective than tamsulosin in men with higher baseline prostate volume or PSA and worse symptoms.

Efficacy of solifenacin in patients previously treated with tolterodine extended release 4 mg: results of a 12-week, multicenter, open-label, flexible-dose study.

OBJECTIVE: This study evaluated the use of solifenacin in patients experiencing residual urgency symptoms during treatment with tolterodine extended release (ER) 4 mg for overactive bladder (OAB). METHODS: This was a 12-week, multicenter, openlabel, flexible-dose study of the efficacy, tolerability, and effects on health-related quality of life (HRQL) of solifenacin in patients aged >or=18 years who had symptoms of OAB for >or=3 months, had been treated with tolterodine ER 4 mg for >or=4 weeks, and wished to switch therapy because of a lack of sufficient subjective improvement in urgency. At baseline (before washout of tolterodine), patients had to have >or=3 urgency episodes/24 hours. After >or=14 days' washout of tolterodine, all patients received oral solifenacin 5 mg/d, with the option of a dose increase to 10 mg at weeks 4 and 8. On 3 consecutive days before the prewashout, postwashout (no drug treatment for OAB), and week 4, 8, and 12 visits (during and at the end of treatment with solifenacin), patients used a bladder diary to document daily symptoms of urgency, urge incontinence, frequency, nocturia, and nocturnal voids. Changes in these measures at study end were compared with prewashout and postwashout values. The Patient Perception of Bladder Condition (PPBC) and Overactive Bladder Questionnaire (OAB-q) were used to assess patient-reported outcomes at prewashout, postwashout, and week 12. Tolerability was evaluated based on the nature, frequency, and severity of observed or reported adverse events (AEs). RESULTS: Of 606 patients screened, 441 received study medication (mean [SD] age, 61.4 [13.8] years; 88.9% white; 88.2% female). Diary-documented urgency changed from a mean of 6.0 episodes/24 hours at prewashout to 2.6 episodes/24 hours at study end, a mean decrease of 3.4 episodes/24 hours (95% CI, -3.8 to -3.0; P < 0.001). The frequency of all other diary variables was also significantly reduced from prewashout to study end (P < 0.001). The mean PPBC score changed from 4.2 points at prewashout to 3.0 points at study end, a mean improvement of 1.2 points (95% CI, -1.3 to -1.1; P < 0.001). Changes in all OAB-q scales and domains (symptom bother, coping, concern, sleep, social interaction, and total HRQL) from prewashout and postwashout to study end were also statistically significant (P < 0.001). Treatment-emergent AEs were mainly mild or moderate (237/261 [90.8%]) and led to few discontinuations (16/441 [3.6%]). Treatment-emergent AEs included anticholinergic AEs such as dry mouth (77 [17.5%]), constipation (51 [11.6%]), and blurred vision (10 [2.3%]). CONCLUSIONS: Among these patients with residual urgency after treatment with tolterodine ER 4 mg, solifenacin was associated with significant improvements in urgency and other diary-documented symptoms of OAB. Patients receiving solifenacin also had significant improvements in HRQL and the perceived bother of OAB.

The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study.

PURPOSE: We investigated whether combination therapy with dutasteride and tamsulosin is more effective than either monotherapy alone for improving symptoms and long-term outcomes in men with moderate to severe lower urinary tract symptoms and prostatic enlargement (30 cc or greater). We report preplanned 2-year analyses. MATERIALS AND METHODS: The CombAT study is an ongoing, multicenter, randomized, double-blind, parallel group study. Men 50 years or older with a clinical diagnosis of benign prostatic hyperplasia, International Prostate Symptom Score 12 points or greater, prostate volume 30 cc or greater, total serum prostate specific antigen 1.5 ng/ml or greater to 10 ng/ml or less and peak urinary flow greater than 5 to 15 ml per second or less with a minimum voided volume of 125 ml or greater were randomized to 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination once daily for 4 years. Symptoms were assessed every 3 months and peak urinary flow was assessed every 6 months. The primary end point at 2 years was the change in International Prostate Symptom Score from baseline. RESULTS: Combination therapy resulted in significantly greater improvements in symptoms vs dutasteride from month 3 and tamsulosin from month 9, and in benign prostatic hyperplasia related health status from months 3 and 12, respectively. There was a significantly greater improvement from baseline in peak urinary flow for combination therapy vs dutasteride and tamsulosin monotherapies from month 6. There was a significant increase in drug related adverse events with combination therapy vs monotherapies, although most did not result in the cessation of therapy. CONCLUSIONS: In men with moderate to severe lower urinary tract symptoms and prostate enlargement (30 cc or greater) combination therapy provides a significantly greater degree of benefit than tamsulosin or dutasteride monotherapy.

Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design.

Benign prostatic hyperplasia (BPH) is a highly prevalent condition in aging men, which can be progressive and lead to acute urinary retention (AUR) and the need for surgery. It is commonly treated with alpha-blockers and 5alpha-reductase inhibitors (5ARIs), both of which improve the symptoms of BPH. Long-term treatment with 5ARIs can also reduce the risk of developing AUR and the need for surgery. The landmark Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated that over 4 years the combination of the type 2-specific 5ARI, finasteride and the alpha-blocker doxazosin was more effective than either agent alone in reducing overall clinical progression. Since the initiation of MTOPS, it has been shown that patients with larger prostates and higher prostate-specific antigen (PSA) levels are at greater risk of BPH progression, and are therefore arguably more likely to benefit from combination therapy. The Combination of Avodart and Tamsulosin (CombAT) trial is a 4-year, global, multicenter, randomized, double-blind, parallel-group study designed to investigate the benefits of combination therapy with the dual 5ARI dutasteride and the alpha-blocker tamsulosin compared with each monotherapy in improving symptoms and long-term outcomes in men with moderate-to-severe symptoms of BPH and prostate enlargement. Symptoms and long-term outcomes (AUR and surgery) will be assessed as separate primary endpoints at 2 and 4 years, respectively. Eligible patients were at least 50 years old with prostate volume > or =30 cm(3) and PSA level > or =1.5 ng/mL. A total of 4838 subjects have been enrolled. This paper describes the rationale, design and baseline data of the CombAT study.

Long-term treatment with darifenacin for overactive bladder: results of a 2-year, open-label extension study.

OBJECTIVE: To examine, in a 2-year, non-comparative, open-label extension study, the safety, tolerability and efficacy of darifenacin controlled-release (CR) 7.5/15 mg once daily in patients with overactive bladder (OAB) who completed two 12-week randomized, double-blind, placebo-controlled 'feeder' studies. PATIENTS AND METHODS: Patients entering the extension received darifenacin 7.5 mg once daily for 2 weeks, after which a voluntary increase in dose to 15 mg was permitted. Thereafter, patients could adjust the dose (either 7.5 or 15 mg). Safety and tolerability were assessed from adverse events (AEs) and discontinuations. Efficacy was determined using various endpoints. RESULTS: In all, 716 patients entered the extension (mean age 57.3 years; 85.1% women) and 475 (66.3%) completed it (1089.9 patient-years of exposure). Darifenacin was well tolerated with no significant safety concerns. The most commonly reported AEs were dry mouth and constipation (all-causality rates 23.3% and 20.9%, respectively), leading to discontinuation in 1.3% and 2.4% of patients, respectively. Constipation infrequently required intervention, and analysis of bowel-habit questionnaires revealed that the reporting of constipation was related to minor changes in bowel habit rather than true constipation. The efficacy of darifenacin was maintained, including significant improvements in the number of incontinence episodes/week (median change -84.4% at 2 years, P < 0.001 vs feeder-study baseline). After 2 years, > 40% of patients achieved a > or = 90% reduction in incontinence episodes/week. CONCLUSION: In the first published 2-year, open-label study of a CR antimuscarinic agent, darifenacin 7.5/15 mg once daily had a favourable safety, tolerability and efficacy profile during the long-term treatment of OAB. As such, darifenacin represents a valuable therapeutic option for OAB.

Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5alpha-reductase inhibitor dutasteride: results of 4-year studies.

OBJECTIVE: To report additional analyses of efficacy over the initial 2 years and during a 2-year open-label extension of the three pivotal phase 3 studies in which dutasteride, a dual inhibitor of type 1 and 2 5alpha-reductase, was shown to be effective and well tolerated. PATIENTS AND METHODS: All patients in the placebo and active groups were eligible for entry into the 2-year open-label extension, with all receiving dutasteride 0.5 mg daily. Mean changes from baseline were calculated for the American Urologic Association Symptom Index (AUA-SI) score at each scheduled time in the double-blind and open-label phase. The additional analyses included a breakdown of the AUA-SI score, including stratifying patients by symptom severity, assessment by baseline age and prostate volume, and the evaluation of symptoms responders. RESULTS: There was a clinically meaningful improvement in AUA-SI in patients on dutasteride in the double-blind phase, but not in those on placebo. At 48 months, patients on dutasteride in both study phases had greater improvements in AUA-SI score and individual question scores than those on dutasteride in the open-label phase only. The proportion of patients with severe symptoms declined in both study groups, although these changes were more profound in those receiving dutasteride for the 4-year duration of the study. CONCLUSION: In men with symptomatic benign prostatic hyperplasia, long-term (4-year) treatment with the dual isozyme 5alpha-reductase inhibitor dutasteride resulted in sustained and continued improvements in symptoms and flow rate. For 4 vs 2 years, longer dutasteride therapy resulted in greater symptom improvement.

A multicenter, prospective, open-label study of tolterodine extended-release 4 mg for overactive bladder: the speed of onset of therapeutic assessment trial (STAT).

BACKGROUND: Antimuscarinic agents are the primary treatment for overactive bladder (OAB), but there is a lack of information regarding when maximum symptom relief and maximum perceived patient benefit occur. OBJECTIVE: This study assessed the speed of onset of therapeutic benefit with tolterodine extended-release (ER) 4 mg. METHODS: This 12-week, multicenter, prospective, open-label study enrolled patients with OAB who either had received no previous pharmacologic treatment for OAB (drug naive) or were receiving such treatment at enrollment (previously treated). Efficacy was assessed at 1, 4, and 12 weeks using a micturition diary and measures of patients' and physicians' perceptions of improvement. Safety was assessed in terms of adverse events and study withdrawals. RESULTS: The intent-to-treat population included 1138 patients (302 men, 836 women; 88.4% white; age range, 18-91 years), 735 drug naive and 403 receiving treatment for OAB at enrollment. After 1 week, tolterodine ER 4 mg had produced a significant improvement in all efficacy variables in both groups of patients (P < 0.01); 72% of the maximum effect on urge incontinence was observed in both groups; and 84.7% of drug-naive patients and 83.6% of previously treated patients perceived a benefit from treatment. After 4 weeks, drug-naive and previously treated patients reported a respective 93% and 100% of the maximum effect on episodes of urge incontinence. Tolterodine was well tolerated, with dry mouth (mostly mild) the most commonly reported adverse event (15.5% in each group). The 330 (81.9%) patients who had reported unacceptable efficacy and the 87 (21.6%) patients who had reported unacceptable tolerability of previous OAB treatment responded favorably to tolterodine ER 4 mg. CONCLUSIONS: Tolterodine ER 4 mg was effective and well tolerated in both drug-naive and previously treated patients with OAB. More than 80% of patients reported benefit from treatment after 1 week, but maximum symptom relief was achieved with longer treatment.