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Efficacy and safety of a fixeddose 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 treatmentnave men with moderately symptomatic benign prostatic hyperplasia: 2year conduct study results

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 TrianglePark, 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 andEstablished Medicines, GlaxoSmithKline, London, UK With FDC, the risk of BPH progression was reduced by To investigate whether a fixed-dose combination (FDC) of 43.1% (P < 0.001); 29% and 18% of men in the WW-All 0.5 mg dutasteride and 0.4 mg tamsulosin is more effective and FDC groups had clinical progression, respectively, than watchful waiting with protocol-defined initiation of comprising symptomatic progression in most patients.
tamsulosin therapy if symptoms did not improve (WW-All) in Improvements in QoL (BPH Impact Index and question 8 of treatment-naïve men with moderately symptomatic benign the IPSS) were seen in both groups but were significantly prostatic hyperplasia (BPH) at risk of progression.
greater with FDC (P < 0.001). The safety profile of FDC wasconsistent with established profiles of dutasteride and Patients and Methods This was a multicentre, randomised, open-label, parallel-groupstudy (NCT01294592) in 742 men with an International Prostate Symptom Score (IPSS) of 8–19, prostate volume FDC therapy with dutasteride and tamsulosin, plus lifestyle ≥30 mL and total serum PSA level of ≥1.5 ng/mL. Patients advice, resulted in rapid and sustained improvements in men were randomised to FDC (369 patients) or WW-All (373) and with moderate BPH symptoms at risk of progression with followed for 24 months. All patients were given lifestyle significantly greater symptom and QoL improvements and a advice. The primary endpoint was symptomatic improvement significantly reduced risk of BPH progression compared with from baseline to 24 months, measured by the IPSS. Secondary WW plus initiation of tamsulosin as per protocol.
outcomes included BPH clinical progression, impact onquality of life (QoL), and safety.
benign prostatic hyperplasia, dutasteride, fixed-dose The change in IPSS at 24 months was significantly greater combination, lower urinary tract symptoms, tamsulosin, for FDC than WW-All (–5.4 vs −3.6 points, P < 0.001).
2015 The AuthorsBJU International 2015 BJU International doi:10.1111/bju.13033 BJU Int 2015 Published by John Wiley & Sons Ltd. www.bjui.org Roehrborn et al.
commonly used in clinical practice; how does combined In the primary care setting, ≈ 60% of men with symptomatic therapy perform in treatment-naïve men with more moderate BPH have moderate LUTS at the time of diagnosis [1,2]. An symptoms (IPSS 8–12); and how quickly are the benefits of ageing population, together with the global adoption of combined therapy experienced after treatment initiation? screening and diagnostic strategies, means the prevalence of The CONDUCT study was initiated to investigate whether BPH and impact of LUTS is likely to escalate [3,4].
immediate treatment in eligible men with a fixed-dosecombination (FDC) of 0.5 mg dutasteride and 0.4 mg BPH is defined by the presence of hyperplastic glands on tamsulosin offers faster and more profound symptom pathological inspection of prostatic tissue. LUTS that are reduction than that offered by WW plus initiation of commonly attributed to BPH (e.g. increased urinary frequency, tamsulosin if symptoms did not improve.
urgency, nocturia, decreased and intermittent force of stream,sensation of incomplete bladder emptying) are nonspecific andmay result from a variety of other causes. However, the most Patients and Methods important cause of LUTS is BOO, which may occur via two mechanisms. Firstly, an overgrowth of prostate tissue obstructsurinary flow and secondly, prostatic smooth muscle cells The FDC114615 (CONDUCT) study (GlaxoSmithKline; increase in number and tone to increase resistance to urinary NCT01294592) was an international, multicentre, randomised, flow in the urethra [5,6]. LUTS are assessed using the IPSS, with open-label, parallel-group Phase IV study conducted between a score of 0–7 indicative of mild symptoms, 8–19 of moderate December 2010 and October 2013. Eligible patients were symptoms and 20–35 of severe symptoms.
randomised 1:1 to self-administer a fixed-dose, single-capsulecombination of dutasteride 0.5 mg and tamsulosin 0.4 mg BPH progression is characterised by an increase in LUTS over once daily (QD) (Duodart™, GlaxoSmithKline), or to WW time and, in some men, serious outcomes such as acute with initiation of tamsulosin 0.4 mg QD if any IPSS after urinary retention (AUR) and the need for surgery, most randomisation was the same or greater than the baseline value commonly TURP. Although TURP reduces LUTS in many (forthwith referred to as WW-All). Lifestyle advice about cases, it can be associated with adverse events (AEs) including caffeine and alcohol avoidance, fluid management and bladder urinary incontinence and retrograde ejaculation [7,8].
retraining was provided at baseline to patients in bothtreatment groups (Table 1) [23].
The goals of BPH therapy are to decrease symptoms, improvequality of life (QoL), reduce BOO, decrease post-void residual Patients visited the clinic 4 weeks after randomisation and at urine volume, reverse urinary retention/renal insufficiency 13-week intervals thereafter, for up to 24 months.
when present, and prevent disease progression [6]. For men Patient-reported symptoms, symptom impact, BPH-related with mild-to-moderate symptoms, sequential step-up therapy QoL, and treatment satisfaction were assessed using the IPSS, starting with watchful waiting (WW) and escalating to single BPH Impact Index (BII) score, question 8 of the IPSS or multiple medical therapies and, in some cases surgery, (IPSS-Q8; ‘if you were to spend the rest of your life with constitutes common clinical practice [9–13]. Men with your urinary condition just the way it is now, how would bothersome moderate-to-severe LUTS who are at higher risk you feel about that?'), and patient perception of study for disease progression (identified by a PSA level of treatment (PPST) at every visit. The IPSS is a seven-item >1.5 ng/mL and/or a prostate size of >30–40 mL) can be questionnaire that quantitatively measures the level of offered combined treatment with an α urinary symptoms reported as a total IPSS. The total IPSS 1-adrenergic blocking agent (α-blocker) together with a 5α-reductase inhibitor can range from 0 to 35 and classifies BPH symptoms into (5ARI) [9,12–18]. Accumulating evidence also suggests mild (0–7), moderate (8–19), or severe (20–35). An phosphodiesterase type 5 (PDE5) inhibitors can affect bladder, additional, independent eighth question (IPSS-Q8) was prostate and urethra function to relieve LUTS associated with added to assess self-perceived QoL and BPH-related health prostate hyperplasia; however, the exact mechanism by which status. The IPSS-Q8 score ranges from 0 to 6 where 0 means PDE5 inhibitors exert their effect on urinary symptoms is not ‘delighted' and 6 means ‘terrible' life. The BII is a four-item completely understood [19]. Overall, the most commonly used questionnaire that measures the impact of urinary problems first-line agents are α-blockers, regardless of prostate size or on a subject's general sense of wellbeing in four domains of serum PSA level [12,13].
health: physical discomfort from urinary problems, worryabout health because of urinary problems, bothersomeness of Combined therapy with dutasteride (5ARI) and tamsulosin urinary symptoms and limitation of activities of daily living (α-blocker) was extensively investigated in the Combination because of urinary problems. The total BII score ranges from of Avodart and Tamsulosin (CombAT) study [20–22].
0 (no symptom impact) to 13 (significant symptom impact).
However, after this study, several questions remain, including: The PPST questionnaire consists of two questions that assess how does combined therapy compare with other approaches a subject's perception and satisfaction with the effect of 2015 The Authors 2 BJU International 2015 BJU International
2-year conduct study results 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 symptomsFluid management• Advise a daily fluid intake of 1500–2000 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. spiritsTypes 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 200–400 mL (daytime). The urge to void should be suppressed for 1 min, then 5 min, then 10 min,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 and the time to, and proportion of, patients with clinical was ‘Overall, how satisfied are you with the treatment and its progression of BPH [rise in total IPSS of ≥3 points compared effect on your urinary problems?', and question 2 was ‘Would with baseline, BPH-related AUR, recurrent UTI, overflow or you ask your doctor for the treatment you received in this urge incontinence or renal insufficiency (single ≥50% rise study?'. Question 1 was rated on a seven-point scale from from baseline serum creatinine and total value ≥1.5 mg/dL)].
‘very satisfied' to ‘very dissatisfied'. Question 2 was rated on a Health outcomes included change in BII score from baseline; three-point scale of ‘yes', ‘no' or ‘not sure'.
rating of IPSS-Q8; and responses to two questions of the PPSTquestionnaire.
At baseline and months 12 and 24, patients underwent DRE,evaluation of gynaecomastia, blood chemistry analysis, The intent-to-treat population was the primary population for haematology and PSA tests, and urine analysis by dipstick.
efficacy analyses and consisted of all randomised patients.
Data on AEs were collected from the time of administration of Analyses of exposure to study drug, compliance to study drug, the first study treatment dose until discontinuation.
and AEs were performed in all patients receiving medicaltherapy (FDC or tamsulosin) as per protocol (treated Written informed consent was obtained from each patient before the performance of any study-specific procedures. Thestudy protocol was approved by a national, regional, or The primary study comparison was 0.5 mg dutasteride and investigational centre ethics committee or Institutional Review 0.4 mg tamsulosin (FDC group) vs WW with Board in accordance with International Conference on protocol-defined initiation of tamsulosin if symptoms did Harmonisation of Technical Requirements for Registration of not improve (WW-All), for which the study was powered at Pharmaceuticals for Human Use-Good Clinical Practice 90%. Sample size estimates were computed assuming a (ICH-GCP) and the ethical principles outlined in the normal distribution, mean difference between IPSS change Declaration of Helsinki 2008.
from baseline of 1.6, a standard deviation (SD) of 6 and 0.05level of significance. The value of 1.6 as a Δ between the FDC and WW-All groups was chosen based on previous Men aged ≥50 years, with a confirmed clinical diagnosis of experience. In men with an IPSS of 12−20 in the CombAT BPH and moderate LUTS (IPSS of 8–19), prostate volume study, the difference between the combination and ≥30 mL by TRUS (at screening) and total serum PSA level of monotherapy arms was 1.3 and 2.1 IPSS units at months 24 ≥1.5 ng/mL (at screening) were eligible for inclusion. Key and 48, respectively. The Δ of 1.6 points represented an exclusion criteria included: total serum PSA level of appropriate mid-point, allowing for a large proportion of >10.0 ng/mL, history or evidence of prostate cancer, and any men in the WW-All arm to convert to tamsulosin therapy.
current or prior treatment related to BPH.
With a 20% discontinuation assumed by month 24, aminimum sample size of 370 per arm was required to ensure Study Endpoints and Statistical Analyses adequate power for last observation carried forward and at The primary efficacy endpoint was the change in IPSS from visit analyses. Data from patients in the WW-All group who baseline to month 24. Secondary efficacy endpoints included: did or did not initiate treatment with tamsulosin were categorical improvements in IPSS (≥2, ≥ 3 points or ≥25%) supplemental and for descriptive purposes only.
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Change from baseline in IPSS, BII score and IPSS-Q8 was tamsulosin in error upon an improvement in IPSS. An analysis analysed according to last observation carried forward of the effects of baseline covariates on starting tamsulosin methodology. Mean scores were compared between treatment showed only age and BII at baseline were significantly groups at each post-baseline visit using t-tests from a general associated with starting tamsulosin as per protocol, with odds linear model with effects for treatment, cluster, and baseline ratios of 1.04 (P = 0.010) and 1.17 values at α = 0.05. A log-rank test was used to compare time (P = 0.005), respectively.
to first BPH clinical progression across groups, stratified bycluster at the 0.05 level of significance.
Primary Efficacy Endpoint The adjusted mean decrease in IPSS at each post-baseline visit over 24 months was significantly greater with FDC than withWW-All, with a significant difference already observed by Patient Disposition and Demographics month 1 (P < 0.001; Fig. 2A). At month 24, the mean change In all, 742 patients from eight countries were randomised into in IPSS was −5.4 with combined therapy vs −3.6 points with the study (recruitment period December 2010 to October WW-All (P < 0.001, 95% CI −2.5, −1.2). Considering IPSS 2011), 369 and 373 in the FDC and WW-All groups, score at each visit, all patients in the FDC group had a mean respectively. Of these, 292 (79%) and 300 (80%) completed 24 IPSS indicative of mild symptoms (<8) by month 9, whereas months of treatment (Fig. 1). Baseline characteristics were the symptoms of patients in the WW-All group remained similar between groups and indicative of a population with a moderate (8–19) throughout the study (Fig. 2B).
moderate symptom burden at risk of progression (Table 2).
Secondary Efficacy Endpoints In the WW-All group, 229 (61%) patients were administered Categorical changes in IPSS tamsulosin according to protocol-defined criteria, usuallywithin the first 6 months (190, 83%). Deterioration of IPSS Categorical changes in IPSS were significantly greater at from baseline was the most common reason for starting month 24 with FDC than with WW-All, with IPSS improving tamsulosin (158, 69%). In all, 57 (25%) men began tamsulosin by ≥3 points or ≥25% in 77% vs 64% and 73% vs 60% patients, due to no change in IPSS from baseline and 14 (6%) began respectively (P < 0.001).
Fig. 1 Participant flow diagram.
Randomise (n = 742) Allocation to watchful waiting with Allocation to fixed-dose initiation of tamsulosin if symptoms combination (n = 369) did not improve (n = 373) Lost to follow-up (n = 7) Lost to follow-up (n = 9) Discontinued intervention due to: Discontinued intervention due to: • Adverse event (n = 28) • Adverse event (n = 13) • Lack of efficacy (n = 7) • Lack of efficacy (n = 5) • Protocol violation (n = 1) • Protocol violation (n = 7) • Investigator discretion (n = 6) • Investigator discretion (n = 11) • Subject withdrew consent (n = 28) • Subject withdrew consent (n = 28) Intention-to-treat population used Intention-to-treat population used for efficacy analyses (n = 369) for efficacy analyses (n = 373) Treated population used for analysis Treated population used for analysis of adverse events (n = 369) of adverse events (n = 229) 2015 The Authors 4 BJU International 2015 BJU International
2-year conduct study results Table 2 Baseline characteristics.
Mean (SD)
FDC of dutasteride and tamsulosin
(n = 369)
(n = 373)
Body mass index, kg/m2 Time since first LUTS, years Time since BPH diagnosis, years Prostate volume, mL *WW with initiation of tamsulosin if symptoms did not improve. Both treatment arms received lifestyle advice. Fig. 2 (A) The mean change from baseline in IPSS
Fixed dose combination of dutasteride and tamsulosin (n = 369) at each study visit. (B) the mean IPSS at each study
WW with initiation of tamsulosin if symptoms did not improve (n = 373) P < 0.001 Adjusted mean change in IPSS –5 Months from randomisation Fixed dose combination of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin if symptoms did not improve (n = 373) Months from randomisation Clinical progression compared with WW-All (P < 0.001), with an absolute riskreduction (risk difference) of 11.3% (Fig. 3). In both groups, By month 24, 29% of men in the WW-All group had clinical symptom progression (rise in total IPSS of ≥3 points from progression compared with 18% of men in the FDC group.
baseline) was the most common component of BPH clinical Combined therapy significantly reduced the relative risk of progression, occurring in 16% and 27% of men in the FDC clinical progression by 43.1% (95% CI 22.5, 58.2) when and WW-All groups, respectively (Table 3).
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Table 3 BPH clinical progression.
FDC of dutasteride and
tamsulosin (n = 369)
(n = 373)
P value vs WW-All 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) 3 (<1; 0.0, 1.7) BPH-related urinary incontinence 3 (<1; 0.0, 1.7) 2 (<1; 0.0, 1.3) BPH-related renal insufficiency 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
favour of the FDC group were also seen at months 3 and 6 for question 1 and month 3 for question 2.
Fixed dose combination of dutasteride and tamsulosin Safety and Tolerability WW with initiation of tamsulosin if symptomsdid not improve AEs were monitored in all patients receiving FDC (369patients) and who started treatment with tamsulosin (229).
The mean overall exposure for these groups was 639.8 daysand 566.3 days, respectively. The most commonly reportedAEs across both groups were erectile dysfunction and retrograde ejaculation, which occurred in 8% vs 0% and 5% vs 43.1% relative risk reduction (P < 0.001) 4% patients in the FDC and tamsulosin groups, respectively Subjects with progression, % 11.3% absolute risk reduction (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 Number of events/subjects at risk FDC group but were not considered serious. The proportion of patients with any cardiovascular AE of special interest andwith cardiac failure was 1.9% (seven patients) and 0.8% (three) Health Outcomes (BII Score, IPSS-Q8 and PPST) in the FDC group and 2.6% (six) and 0.4% (one) in the The adjusted mean decrease in BII and IPSS-Q8 at each tamsulosin group, respectively. There was a mean percentage post-baseline visit over 24 months was significantly greater decrease in total PSA level from baseline in the FDC group, with FDC than with WW-All, with significant differences but an increase among patients who started tamsulosin: observed by month 1 and all post-baseline assessments month 6 (–45.2% vs −1.8%) and month 24 (–48.5% vs 20.1%).
thereafter (P < 0.001; Fig. 4). At month 24, the mean change in Prostate cancer was reported in one patient in the WW-All BII was −2.4 with combined therapy vs −1.6 points with group and no men in the FDC group. Three patients in the WW-All (P < 0.001, 95% CI −1.2, −0.5). Respective changes in WW-All group, including two who started tamsulosin, died; IPSS-Q8 were −1.5 vs −1.1 (P < 0.001, 95% CI −0.6, −0.2), neither death was considered related to treatment.
indicating that more patients in the FDC group were willing to spend the rest of their lives with the symptoms they had at The CONDUCT study was the first to investigate the the time of analysis.
single-capsule combination of dutasteride and tamsulosin in At month 24, the proportion of patients who expressed any men with moderate symptoms of BPH at risk of progression satisfaction with study treatment or were willing to ask the [1,24]. Restricting the study population to men with moderate doctor for study treatment (questions 1 and 2 of the PPST symptoms was based on the understanding that, especially in questionnaire, respectively) was similar between the FDC and an open-label study, men with severe symptoms should ideally WW-All groups (question 1: 87% and 86%, respectively; receive active intervention at the time of diagnosis rather than question 2: 68% and 65%). For both questions, the proportion have a delay of at least 4 weeks before initiation. The inclusion of patients with a positive response at month 1 was criterion of an IPSS score of 8−19 targets men with moderate significantly higher in the FDC group than the WW-All group symptoms and is thought to reflect the breadth of men (P < 0.001); statistically significant differences (P < 0.05) in commonly seen in general and urological practice. In an 2015 The Authors 6 BJU International 2015 BJU International
2-year conduct study results Fig. 4 The mean change from baseline in BII
score (A) and IPSS-Q8 (B) at each study visit.
Fixed dose combination of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin if symptoms did not improve (n = 373) P < 0.001 Adjusted mean change from baseline Months from randomisation Question 8 of IPSS Fixed dose combination of dutasteride and tamsulosin (n = 369) WW with initiation of tamsulosin if symptoms did not improve (n = 373) P < 0.001 Adjusted mean change from baseline Months from randomisation earlier randomised study in 4844 men aged ≥50 years with 24-month treatment period, suggesting that early intervention moderate-to-severe BPH symptoms (the CombAT study), with FDC therapy results in the rapid relief of urinary long-term combined therapy with dutasteride plus tamsulosin symptoms and has a greater positive impact on health-related resulted in a greater degree of symptom reduction, a lower QoL. The adjusted mean difference in IPSS at month 24 (1.8 risk of clinical progression, and improved QoL compared with units) was statistically significant. Considering the adjusted either agent alone [20,21]. CombAT enrolled men with more mean change in IPSS from baseline at month 24, the change severe symptoms of BPH (IPSS of ≥12 to 35) [21].
with FDC therapy (5.4 units) would be considered as a Consequently, nearly 50% of men included in the CONDUCT moderate improvement in symptoms by patients. By study would have been ineligible for inclusion in the CombAT comparison, patients would consider a change of 3.6 units (as study because of a baseline IPSS of 8–12. Both studies provide seen in the WW-All group) to be a slight improvement [25].
important insight into the long-term use of combined therapy The proportion of patients with a clinically meaningful relating to impact on symptoms, side-effect profile, clinical improvement in symptoms of ≥3 points or ≥25% [26] was progression and QoL.
significantly higher at all time-points with FDC comparedwith WW-All.
Results from the CONDUCT study show that, in combinationwith lifestyle advice, immediate intervention with dutasteride The lack of a placebo control group is a potential limitation of plus tamsulosin provides more profound symptomatic the present study. Although treatment guidelines recommend improvement than that offered by WW with initiation of that men with moderate-to-severe LUTS usually require tamsulosin if there is no improvement in symptoms. Superior treatment with medical therapy, the control arm (WW plus symptomatic improvement and improved health outcomes lifestyle advice plus initiation of tamsulosin if symptoms do were seen as early as month 1 and sustained throughout the not improve) is recognised as a clinical approach for some 2015 The Authors BJU International 2015 BJU International 7
Roehrborn et al.
Table 4 Extent of exposure and summary of AEs occurring after randomisation (treated population).
FDC of dutasteride and
WW with initiation of
tamsulosin (n = 369)
tamsulosin (n = 229)
Years of patient exposure* Patients, n (%):Any AE (≥3% patients in any group) AE leading to discontinuation of study drug AE leading to withdrawal from study Drug-related AEs (≥2% patients in any group) Erectile dysfunction Retrograde ejaculation Ejaculation disorder Serious AEs (≥2 patients in any group) Respiratory tract infection Atrial fibrillation *Years of patient exposure is the sum of study drug exposure (days) across patients for each treatment group, divided by365 days. Both treatment arms received lifestyle advice. Patients could have more than one AE. patients at risk of progression, and was therefore chosen to Over the 2-year treatment period, combined therapy enable comparison of FDC with a group that is representative significantly reduced the risk of clinical progression by of a real-life clinical approach. As lifestyle modification has 43.1% compared with WW-All. This finding is similar been shown to significantly improve LUTS, failure to improve to the 44.1% risk reduction seen when comparing combined was considered an appropriate trigger for implementing therapy with tamsulosin monotherapy over a 4-year period tamsulosin therapy in the WW-All group. Although the in the CombAT study [20–22]. Clinical progression in the criteria for escalation to tamsulosin (no improvement in CombAT study was defined as deterioration in the IPSS symptoms from baseline) may not represent typical clinical symptom score of ≥4 points. However, as patients in practice, they were specified to avoid statistical noise and CONDUCT had lower symptom scores at baseline, the atypical practice, such as the introduction of active medication threshold for clinical progression was lower (≥3 IPSS points).
despite an improvement in symptoms. Physicians may choose This, together with the similar risk reduction seen in to escalate from WW to α-blockers, 5ARI, phytotherapy, CONDUCT over a shorter period, suggests early intervention antimuscarinics, or combinations of these [27,28]. In the with FDC therapy could reduce the long-term risk of present study, escalation to tamsulosin was chosen to symptomatic progression in men with moderate-to-severe represent real-life clinical practice based on data from >2300 LUTS. Additionally, with need for further intervention newly-diagnosed patients in six European countries showing lessened, the burden on healthcare systems and practitioners that tamsulosin was the most commonly prescribed drug in all may be reduced.
countries [12]. This finding was supported by an analysis ofdata from a large integrated healthcare delivery system that The effects of combined therapy can be explained by the was performed to provide a better estimate of the real-world synergistic mechanisms of action of the component drugs management of LUTS. In this analysis of nearly 400 000 new [29]. Tamsulosin relaxes the smooth muscle tissue in the cases of LUTS, 58% men underwent WW and 42% received prostate and bladder neck, allowing urine to flow more freely.
medical therapy within the first 3 months of diagnosis. Of Treatment provides a relatively rapid improvement of LUTS men receiving medical therapy, nearly 80% received but has no effect on prostate growth. Dutasteride blocks the monotherapy with an α-blocker [13]. The possibility that production of dihydrotestosterone, the metabolic driver of escalation to an alternative drug, such as dutasteride or FDC, prostate growth. This impedes the development of symptoms would have led to more profound symptomatic improvement related to prostatic overgrowth and, consequently, the than tamsulosin, however, requires further consideration.
incidence of AUR and prostate-related surgery.
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2-year conduct study results Further investigation into the characteristics of patients who do or do not progress, together with an understanding of the Medical writing support was provided by Spirit Medical pharmacological activity of different treatments, may help Communications, funded by GlaxoSmithKline.
guide treatment decisions in future. Results from theSymptom Management after Reducing Therapy (SMART-1) The authors thank the following investigators and their study, for example, showed that the symptomatic relief patients for participating in the study. France: Abdel-Rahmène provided by dutasteride plus tamsulosin in patients with BPH Azzouzi, Alain Boye, Christian Duroy, Daniel Bonneau, Gildas at risk of disease progression was maintained in most patients Ganuchaid, Gwendal Hulot De Collart, Jacques Tondut, when tamsulosin was removed from the combination after 24 Jean-Marc Aroun, Jérôme Basle, Jérôme Tondut, Loïc Boucher, weeks [30]. Investigating whether the single-capsule FDC Michel Lambert, Nicolas Tournemine, Patrick Muller, Philippe formulation of dutasteride and tamsulosin is required to Igigabel, Pierre Leroy, Pierre André Ferrand, Robert Arnou, maintain symptomatic control in the long term, or if tapering Thierry Schaupp. Germany: Christian Girke, Christian von to monotherapy with either dutasteride or tamsulosin would Ostau, Detlef Quast, Hans-Carsten Braun, Joachim Dubiel, be sufficient, is therefore a potential area of future research.
Joerg Willgerodt, Klaus Scheunpflug, MarenSchwickardi-Jerrentrup, Rainer Klammert, Ralk Eckert, Tilo Lifestyle factors, such as obesity, physical activity and diet, can Koettig, Wolf-Christian Hagel, Wolfgang Warnack. Greece: have an impact on urinary symptoms in men with BPH [31].
Anastasios Thanos, Andreas Skolarikos, Apostolos Apostolidis, All patients in CONDUCT were provided lifestyle advice; Athanasios Papathanasiou, Georgios Moutzouris, Harilaos, however, as the extent to which the advice was incorporated Katsifotis, Michael Melekos, Nikolaos Papandreou, Panagiotis or adhered to is unknown, no definitive conclusions can be Kalafitis, Pteros Perimenis. Italy: Cesare Selli, Francesco made and further studies on the effect of lifestyle advice on Montorsi, Giuseppe Carrieri, Luigi Schips, Mauro Frongia, patient outcomes are required.
Paolo Gontero, Vincenzo Gentile, Vincenzo Mirone, VirgilioCicalese. The Netherlands: Arnoldus G.H. Geboers, Hendrik A.
The safety profile of FDC therapy was similar to that reported Dirkse, Hendrikus G.M. Mevissen, Jos L Bruins. Romania: Ioan in other studies of dutasteride and tamsulosin in combination, Ioiart, Marius Dinu, Viorel Jinga. Spain: Javier Angulo Cuesa, including CombAT [21,30]. The most common drug-related Javier Extraniana, Javier Garcia Penit, Jose Martinez Javaloyas, AEs in either group were those affecting sexual function. The José A. Gallego Sánchez, José María Del Rosal Samaniego, proportion of patients with sexual AEs was highest during the MªJose Requena Tapia, Manuel Fernández Arjona, Manuel first 6 months of therapy, and diminished over the course of Montesino. UK: Ramesh Corbarsanellore, Jonathan McFarlane, either treatment. The observed imbalance in the proportion of M. Naeem Akhtar, Neil Paul.
patients with drug-related AEs, serious AEs, and AEs leadingto study drug discontinuation or withdrawal from the study Conflicts of Interest was not unexpected. Ejaculatory dysfunction, for example, isan established, low-incidence AE of α-blockers and 5ARIs, C.G.R. has served as a consultant for GlaxoSmithKline.
although probably through different mechanisms. The distinct B.B., F.W., J.M.P., A.V and M.J.M. are all paid employees of mechanisms of action of dutasteride and tamsulosin may GlaxoSmithKline and as such, have historically received stock 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 N.C.'s institution (Uroandromed) received monetary almost twice as high in the combined therapy group as in the compensation from Pfizer, Lilly and Astellas for board step-up group. Overall, the risks with FDC are membership and lectures; Pfizer, Sanofi and GlaxoSmithKline well-characterised and manageable. As FDC provides for consultancy work, and from Sanofi, GlaxoSmithKline, symptomatic relief and decreases the rate of progression to Storz and Angelini for lectures.
AUR and surgery in men with moderate LUTS, the I.O.P and E.P.M.R. have no conflicts of interest to declare.
benefit–risk profile can be considered favourable but shouldbe carefully assessed in each patient before treatment.
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onset of clinically meaningful improvement with tadalafil 5mg once dailyin the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analysis of data pooled from four pivotal,double-blind, placebo-controlled studies. J Urol 2014 [Epub ahead of Abbreviations: α-blocker, α1-adrenergic blocking agent; AE, adverse events; 5ARI, 5α-reductase inhibitor; AUR, acute 20 Montorsi F, Henkel T, Geboers A et al. Effect of dutasteride, tamsulosin
urinary retention; BII, BPH Impact Index; CombAT, the and the combination on patient-reported quality of life and treatment Combination of Avodart and Tamsulosin (study); FDC, satisfaction in men with moderate-to-severe benign prostatic hyperplasia: fixed-dose combinationn; IPSS-Q8, question 8 of the IPSS; 4-year data from the CombAT study. Int J Clin Pract 2010; 64: 1042–51 PDE5, phosphodiesterase type 5; PPST, patient perception of 21 Roehrborn CG, Barkin J, Siami P et al. Clinical outcomes after
combined therapy with dutasteride plus tamsulosin or either study treatment; QD, once daily; QoL, quality of life; WW, monotherapy in men with benign prostatic hyperplasia (BPH) by baseline watchful waiting.
2015 The Authors 10 BJU International 2015 BJU International

Source: http://www.livemed.in/documents/152553/1750095/conductStudyResults/925c9fd8-6c66-452d-a294-f44822ba5694

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Gen. Physiol. Biophys. (2004), 23, 265—295 Endothelial Dysfunction and Reactive Oxygen SpeciesProduction in Ischemia/Reperfusion and Nitrate Tolerance Institute of Experimental Pharmacology, Slovak Academy of Sciences,Bratislava, Slovakia Abstract. Reactive oxygen species (ROS), as superoxide and its metabolites, haveimportant roles in vascular homeostasis as they are involved in various signalingprocesses. In many cardiovascular disease states, however, the release of ROS is in-creased. Uncontrolled ROS production leads to impaired endothelial function andconsequently to vascular dysfunction. This review focuses on two clinical condi-tions associated with elevated ROS levels: ischemia/reperfusion and nitrate toler-ance. Injury caused by ischemia/reperfusion is an important limitation of trans-plantations, and complicates the management of stroke and myocardial infarction.Nitrates, which are used to treat transient myocardial ischemia (angina pectoris),decrease in efficacy in long-term continuous administration. There are several en-zyme systems, such as xanthine oxidase, cyclooxygenase, uncoupled endothelialnitric oxide synthase, NAD(P)H oxidase, cytochrome P450 and the mitochondrialelectron transport chain, which are responsible for the increased vascular produc-tion of superoxide. The contribution of particular ROS producing enzymes and theeffect of antioxidant treatment are discussed in both pathological conditions.

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An Evolutionary Analysis of Pre-Play Communication and Efficiency in Games Kenichi Amaya∗ November 17, 2004 This paper studies the effects of pre-play communication on equi- librium selection in 2 × 2 symmetric coordination games. The playersrepeatedly play a coordination game preceded by an opportunity toexchange payoff irrelevant messages and gradually adjust their behav-ior. In short run, the players' access to the actions of the coordinationgame may be restricted. While the players can revise the set of acces-sible actions only occasionally, they frequently adjust their behaviorin the cheap-talk game, taking the set of currently available actions asgiven. We obtain an efficient-equilibrium-selection result if the under-lying coordination game satisfies the self-signalling condition. On theother hand, if the game is not self-signalling, both the efficient andthe inefficient equilibrium outcomes are stable.