Conclusion. Keywords. The Authors BJU Int 2015; 116:

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1 Efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin treatment (Duodart ) compared with watchful waiting with initiation of tamsulosin therapy if symptoms do not improve, both provided with lifestyle advice, in the management of treatment-naïve men with moderately symptomatic benign prostatic hyperplasia: 2-year CONDUCT study results Claus G. Roehrborn, Igor Oyarzabal Perez*, Erik P.M. Roos, Nicolae Calomfirescu, Betsy Brotherton, Fang Wang, Juan Manuel Palacios**, Averyan Vasylyev and Michael J. Manyak Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, GlaxoSmithKline, Research Triangle Park, NC, USA, GlaxoSmithKline, King of Prussia, PA, USA, *Department of Urology, Mendaro Hospital, Gipuzkoa, Spain, Department of Urology, Antonius Hospital Sneek, Sneek, The Netherlands, Urology Clinic, Uroandromed, Bucharest, Romania, **Urology, Classic & Established Medicines, GlaxoSmithKline, Madrid, Spain, and Urology, Classic and Established Medicines, GlaxoSmithKline, London, UK Objective To investigate whether a fixed-dose combination (FDC) of 0.5 mg dutasteride and 0.4 mg tamsulosin is more effective than watchful waiting with protocol-defined initiation of tamsulosin therapy if symptoms did not improve (WW-All) in treatment-naïve men with moderately symptomatic benign prostatic hyperplasia (BPH) at risk of progression. Patients and Methods This was a multicentre, randomised, open-label, parallel-group study (NCT ) in 742 men with an International Prostate Symptom Score (IPSS) of 8 19, prostate volume 30 ml and total serum PSA level of 1.5 ng/ml. Patients were randomised to FDC (369 patients) or WW-All (373) and followed for 24 months. All patients were given lifestyle advice. The primary endpoint was symptomatic improvement from baseline to 24 months, measured by the IPSS. Secondary outcomes included BPH clinical progression, impact on quality of life (QoL), and safety. Results The change in IPSS at 24 months was significantly greater for FDC than WW-All ( 5.4 vs 3.6 points, P < 0.001). With FDC, the risk of BPH progression was reduced by 43.1% (P < 0.001); 29% and 18% of men in the WW-All and FDC groups had clinical progression, respectively, comprising symptomatic progression in most patients. Improvements in QoL (BPH Impact Index and question 8 of the IPSS) were seen in both groups but were significantly greater with FDC (P < 0.001). The safety profile of FDC was consistent with established profiles of dutasteride and tamsulosin. Conclusion FDC therapy with dutasteride and tamsulosin, plus lifestyle advice, resulted in rapid and sustained improvements in men with moderate BPH symptoms at risk of progression with significantly greater symptom and QoL improvements and a significantly reduced risk of BPH progression compared with WW plus initiation of tamsulosin as per protocol. Keywords benign prostatic hyperplasia, dutasteride, fixed-dose combination, lower urinary tract symptoms, tamsulosin, watchful waiting [Correction added on 13 February 2015 after first online publication: The trademark symbol for Duodart has been changed to a registered symbol] BJU Int 2015; 116: BJU International doi: /bju wileyonlinelibrary.com published by John Wiley & Sons Ltd on behalf of BJU International. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 2 year conduct study results Introduction In the primary care setting, 60% of men with symptomatic BPH have moderate LUTS at the time of diagnosis [1,2]. An ageing population, together with the global adoption of screening and diagnostic strategies, means the prevalence of BPH and impact of LUTS is likely to escalate [3,4]. BPH is defined by the presence of hyperplastic glands on pathological inspection of prostatic tissue. LUTS that are commonly attributed to BPH (e.g. increased urinary frequency, urgency, nocturia, decreased and intermittent force of stream, sensation of incomplete bladder emptying) are nonspecific and may result from a variety of other causes. However, the most important cause of LUTS is BOO, which may occur via two mechanisms. Firstly, an overgrowth of prostate tissue obstructs urinary flow and secondly, prostatic smooth muscle cells increase in number and tone to increase resistance to urinary flow in the urethra [5,6]. LUTS are assessed using the IPSS, with a score of 0 7 indicative of mild symptoms, 8 19 of moderate symptoms and of severe symptoms. BPH progression is characterised by an increase in LUTS over time and, in some men, serious outcomes such as acute urinary retention (AUR) and the need for surgery, most commonly TURP. Although TURP reduces LUTS in many cases, it can be associated with adverse events (AEs) including urinary incontinence and retrograde ejaculation [7,8]. The goals of BPH therapy are to decrease symptoms, improve quality of life (QoL), reduce BOO, decrease post-void residual urine volume, reverse urinary retention/renal insufficiency when present, and prevent disease progression [6]. For men with mild-to-moderate symptoms, sequential step-up therapy starting with watchful waiting (WW) and escalating to single or multiple medical therapies and, in some cases surgery, constitutes common clinical practice [9 13]. Men with bothersome moderate-to-severe LUTS who are at higher risk for disease progression (identified by a PSA level of >1.5 ng/ml and/or a prostate size of >30 40 ml) can be offered combined treatment with an α 1-adrenergic blocking agent (α-blocker) together with a 5α-reductase inhibitor (5ARI) [9,12 18]. Accumulating evidence also suggests phosphodiesterase type 5 (PDE5) inhibitors can affect bladder, prostate and urethra function to relieve LUTS associated with prostate hyperplasia; however, the exact mechanism by which PDE5 inhibitors exert their effect on urinary symptoms is not completely understood [19]. Overall, the most commonly used first-line agents are α-blockers, regardless of prostate size or serum PSA level [12,13]. Combined therapy with dutasteride (5ARI) and tamsulosin (α-blocker) was extensively investigated in the Combination of Avodart and Tamsulosin (CombAT) study [20 22]. However, after this study, several questions remain, including: how does combined therapy compare with other approaches commonly used in clinical practice; how does combined therapy perform in treatment-naïve men with more moderate symptoms (IPSS 8 12); and how quickly are the benefits of combined therapy experienced after treatment initiation? The CONDUCT study was initiated to investigate whether immediate treatment in eligible men with a fixed-dose combination (FDC) of 0.5 mg dutasteride and 0.4 mg tamsulosin offers faster and more profound symptom reduction than that offered by WW plus initiation of tamsulosin if symptoms did not improve. Patients and Methods Study Design The FDC (CONDUCT) study (GlaxoSmithKline; NCT ) was an international, multicentre, randomised, open-label, parallel-group Phase IV study conducted between December 2010 and October Eligible patients were randomised 1:1 to self-administer a fixed-dose, single-capsule combination of dutasteride 0.5 mg and tamsulosin 0.4 mg once daily (QD) (Duodart, GlaxoSmithKline), or to WW with initiation of tamsulosin 0.4 mg QD if any IPSS after randomisation was the same or greater than the baseline value (forthwith referred to as WW-All). Lifestyle advice about caffeine and alcohol avoidance, fluid management and bladder retraining was provided at baseline to patients in both treatment groups (Table 1) [23]. Patients visited the clinic 4 weeks after randomisation and at 13-week intervals thereafter, for up to 24 months. Patient-reported symptoms, symptom impact, BPH-related QoL, and treatment satisfaction were assessed using the IPSS, BPH Impact Index (BII) score, question 8 of the IPSS (IPSS-Q8; if you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that? ), and patient perception of study treatment (PPST) at every visit. The IPSS is a seven-item questionnaire that quantitatively measures the level of urinary symptoms reported as a total IPSS. The total IPSS can range from 0 to 35 and classifies BPH symptoms into mild (0 7), moderate (8 19), or severe (20 35). An additional, independent eighth question (IPSS-Q8) was added to assess self-perceived QoL and BPH-related health status. The IPSS-Q8 score ranges from 0 to 6 where 0 means delighted and 6 means terrible life. The BII is a four-item questionnaire that measures the impact of urinary problems on a subject s general sense of wellbeing in four domains of health: physical discomfort from urinary problems, worry about health because of urinary problems, bothersomeness of urinary symptoms and limitation of activities of daily living because of urinary problems. The total BII score ranges from 0 (no symptom impact) to 13 (significant symptom impact). The PPST questionnaire consists of two questions that assess a subject s perception and satisfaction with the effect of BJU International published by John Wiley & Sons Ltd on behalf of BJU International 451

3 Roehrborn et al. Table 1 Summary of lifestyle advice discussed over 30-min period with a nurse practitioner. Education Discuss the causes of LUTS, including normal prostate and bladder function Discuss the natural history of BPH and LUTS, including the expected future symptoms Fluid management Advise a daily fluid intake of ml (minor adjustments made for climate and activity), avoid inadequate or excessive intake on the basis of a frequency/volume chart Advise fluid restriction when symptoms are most inconvenient, e.g. long journeys or when out in public Advise evening fluid restriction for nocturia (no fluid for 2 h before retiring) Caffeine and alcohol Avoid caffeine by substituting with alternatives, e.g. decaffeinated or non-caffeinated drinks Avoid alcohol in the evening if nocturia is bothersome Substitute large volume alcoholic drinks, e.g. pint of beer, with small volume alcoholic drinks, e.g. spirits Types of toileting and bladder re-training Advise men to double-void Advise urethral milking for men with post-micturition dribble Advise bladder retraining. Using distraction techniques (predetermined mind exercise, perineal pressure or pelvic floor exercises) aim to increase the minimum time between voids to 3 h (daytime) and/or the minimum voided volume to between ml (daytime). The urge to void should be suppressed for 1 min, then 5 min, then 10min, increasing on a weekly basis. Use frequency/volume charts to monitor progress Miscellaneous Avoid constipation in men with LUTS study treatment on control of urinary symptoms. Question 1 was Overall, how satisfied are you with the treatment and its effect on your urinary problems?, and question 2 was Would you ask your doctor for the treatment you received in this study?. Question 1 was rated on a seven-point scale from very satisfied to very dissatisfied. Question 2 was rated on a three-point scale of yes, no or not sure. At baseline and months 12 and 24, patients underwent DRE, evaluation of gynaecomastia, blood chemistry analysis, haematology and PSA tests, and urine analysis by dipstick. Data on AEs were collected from the time of administration of the first study treatment dose until discontinuation. Written informed consent was obtained from each patient before the performance of any study-specific procedures. The study protocol was approved by a national, regional, or investigational centre ethics committee or Institutional Review Board in accordance with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use-Good Clinical Practice (ICH-GCP) and the ethical principles outlined in the Declaration of Helsinki Study Population Men aged 50 years, with a confirmed clinical diagnosis of BPH and moderate LUTS (IPSS of 8 19), prostate volume 30 ml by TRUS (at screening) and total serum PSA level of 1.5 ng/ml (at screening) were eligible for inclusion. Key exclusion criteria included: total serum PSA level of >10.0 ng/ml, history or evidence of prostate cancer, and any current or prior treatment related to BPH. Study Endpoints and Statistical Analyses The primary efficacy endpoint was the change in IPSS from baseline to month 24. Secondary efficacy endpoints included: categorical improvements in IPSS ( 2, 3 points or 25%) and the time to, and proportion of, patients with clinical progression of BPH [rise in total IPSS of 3 points compared with baseline, BPH-related AUR, recurrent UTI, overflow or urge incontinence or renal insufficiency (single 50% rise from baseline serum creatinine and total value 1.5 mg/dl)]. Health outcomes included change in BII score from baseline; rating of IPSS-Q8; and responses to two questions of the PPST questionnaire. The intent-to-treat population was the primary population for efficacy analyses and consisted of all randomised patients. Analyses of exposure to study drug, compliance to study drug, and AEs were performed in all patients receiving medical therapy (FDC or tamsulosin) as per protocol (treated population). The primary study comparison was 0.5 mg dutasteride and 0.4 mg tamsulosin (FDC group) vs WW with protocol-defined initiation of tamsulosin if symptoms did not improve (WW-All), for which the study was powered at 90%. Sample size estimates were computed assuming a normal distribution, mean difference between IPSS change from baseline of 1.6, a standard deviation (SD) of 6 and 0.05 level of significance. The value of 1.6 as a Δ between the FDC and WW-All groups was chosen based on previous experience. In men with an IPSS of in the CombAT study, the difference between the combination and monotherapy arms was 1.3 and 2.1 IPSS units at months 24 and 48, respectively. The Δ of 1.6 points represented an appropriate mid-point, allowing for a large proportion of men in the WW-All arm to convert to tamsulosin therapy. With a 20% discontinuation assumed by month 24, a minimum sample size of 370 per arm was required to ensure adequate power for last observation carried forward and at visit analyses. Data from patients in the WW-All group who did or did not initiate treatment with tamsulosin were supplemental and for descriptive purposes only. 452 BJU International published by John Wiley & Sons Ltd on behalf of BJU International

4 2 year conduct study results Change from baseline in IPSS, BII score and IPSS-Q8 was analysed according to last observation carried forward methodology. Mean scores were compared between treatment groups at each post-baseline visit using t-tests from a general linear model with effects for treatment, cluster, and baseline values at α=0.05. A log-rank test was used to compare time to first BPH clinical progression across groups, stratified by cluster at the 0.05 level of significance. Results Patient Disposition and Demographics In all, 742 patients from eight countries were randomised into the study (recruitment period December 2010 to October 2011), 369 and 373 in the FDC and WW-All groups, respectively. Of these, 292 (79%) and 300 (80%) completed 24 months of treatment (Fig. 1). Baseline characteristics were similar between groups and indicative of a population with a moderate symptom burden at risk of progression (Table 2). In the WW-All group, 229 (61%) patients were administered tamsulosin according to protocol-defined criteria, usually within the first 6 months (190, 83%). Deterioration of IPSS from baseline was the most common reason for starting tamsulosin (158, 69%). In all, 57 (25%) men began tamsulosin due to no change in IPSS from baseline and 14 (6%) began tamsulosin in error upon an improvement in IPSS. An analysis of the effects of baseline covariates on starting tamsulosin showed only age and BII at baseline were significantly associated with starting tamsulosin as per protocol, with odds ratios of 1.04 (P = 0.010) and 1.17 (P = 0.005), respectively. Primary Efficacy Endpoint The adjusted mean decrease in IPSS at each post-baseline visit over 24 months was significantly greater with FDC than with WW-All, with a significant difference already observed by month 1 (P < 0.001; Fig. 2A). At month 24, the mean change in IPSS was 5.4 with combined therapy vs 3.6 points with WW-All (P < 0.001, 95% CI 2.5, 1.2). Considering IPSS score at each visit, all patients in the FDC group had a mean IPSS indicative of mild symptoms (<8) by month 9, whereas the symptoms of patients in the WW-All group remained moderate (8 19) throughout the study (Fig. 2B). Secondary Efficacy Endpoints Categorical changes in IPSS Categorical changes in IPSS were significantly greater at month 24 with FDC than with WW-All, with IPSS improving by 3 points or 25% in 77% vs 64% and 73% vs 60% patients, respectively (P < 0.001). Fig. 1 Participant flow diagram. Randomise (n = 742) Allocation Allocation to fixed-dose combination (n = 369) Allocation to watchful waiting with initiation of tamsulosin if symptoms did not improve (n = 373) Follow-up Lost to follow-up (n = 7) Discontinued intervention due to: Adverse event (n = 28) Lack of efficacy (n = 7) Protocol violation (n = 1) Investigator discretion (n = 6) Subject withdrew consent (n = 28) Lost to follow-up (n = 9) Discontinued intervention due to: Adverse event (n = 13) Lack of efficacy (n = 5) Protocol violation (n = 7) Investigator discretion (n = 11) Subject withdrew consent (n = 28) Analysis Intention-to-treat population used for efficacy analyses (n = 369) Treated population used for analysis of adverse events (n = 369) Intention-to-treat population used for efficacy analyses (n = 373) Treated population used for analysis of adverse events (n = 229) BJU International published by John Wiley & Sons Ltd on behalf of BJU International 453

5 Roehrborn et al. Table 2 Baseline characteristics. Variable Mean (SD) FDC of dutasteride and tamsulosin (n = 369) WW-All* (n = 373) Age, years 66.3 (7.78) 66.2 (7.34) Weight, kg (12.55) (12.63) Body mass index, kg/m (3.53) (3.77) Time since first LUTS, years 3.8 (4.06) 3.7 (3.94) Time since BPH diagnosis, years 2.7 (3.63) 2.5 (3.69) PSA level, ng/ml 3.9 (2.00) 3.7 (1.91) IPSS 13.2 (4.06) 12.9 (3.95) Prostate volume, ml 51.0 (18.17) 52.6 (19.57) BII score 4.8 (2.75) 4.4 (2.64) IPSS-Q8 3.2 (1.15) 3.0 (1.20) *WW with initiation of tamsulosin if symptoms did not improve. Both treatment arms received lifestyle advice. A Adjusted mean change in IPSS Fixed dose combination of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin if symptoms did not improve (n = 373) P < Fig. 2 (A) The mean change from baseline in IPSS at each study visit. (B) the mean IPSS at each study visit Months from randomisation B Fixed dose combination of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin if symptoms did not improve (n = 373) Mean IPSS Months from randomisation Clinical progression By month 24, 29% of men in the WW-All group had clinical progression compared with 18% of men in the FDC group. Combined therapy significantly reduced the relative risk of clinical progression by 43.1% (95% CI 22.5, 58.2) when compared with WW-All (P < 0.001), with an absolute risk reduction (risk difference) of 11.3% (Fig. 3). In both groups, symptom progression (rise in total IPSS of 3 points from baseline) was the most common component of BPH clinical progression, occurring in 16% and 27% of men in the FDC and WW-All groups, respectively (Table 3). 454 BJU International published by John Wiley & Sons Ltd on behalf of BJU International

6 2 year conduct study results Table 3 BPH clinical progression. FDC of dutasteride and tamsulosin (n = 369) WW-All* (n = 373) Incidence, n (%) 65 (18) 108 (29) 95% CI 13.7, , 33.6 P value vs WW-All <0.001 Patients with BPH clinical progression component (any occurrence), n (%; 95% CI) Symptom progression 60 (16; 12.5, 20.0) 102 (27; 22.8, 31.9) BPH-related AUR 3 (<1; 0.0, 1.7) 10 (3; 1.0, 4.3) BPH-related urinary incontinence 4 (1; 0.0, 2.1) 3 (<1; 0.0, 1.7) BPH-related UTI 2 (<1; 0.0, 1.3) 6 (2; 0.3, 2.9) BPH-related renal insufficiency 0 1 (<1; 0.0, 0.8) *WW with initiation of tamsulosin if symptoms did not improve. Both treatment arms received lifestyle advice. Fig. 3 Proportion of men with BPH clinical progression over the study period. Subjects with progression, % Fixed dose combination of dutasteride and tamsulosin WW with initiation of tamsulosin if symptoms did not improve 43.1% relative risk reduction (P < 0.001) 11.3% absolute risk reduction Number of events/subjects at risk 48/369 94/373 29% 18% 17/276 14/251 Health Outcomes (BII Score, IPSS-Q8 and PPST) The adjusted mean decrease in BII and IPSS-Q8 at each post-baseline visit over 24 months was significantly greater with FDC than with WW-All, with significant differences observed by month 1 and all post-baseline assessments thereafter (P < 0.001; Fig. 4). At month 24, the mean change in BII was 2.4 with combined therapy vs 1.6 points with WW-All (P < 0.001, 95% CI 1.2, 0.5). Respective changes in IPSS-Q8 were 1.5 vs 1.1 (P < 0.001, 95% CI 0.6, 0.2), indicating that more patients in the FDC group were willing to spend the rest of their lives with the symptoms they had at the time of analysis. At month 24, the proportion of patients who expressed any satisfaction with study treatment or were willing to ask the doctor for study treatment (questions 1 and 2 of the PPST questionnaire, respectively) was similar between the FDC and WW-All groups (question 1: 87% and 86%, respectively; question 2: 68% and 65%). For both questions, the proportion of patients with a positive response at month 1 was significantly higher in the FDC group than the WW-All group (P < 0.001); statistically significant differences (P < 0.05) in favour of the FDC group were also seen at months 3 and 6 for question 1 and month 3 for question 2. Safety and Tolerability AEs were monitored in all patients receiving FDC (369 patients) and who started treatment with tamsulosin (229). The mean overall exposure for these groups was days and days, respectively. The most commonly reported AEs across both groups were erectile dysfunction and retrograde ejaculation, which occurred in 8% vs 0% and 5% vs 4% patients in the FDC and tamsulosin groups, respectively (Table 4). The occurrence of drug-related AEs, serious AEs, or AEs leading to study/drug discontinuation was greater in the FDC group. Breast disorder AEs occurred in 2% of men in the FDC group but were not considered serious. The proportion of patients with any cardiovascular AE of special interest and with cardiac failure was 1.9% (seven patients) and 0.8% (three) in the FDC group and 2.6% (six) and 0.4% (one) in the tamsulosin group, respectively. There was a mean percentage decrease in total PSA level from baseline in the FDC group, but an increase among patients who started tamsulosin: month 6 ( 45.2% vs 1.8%) and month 24 ( 48.5% vs 20.1%). Prostate cancer was reported in one patient in the WW-All group and no men in the FDC group. Three patients in the WW-All group, including two who started tamsulosin, died; neither death was considered related to treatment. Discussion The CONDUCT study was the first to investigate the single-capsule combination of dutasteride and tamsulosin in men with moderate symptoms of BPH at risk of progression [1,24]. Restricting the study population to men with moderate symptoms was based on the understanding that, especially in an open-label study, men with severe symptoms should ideally receive active intervention at the time of diagnosis rather than have a delay of at least 4 weeks before initiation. The inclusion criterion of an IPSS score of 8 19 targets men with moderate symptoms and is thought to reflect the breadth of men commonly seen in general and urological practice. In an BJU International published by John Wiley & Sons Ltd on behalf of BJU International 455

7 Roehrborn et al. A Adjusted mean change from baseline BII Fixed dose combination of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin if symptoms did not improve (n = 373) P < Fig. 4 The mean change from baseline in BII score (A) and IPSS-Q8 (B) at each study visit Months from randomisation B Question 8 of IPSS Adjusted mean change from baseline Fixed dose combination of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin if symptoms did not improve (n = 373) P < Months from randomisation earlier randomised study in 4844 men aged 50 years with moderate-to-severe BPH symptoms (the CombAT study), long-term combined therapy with dutasteride plus tamsulosin resulted in a greater degree of symptom reduction, a lower risk of clinical progression, and improved QoL compared with either agent alone [20,21]. CombAT enrolled men with more severe symptoms of BPH (IPSS of 12 to 35) [21]. Consequently, nearly 50% of men included in the CONDUCT study would have been ineligible for inclusion in the CombAT study because of a baseline IPSS of Both studies provide important insight into the long-term use of combined therapy relating to impact on symptoms, side-effect profile, clinical progression and QoL. Results from the CONDUCT study show that, in combination with lifestyle advice, immediate intervention with dutasteride plus tamsulosin provides more profound symptomatic improvement than that offered by WW with initiation of tamsulosin if there is no improvement in symptoms. Superior symptomatic improvement and improved health outcomes were seen as early as month 1 and sustained throughout the 24-month treatment period, suggesting that early intervention with FDC therapy results in the rapid relief of urinary symptoms and has a greater positive impact on health-related QoL. The adjusted mean difference in IPSS at month 24 (1.8 units) was statistically significant. Considering the adjusted mean change in IPSS from baseline at month 24, the change with FDC therapy (5.4 units) would be considered as a moderate improvement in symptoms by patients. By comparison, patients would consider a change of 3.6 units (as seen in the WW-All group) to be a slight improvement [25]. The proportion of patients with a clinically meaningful improvement in symptoms of 3 points or 25% [26] was significantly higher at all time-points with FDC compared with WW-All. The lack of a placebo control group is a potential limitation of the present study. Although treatment guidelines recommend that men with moderate-to-severe LUTS usually require treatment with medical therapy, the control arm (WW plus lifestyle advice plus initiation of tamsulosin if symptoms do not improve) is recognised as a clinical approach for some 456 BJU International published by John Wiley & Sons Ltd on behalf of BJU International

8 2 year conduct study results Table 4 Extent of exposure and summary of AEs occurring after randomisation (treated population). FDC of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin (n = 229) Years of patient exposure* Patients, n (%): Any AE ( 3% patients in any group) 190 (51) 95 (41) AE leading to discontinuation of study drug 27 (7) 11 (5) AE leading to withdrawal from study 27 (7) 11 (5) Drug-related AEs ( 2% patients in any group) Any 87 (24) 23 (10) Erectile dysfunction 29 (8) 0 Retrograde ejaculation 18 (5) 9 (4) Dizziness 9 (2) 4 (2) Decreased libido 9 (2) 0 Ejaculation disorder 6 (2) 0 Loss of libido 6 (2) 0 Vertigo 6 (2) 0 Serious AEs ( 2 patients in any group) Any 38 (10) 19 (8) Respiratory tract infection 4 (1) 2 (<1) Atrial fibrillation 1 (<1) 2 (<1) Cellulitis 2 (<1) 0 Diverticulitis 0 1 (<1) Inguinal hernia 2 (<1) 0 Presyncope 2 (<1) 0 Prostatitis 1 (<1) 1 (<1) Colon cancer 0 2 (<1) Prostate cancer 0 1 (<1) *Years of patient exposure is the sum of study drug exposure (days) across patients for each treatment group, divided by 365 days. Both treatment arms received lifestyle advice. Patients could have more than one AE. patients at risk of progression, and was therefore chosen to enable comparison of FDC with a group that is representative of a real-life clinical approach. As lifestyle modification has been shown to significantly improve LUTS, failure to improve was considered an appropriate trigger for implementing tamsulosin therapy in the WW-All group. Although the criteria for escalation to tamsulosin (no improvement in symptoms from baseline) may not represent typical clinical practice, they were specified to avoid statistical noise and atypical practice, such as the introduction of active medication despite an improvement in symptoms. Physicians may choose to escalate from WW to α-blockers, 5ARI, phytotherapy, antimuscarinics, or combinations of these [27,28]. In the present study, escalation to tamsulosin was chosen to represent real-life clinical practice based on data from >2300 newly-diagnosed patients in six European countries showing that tamsulosin was the most commonly prescribed drug in all countries [12]. This finding was supported by an analysis of data from a large integrated healthcare delivery system that was performed to provide a better estimate of the real-world management of LUTS. In this analysis of nearly new cases of LUTS, 58% men underwent WW and 42% received medical therapy within the first 3 months of diagnosis. Of men receiving medical therapy, nearly 80% received monotherapy with an α-blocker [13]. The possibility that escalation to an alternative drug, such as dutasteride or FDC, would have led to more profound symptomatic improvement than tamsulosin, however, requires further consideration. Over the 2-year treatment period, combined therapy significantly reduced the risk of clinical progression by 43.1% compared with WW-All. This finding is similar to the 44.1% risk reduction seen when comparing combined therapy with tamsulosin monotherapy over a 4-year period in the CombAT study [20 22]. Clinical progression in the CombAT study was defined as deterioration in the IPSS symptom score of 4 points. However, as patients in CONDUCT had lower symptom scores at baseline, the threshold for clinical progression was lower ( 3 IPSS points). This, together with the similar risk reduction seen in CONDUCT over a shorter period, suggests early intervention with FDC therapy could reduce the long-term risk of symptomatic progression in men with moderate-to-severe LUTS. Additionally, with need for further intervention lessened, the burden on healthcare systems and practitioners may be reduced. The effects of combined therapy can be explained by the synergistic mechanisms of action of the component drugs [29]. Tamsulosin relaxes the smooth muscle tissue in the prostate and bladder neck, allowing urine to flow more freely. Treatment provides a relatively rapid improvement of LUTS but has no effect on prostate growth. Dutasteride blocks the production of dihydrotestosterone, the metabolic driver of prostate growth. This impedes the development of symptoms related to prostatic overgrowth and, consequently, the incidence of AUR and prostate-related surgery. BJU International published by John Wiley & Sons Ltd on behalf of BJU International 457

9 Roehrborn et al. Further investigation into the characteristics of patients who do or do not progress, together with an understanding of the pharmacological activity of different treatments, may help guide treatment decisions in future. Results from the Symptom Management after Reducing Therapy (SMART-1) study, for example, showed that the symptomatic relief provided by dutasteride plus tamsulosin in patients with BPH at risk of disease progression was maintained in most patients when tamsulosin was removed from the combination after 24 weeks [30]. Investigating whether the single-capsule FDC formulation of dutasteride and tamsulosin is required to maintain symptomatic control in the long term, or if tapering to monotherapy with either dutasteride or tamsulosin would be sufficient, is therefore a potential area of future research. Lifestyle factors, such as obesity, physical activity and diet, can have an impact on urinary symptoms in men with BPH [31]. All patients in CONDUCT were provided lifestyle advice; however, as the extent to which the advice was incorporated or adhered to is unknown, no definitive conclusions can be made and further studies on the effect of lifestyle advice on patient outcomes are required. The safety profile of FDC therapy was similar to that reported in other studies of dutasteride and tamsulosin in combination, including CombAT [21,30]. The most common drug-related AEs in either group were those affecting sexual function. The proportion of patients with sexual AEs was highest during the first 6 months of therapy, and diminished over the course of either treatment. The observed imbalance in the proportion of patients with drug-related AEs, serious AEs, and AEs leading to study drug discontinuation or withdrawal from the study was not unexpected. Ejaculatory dysfunction, for example, is an established, low-incidence AE of α-blockers and 5ARIs, although probably through different mechanisms. The distinct mechanisms of action of dutasteride and tamsulosin may therefore account for the increased rate of AEs related to sexual dysfunction seen in the present study [14,32]. Furthermore, exposure to the study drug (in patient years) was almost twice as high in the combined therapy group as in the step-up group. Overall, the risks with FDC are well-characterised and manageable. As FDC provides symptomatic relief and decreases the rate of progression to AUR and surgery in men with moderate LUTS, the benefit risk profile can be considered favourable but should be carefully assessed in each patient before treatment. In conclusion, the 2-year data from the CONDUCT study provide support for the long-term use of dutasteride and tamsulosin combined therapy in men with moderate LUTS due to BPH and prostatic enlargement who are at increased risk of progression. The safety of the FDC was consistent with the established safety profiles of dutasteride and tamsulosin when prescribed individually as monotherapy and when co-administered. Acknowledgements Medical writing support was provided by Spirit Medical Communications, funded by GlaxoSmithKline. The authors thank the following investigators and their patients for participating in the study. France: Abdel-Rahmène Azzouzi, Alain Boye, Christian Duroy, Daniel Bonneau, Gildas Ganuchaid, Gwendal Hulot De Collart, Jacques Tondut, Jean-Marc Aroun, Jérôme Basle, Jérôme Tondut, Loïc Boucher, Michel Lambert, Nicolas Tournemine, Patrick Muller, Philippe Igigabel, Pierre Leroy, Pierre André Ferrand, Robert Arnou, Thierry Schaupp. Germany: Christian Girke, Christian von Ostau, Detlef Quast, Hans-Carsten Braun, Joachim Dubiel, Joerg Willgerodt, Klaus Scheunpflug, Maren Schwickardi-Jerrentrup, Rainer Klammert, Ralk Eckert, Tilo Koettig, Wolf-Christian Hagel, Wolfgang Warnack. Greece: Anastasios Thanos, Andreas Skolarikos, Apostolos Apostolidis, Athanasios Papathanasiou, Georgios Moutzouris, Harilaos, Katsifotis, Michael Melekos, Nikolaos Papandreou, Panagiotis Kalafitis, Pteros Perimenis. Italy: Cesare Selli, Francesco Montorsi, Giuseppe Carrieri, Luigi Schips, Mauro Frongia, Paolo Gontero, Vincenzo Gentile, Vincenzo Mirone, Virgilio Cicalese.The Netherlands: Arnoldus G.H. Geboers, Hendrik A. Dirkse, Hendrikus G.M. Mevissen, Jos L Bruins. Romania: Ioan Ioiart, Marius Dinu, Viorel Jinga. Spain: Javier Angulo Cuesa, Javier Extraniana, Javier Garcia Penit, Jose Martinez Javaloyas, José A. Gallego Sánchez, José María Del Rosal Samaniego, MªJose Requena Tapia, Manuel Fernández Arjona, Manuel Montesino. UK: Ramesh Corbarsanellore, Jonathan McFarlane, M. Naeem Akhtar, Neil Paul. Conflicts of Interest C.G.R. has served as a consultant for GlaxoSmithKline. B.B., F.W., J.M.P., A.V and M.J.M. are all paid employees of GlaxoSmithKline and as such, have historically received stock options. N.C. s institution (Uroandromed) received monetary compensation from Pfizer, Lilly and Astellas for board membership and lectures; Pfizer, Sanofi and GlaxoSmithKline for consultancy work, and from Sanofi, GlaxoSmithKline, Storz and Angelini for lectures. I.O.P and E.P.M.R. have no conflicts of interest to declare. References 1 Carballido J, Fourcade R, Pagliarulo A et al. Can benign prostatic hyperplasia be identified in the primary care setting using only simple tests? Results of the Diagnosis IMprovement in PrimAry Care Trial. Int J Clin Pract 2011; 65: Carballido J, Brenes F, Boye A, Pagliarulo A, Sessa A, Castro R. 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Claus.roehrborn@utsouthwestern.edu Abbreviations: α-blocker, α 1-adrenergic blocking agent; AE, adverse events; 5ARI, 5α-reductase inhibitor; AUR, acute urinary retention; BII, BPH Impact Index; CombAT, the Combination of Avodart and Tamsulosin (study); FDC, fixed-dose combinationn; IPSS-Q8, question 8 of the IPSS; PDE5, phosphodiesterase type 5; PPST, patient perception of study treatment; QD, once daily; QoL, quality of life; WW, watchful waiting. BJU International published by John Wiley & Sons Ltd on behalf of BJU International 459