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.     

Long-term therapy with the dual 5alpha-reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia

OBJECTIVE: To examine the long-term (4-year) safety and tolerability of dutasteride in the treatment of symptomatic benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Patients who completed the double-blind phase of three dutasteride Phase III studies were eligible to enter a 2-year open-label extension, during which all patients received dutasteride 0.5 mg. Safety was assessed, including adverse-event reporting, clinical laboratory assessments, yearly physical examinations, and vital sign assessments. RESULTS: In all, 2340 patients entered the open-label phase, 1188 of whom previously received dutasteride during the double-blind phase of the study. The most common drug-related adverse events (occurring in > or = 1%) were effects on sexual function, which decreased with a longer duration of therapy. Gynaecomastia was reported in a small percentage of men throughout the 4-year study period. The incidence of individual sexual functional adverse events that led to withdrawal was < or = 1% (0.3-1.0%) during the 4-year study period. Dutasteride had no relevant effects on vital signs or clinical laboratory variables. CONCLUSION: These data show that dutasteride is well tolerated during long-term use for the treatment of symptomatic BPH.     

Efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia

Objectives:   To assess the efficacy and safety of dutasteride in Japanese men with benign prostatic hyperplasia (BPH).
Methods:   This was a randomized, double-blind, placebo-controlled, parallel-group study. A total of 378 subjects with clinical BPH having an International Prostate Symptom Score (IPSS) of 8 points or greater, a prostate volume of 30 mL or greater, and a maximal urinary flow rate (Qmax) of 15 mL/s or less were randomized to receive placebo or dutasteride once daily for 52 weeks. Subjects were stratified according to tamsulosin use at baseline. The numbers of subjects with and without tamsulosin use were 242 and 136, respectively. IPSS, Qmax, prostate volume and drug safety were evaluated.
Results:   Continued improvement in IPSS was noted in the dutasteride group, and dutasteride significantly decreased IPSS compared with placebo. At week 52, dutasteride significantly improved Qmax and prostate volume compared with placebo. Drug-related sexual function events in the dutasteride group were infrequent and generally were not treatment limiting.
Conclusions:   Dutasteride improves urinary symptoms and flow rate and reduces prostate volume. In Japanese men with BPH, it is effective and generally well tolerated during the one-year treatment period.     

Symptom-specific quality of life in patients with benign prostatic hyperplasia

BACKGROUND: We investigated which factors are most bothersome to preoperative patients with benign prostatic hyperplasia (BPH). METHODS: A total of 423 newly diagnosed patients and 388 preoperative patients with symptomatic BPH were evaluated. International prostate symptom score (IPSS) and IPSS quality-of-life (QOL) assessment score were used for assessment of symptoms and symptom-specific QOL of the patients with BPH. Uroflow variables were measured in all patients. Other objective variables such as prostate volume, transition zone volume, Schaefer's obstruction grade, and detrusor pressure at maximal urinary flow were evaluated in 209 preoperative patients. We analyzed the relationships between symptom-specific QOL and other variables. Statistical analyses were performed using Spearman's correlation coefficient and a stepwise linear regression model. RESULTS: Symptom-specific QOL scores had moderate to good correlation with IPSS (P < 0.0001; r = 0.525-0.560). Filling symptom subscore had a slightly greater impact on symptom-specific QOL than voiding subscore in both groups of patients. Weak stream, feeling of incomplete emptying, and nocturia significantly decreased symptom-specific QOL in both groups of patients. While newly diagnosed patients suffered from frequency as well, urgency had the strongest impact on symptom-specific QOL of preoperative patients. Objectively measurable variables had no association with symptom-specific QOL. CONCLUSION: Japanese patients with BPH generally suffer from weak stream, feeling of incomplete emptying, and nocturia in all disease phases. Frequency is problematic for newly diagnosed patients and urgency is problematic for preoperative patients as well. Symptom-specific QOL of BPH patients cannot be estimated by physically measurable variables.     

前列腺增生患者生命质量测定量表QLICD-BPH研制中的条目筛选

目的研制前列腺增生患者生命质量测定量表特异性模块。方法采用议题小组和核心小组的程序化决策方式及借鉴国内外建立量表的经验制定本量表,通过定性访谈和定量调查分析相结合的方法对条目进行初筛选、评价和修改形成初步量表,随机抽取25例前列腺增生患者和25名医务工作者进行问卷调查,采用变异度法、相关系数法、因子分析法、患者重要性评分法及医生重要性评法对结果进行分析。结果采用上述5种方法分别选出16、16、15、14、16个条目,综合各种方法最后得出包含16个条目的特异模块。结论该特异模块的条目均按严格的程序筛选得出,具有较好的内容效度和代表性。     

Clinical usefulness of serum prostate specific antigen for the detection of prostate cancer is preserved in men receiving the dual 5alpha-reductase inhibitor dutasteride

PURPOSE: We determined whether the decrease in serum PSA seen with 5alpha-reductase inhibitors affects the clinical usefulness of PSA for prostate cancer screening using data from 2 dutasteride benign prostatic hyperplasia studies. MATERIALS AND METHODS: A total of 2,802 men 50 years or older with a clinical diagnosis of benign prostatic hyperplasia, no history of prostate cancer, PSA 1.5 to 10 ng/ml, prostate volume 30 cc or greater, an American Urological Association symptom score of 12 or greater and peak urinary flow rate 15 ml per second or less were randomized to 0.5 mg dutasteride daily or matching placebo for 24 months. Increases in PSA from baseline and the maximum increase from nadir to month 24 were compared between the groups and analyzed by prostate cancer status, as determined by PSA driven biopsy and an advised cutoff of more than 4 ng/ml after doubling to correct for dutasteride treatment with sensitivity and specificity calculated for each. RESULTS: In placebo treated men without prostate cancer there was an 8.3% median increase in PSA at month 24 compared with -59.5% in those who received dutasteride, using doubled values to correct for dutasteride treatment. In those with prostate cancer these changes were 23.8% and -37.2%, respectively. Using the upper PSA limit of 4 ng/ml sensitivity for prostate cancer in men receiving dutasteride vs placebo was 0.737 vs 0.804, while specificity was 0.671 vs 0.578. Using a PSA increase from nadir of 0.8 ng/ml the sensitivity of dutasteride was 0.548 and its specificity was 0.795. CONCLUSIONS: A doubling factor is effective for maintaining the sensitivity and specificity of PSA for prostate cancer detection in men on dutasteride. Increases in serum PSA in men receiving dutasteride should be considered suspicious and serial PSA measurements should be used to evaluate changes from nadir.     

Effect of the dual 5α‐reductase inhibitor,dutasteride, on serum testosterone and body mass index in men with benign prostatic hyperplasia

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To investigate the effects of dutasteride on serum testosterone level and body mass index (BMI) in men who received medical therapy for benign prostatic hyperplasia (BPH).

PATIENTS AND METHODS

In all, 120 patients with BPH were randomized to three treatment groups: tamsulosin 0.2 mg/day (α‐blocker group), dutasteride 0.5 mg/day (dutasteride group), or tamsulosin 0.2 mg plus dutasteride 0.5 mg/day (combination group) for 1 year. For all patients the BMI and serum testosterone levels were checked at baseline and after 1 year of treatment.

RESULTS

Among the evaluable 107 patients, the dutasteride (33) and combination groups (37) had significantly greater increases in serum testosterone level (16.3% and 15%, respectively) than the α‐blocker group (37; 0.3%) after 1 year of treatment (both P < 0.001). When analysed by baseline serum testosterone tertile, the increases in serum testosterone level among the dutasteride and combination group were greatest in the lowest tertile. For BMI, the dutasteride and combination group had mean decreases of 0.17 and 0.20 kg/m², respectively, at 1 year, whereas the α‐blocker group had a mean increase of 0.04 kg/m². The decreases in BMI for the dutasteride and combination group were statistically significant only in the lowest tertile (P = 0.048 and 0.010, respectively).

CONCLUSION

Our results show that dutasteride treatment in men with BPH led to a significant increase in serum testosterone level and a significant decrease in BMI among those with relatively lower baseline serum testosterone levels.     

度他雄胺治疗良性前列腺增生的研究进展

良性前列腺增生(BPH)是中老年男性的常见病。目前,以5α还原酶抑制剂为主的药物治疗已经替代传统的经尿道前列腺切除术,成为多数BPH患者的首选治疗方案。本文就一种新型的5α还原酶抑制剂——度他雄胺对治疗BPH的研究进展进行综述。     

The efficacy and safety of dutasteride and finasteride in patients with benign prostatic hyperplasia: a systematic review and meta-analysis

BackgroundAlthough the efficacy and safety of monotherapy in the treatment of benign prostatic hyperplasia (BPH) have been established clinically, the efficacy and safety of dutasteride and finasteride have not been compared. The aim was to systematically evaluate the efficacy and safety of the two drugs in the treatment of BPH to provide medical evidence for clinical treatment.MethodsA search of relevant articles was conducted using the electronic databases PubMed, Embase, Medline, Cochrane Library, China Academic Journals Full-text Database (CJFD), Chinese Science and Technology Journal Database (VIP) and Wanfang Database. Randomized controlled trials (RCTs) comparing the efficacy of finasteride (control group) with that of dutasteride (experimental group) in the treatment of BPH with respect to the International Prostate Symptom Score (IPSS), the maximum urinary flow rate (Qmax), prostate volume (PV), quality of life (QOL), serum prostate-specific antigen (PSA) level and adverse drug reactions (ADRs) after medication were strictly evaluated and considered for inclusion. Rev Man 5.4 software was used for the meta-analysis.ResultsA total of 8 RCTs were included, with a total of 2,116, patients. The meta-analysis showed that compared with finasteride, dutasteride can effectively improve the Qmax of patients with BPH [mean difference (MD) =0.32; 95% confidence interval (CI): (0.01, 0.63); P=0.04]. There was no significant difference in reducing IPSS [MD =0.13; 95% CI: (−0.55, 0.82); P=0.70], improving PV [MD =−1.25; 95% CI: (−3.30, 0.79); P=0.23], reducing QOL [MD =−0.44; 95% CI: (−0.93, 0.05); P=0.08] and serum PSA level [MD =−0.04; 95% CI: (−0.15, 0.07); P=0.50], and the occurrence of ADRs [relative risk (RR) =−0.01; 95% CI: (−0.05, 0.04); P=0.72], there was no significant difference.DiscussionDutasteride is better than finasteride in improving the Qmax of patients with BPH. There was no statistically significant difference in symptoms, PV, PSA, QOL, or adverse reactions. Dutasteride is an effective and safe treatment for BPH. Due to the limitations of the methodological quality and sample size of the included studies, this conclusion needs to be verified by stratified RCTS with high volumes and long follow-up times.     

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.     

Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice

OBJECTIVE: To assess the improvements in symptoms, quality of life (QoL), discomfort and satisfaction in patients with symptomatic benign prostatic hyperplasia (BPH) treated with dutasteride in clinical practice. PATIENTS AND METHODS: In a prospective, multicentre open-label study, we evaluated the efficacy and safety in clinical practice of dutasteride, 0.5 mg/day for 24 weeks, in patients with symptomatic BPH. The primary endpoint was the proportion of patients achieving at least a 3-point decrease from baseline in the International Prostate Symptom Score (IPSS) after 24 weeks of treatment. The secondary endpoints included changes from baseline in measures of QoL (IPSS item 8 and BPH Impact Index score, BII), and patient discomfort and satisfaction (visual analogue scales, VAS) at 12 and 24 weeks. RESULTS: Of the 366 patients assessed, 72.5% achieved at least a 3-point reduction in IPSS at 24 weeks; the IPSS decreased from 15.3 at baseline to 10.2 at 12 weeks, and to 9.1 at 24 weeks. There were significant (P < 0.001) decreases in all the individual IPSS items at 12 and 24 weeks, with more marked improvements in voiding symptoms than storage symptoms. There were also significant (P < 0.001) improvements in the BII and VAS scores for patient discomfort and satisfaction at both times. CONCLUSIONS: Dutasteride treatment for 24 weeks significantly improved BPH symptoms, QoL and patient discomfort and satisfaction, and was well tolerated in clinical practice.     

Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS)

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Both dutasteride and finasteride inhibit type 2 5α‐reductase, the dominant form of 5α‐reductase in benign prostatic tissue, making these effective treatments for BPH. In comparison with finasteride, dutasteride has a longer half‐life and leads to a greater and more consistent suppression of serum and intraprostatic DHT. EPICS is currently the only prospective, randomized, double‐blind study of finasteride vs dutasteride for BPH endpoints conducted for longer than a few months. Over a one‐year period, treatment with dutasteride and finasteride led to similar reductions in prostate volume, and improvements in peak urine flow and urinary symptoms associated with BPH in men with an enlarged prostate. Men treated with finasteride and dutasteride also experienced similar rates of adverse events over the course of one year, which suggests that inhibition of both type 1 and type 2 5α‐reductase, resulting in greater DHT suppression than type 2 inhibition alone, does not confer an increase in adverse events. Given the long‐term, progressive nature of BPH, the one‐year duration of EPICS may limit the potential to observe major differences between dutasteride and finasteride treatment.

OBJECTIVE

• ? To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months.

PATIENTS AND METHODS

• ? The Enlarged Prostate International Comparator Study was a multicentre, randomized, double‐blind, 12‐month, parallel‐group study.
• ? Men aged ≥50 years with a clinical diagnosis of BPH received once‐daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4‐week placebo run‐in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24‐month, open‐label phase, during which patients received dutasteride 0.5 mg once daily.
• ? The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA‐SI) scores, improvement in maximum urinary flow rate (Q_max) and long‐term safety in the 24‐month open‐label phase.

RESULTS

• ? Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study.
• ? Similar reductions in mean AUA‐SI scores and Q_max were also observed for men in both treatment groups.
• ? A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open‐label phase.

CONCLUSION

• ? Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Q_max and urinary symptoms associated with BPH in men with an enlarged prostate.

     

Effects of Bowman-Birk inhibitor concentrate (BBIC) in patients with benign prostatic hyperplasia

BACKGROUND: The Bowman-Birk inhibitor is a soybean-derived protease inhibitor that has anti-inflammatory and anticarcinogenic activities. METHODS: A Phase I trial of Bowman-Birk inhibitor concentrate (BBIC) in 19 male subjects with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) has been performed. RESULTS: The results of the trial indicated that there was no dose-limiting toxicity of BBIC. There was a statistically significant decrease in serum PSA levels in all BBIC-treated patients. Some BBIC-treated patients exhibited a relatively large reduction in serum PSA levels, ranging up to a 43% reduction. There was also a statistically significant decrease in serum triglyceride levels and a decrease in prostate volume in the treated patients. The scores recorded in response to a urinary symptom questionnaire indicated improved urinary activities in the BBIC-treated patients; however, the control subjects exhibited similar improvements in urinary activities during the course of the trial. CONCLUSIONS: The data obtained in this trial, particularly the data suggesting that BBIC treatment may lead to reduced serum PSA levels and reduced prostate volumes, suggest that a Phase II clinical trial of BBIC for the therapy of BPH is warranted.     

Impact of interventional therapy for benign prostatic hyperplasia on quality of life and sexual function: a prospective study

PURPOSE: Treatment for benign prostatic hyperplasia (BPH), including minimally invasive therapy, can impair the quality of life. We prospectively determined the impact of 4 different interventional therapies on quality of life and sexual function. MATERIALS AND METHODS: A total of 173 patients were prospectively evaluated between February 1995 and August 1997. Treatment modalities consisted of standard transurethral resection of the prostate in 55 cases, transurethral microwave thermotherapy in 34, interstitial laser coagulation of the prostate in 42 and transurethral needle ablation in 42. Disease specific quality of life was assessed using the International Prostate Symptom Score quality of life assessment index and BPH impact index. In addition, a self-reporting questionnaire was completed before and 3 months after treatment to determine the impact on sexual function. RESULTS: All 4 treatment groups showed significant improvement in the symptom score, International Prostate Symptom Score quality of life assessment score and BPH impact index score. Satisfaction with treatment was highest in patients treated with transurethral resection or laser coagulation. A mild to moderate decrease in erectile function was noted in 26.5%, 18.2%, 18.4% and 20.0% of the transurethral resection, microwave thermotherapy, laser coagulation and needle ablation groups, respectively, but there was no significant difference of mean pretreatment and posttreatment erectile function or libido scores in any group. Ejaculation loss or severe decrease in ejaculate volume was reported by 48.6%, 28.1%, 21.6% and 24.3% of the patients, respectively. Interestingly, 20 of the 44 patients (45. 5%) with loss of ejaculation or severe decrease in ejaculate reported deterioration of the sex life, while only 2 (3.6%) of the 56 without any change in ejaculate volume reported such deterioration. The association of ejaculatory dysfunction with an adverse impact on sexual activity was highly significant (p <0.0001). CONCLUSIONS: Significant improvement in quality of life could be achieved with the present assessed interventional therapies. There was no significant change in sexual desire or erectile function with these therapies. Posttreatment sexual dysfunction appears to be mainly related to impaired ejaculatory function. Urologists should provide proper counseling regarding the possibility of this complication even in patients receiving minimally invasive treatment.     

症状性良性前列腺增生患者生活质量分析

目的了解伴下尿路症状（LUTS）的良性前列腺增生（BPH）患者的生活质量.方法88例具有典型LUTS的BPH患者,平均年龄68岁.患者治疗前均行国际前列腺症状评分（IPSS）、勃起功能国际问卷（IIEF-5）、简明性功能问卷（BSFI）、焦虑自评量表、老年抑郁量表和BPH影响指数问卷（BII）调查,同时检测尿流率、前列腺体积和血清睾酮.应用多元逐步回归分析方法和一元相关回归分析方法评价各检测变量间的相关性.结果统计学分析显示：年龄与BSFI中勃起功能和IIEF-5有显著相关性（r=-0.552和r=-0.567,P=0.000）,IPSS评分与年龄有显著相关性（r=0.213,P=0.047）,BII与年龄无明显相关性.IPSS评分与BSFI中勃起功能和满意度有显著相关性（r=-0.332,P=0.002;r=0.302,P=0.005）,IPSS与BII间有显著相关性（r=0.420,P=0.000）.BII与抑郁评分间有显著相关性（r=0.426,P=0.002）.最大尿流率、前列腺体积和睾酮与BII评分间无明显相关性.结论LUTS对BPH患者的日常生活、性功能和心理有明显影响,BPH治疗前需重视老年患者的心理和生活质量.     

Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia

OBJECTIVE: The objective of this paper is to examine safety and tolerability data from a number of recently completed clinical trials with the novel, dual 5alpha-reductase inhibitor, dutasteride.METHODS: Intent-to-treat analyses were conducted on data for dutasteride 0.5 mg/day for drug-related adverse events, clinical laboratory test results, and prostate-specific antigen (PSA) levels derived from four large, randomised, double-blind clinical trials (n=5655). Further data were derived from a randomised, double-blind combination study of dutasteride 0.5 mg/day and tamsulosin 0.4 mg/day (n=327), and several safety studies conducted in healthy volunteers. RESULTS: Data from two-year blinded clinical studies demonstrate that dutasteride is well tolerated, with a profile comparable with that of placebo. The exception is a modestly elevated incidence of impotence, decreased libido, ejaculation disorders, and gynaecomastia. Clinical laboratory test abnormalities were reported by <1% of patients treated with dutasteride, and abnormal values occurred with similar frequency versus placebo-treated patients. In a healthy volunteer study, when dutasteride was administered daily for 1 year, it did not significantly affect bone metabolism markers, bone mineral density or lipid profiles. Dutasteride reduced total serum PSA concentrations by approximately 50% following 6, 12, and 24 months of treatment but had no effect on free-to-total PSA levels. The safety profile of dutasteride did not differ from that of finasteride in a large, parallel-group, comparator trial. Additionally, when dutasteride was used in combination with an alpha(1)-blocker, the drug-related adverse event profiles were as would be expected for the individual agents. CONCLUSIONS: Considered together, these data demonstrate dutasteride to be well-tolerated.