Monique Klaver

Combination Therapy with Solifenacin and Tamsulosin Oral Controlled Absorption System in a Single Tablet for Lower Urinary Tract Symptoms in Men: Efficacy and Safety Results from the Randomised Controlled NEPTUNE Trial

BACKGROUND Storage symptoms are particularly bothersome in men with lower urinary tract symptoms (LUTS) but may not be adequately treated by α-blocker monotherapy. OBJECTIVE To assess the efficacy and safety of a fixed-dose combination (FDC) of solifenacin and an oral controlled absorption system (OCAS) formulation of tamsulosin compared with placebo and compared with tamsulosin OCAS (TOCAS) monotherapy in men with moderate to severe storage symptoms and voiding symptoms. DESIGN, SETTING, AND PARTICIPANTS A double-blind 12-wk phase 3 study in 1334 men with storage and voiding LUTS: total International Prostate Symptom Score (IPSS) ≥ 13, maximum urinary flow rate (Qmax) 4.0-12.0 ml/s, two or more urgency episodes per 24 h of Patient Perception of Intensity of Urgency Scale grade 3 or 4, and eight or more micturitions per 24h. INTERVENTION Patients were randomised to placebo, TOCAS 0.4 mg, FDC solifenacin 6 mg plus TOCAS 0.4 mg, or FDC solifenacin 9 mg plus TOCAS 0.4 mg. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary efficacy end points were (1) total IPSS and (2) Total Urgency and Frequency Score (TUFS). An FDC met the success criteria if it demonstrated superiority compared with placebo and noninferiority compared with TOCAS for total IPSS, as well as superiority compared with TOCAS for TUFS. RESULTS AND LIMITATIONS Reductions in total IPSS and TUFS were observed with both solifenacin 6 mg plus TOCAS (-7.0 and -8.1, respectively) and solifenacin 9 mg plus TOCAS (-6.5 and -7.6, respectively) compared with TOCAS (-6.2 and -6.7, respectively) and placebo (-5.4 and -4.4, respectively). Solifenacin 6 mg plus TOCAS met all prespecified success criteria for both primary end points, while solifenacin 9 mg plus TOCAS met success criteria compared with placebo but not compared with TOCAS. Both FDCs improved quality of life (QoL) measures and were well tolerated, with low incidences of acute urinary retention. CONCLUSIONS The FDC of solifenacin 6 mg plus TOCAS significantly improved storage and voiding symptoms, as well as QoL parameters, compared with placebo. This FDC also improved storage symptoms and QoL compared with TOCAS alone in men with moderate to severe storage symptoms and voiding symptoms, and it was well tolerated.

Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN)

BACKGROUND Storage symptoms are often undertreated in men with lower urinary tract symptoms (LUTS). OBJECTIVE To evaluate the combination of an antimuscarinic (solifenacin) with an α-blocker (tamsulosin) versus tamsulosin alone in the treatment of men with LUTS. DESIGN, SETTING, AND PARTICIPANTS A double-blind, 12-wk, phase 2 study in 937 men with LUTS (≥ 3 mo, total International Prostate Symptom Score [IPSS] ≥ 13, and maximum urinary flow rate 4.0-15.0 ml/s). INTERVENTION Eight treatment groups: tamsulosin oral controlled absorption system (OCAS) 0.4 mg; solifenacin 3, 6, or 9 mg; solifenacin 3, 6 or 9 mg plus tamsulosin OCAS 0.4 mg; or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary efficacy end point was change from baseline in total IPSS. Secondary end points included micturition diary and quality-of-life (QoL) parameters. Post hoc subgroup analyses were performed by severity of baseline storage symptoms, with statistical comparisons presented only for tamsulosin OCAS alone versus combination therapy, due to the small sample size of the solifenacin monotherapy and placebo subgroups. RESULTS AND LIMITATIONS Combination therapy was associated with significant improvements in micturition frequency and voided volume versus tamsulosin OCAS alone in the total study population; improvements in total IPSS were not significant. Statistically significant improvements in urgency episodes, micturition frequency, total urgency score, voided volume, IPSS storage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed in a subpopulation of men with two or more urgency episodes per 24h (Patient Perception of Intensity of Urgency Scale grade 3 or 4) and eight or more micturitions per 24h at baseline (storage symptoms subgroup) with combination therapy versus tamsulosin OCAS alone (p ≤ 0.05 for the dose-response slope, all variables). Combination therapy was well tolerated, and adverse events were consistent with the safety profiles of both compounds. CONCLUSIONS Solifenacin plus tamsulosin OCAS did not significantly improve IPSS in the total study population but offered significant efficacy and QoL benefits over tamsulosin OCAS monotherapy in men with both voiding and storage symptoms at baseline. Combination therapy was well tolerated. TRIAL REGISTRATION Clinical Trials.gov Identifier: NCT00510406.

Long-term safety and efficacy of single-tablet combinations of solifenacin and tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract symptoms: results from the NEPTUNE Study and NEPTUNE II open-label extension.

BACKGROUND Short-term trials have demonstrated the efficacy and safety of combination therapy using antimuscarinics and α-blockers in men with lower urinary tract symptoms (LUTS). The Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS (oral controlled absorption system) in Males with Lower Urinary Tract Symptoms (NEPTUNE) II is the first long-term study using solifenacin (Soli) and the oral controlled absorption system formulation of tamsulosin (TOCAS). OBJECTIVE To evaluate long-term (up to 52 wk) safety and efficacy of flexible dosing of two fixed-dose combinations (FDC) of Soli plus TOCAS in men with moderate to severe storage symptoms and voiding symptoms. DESIGN, SETTING, AND PARTICIPANTS Patients with both storage and voiding LUTS, maximum urinary flow rate of 4.0-12.0 ml/s, prostate size <75 ml, and postvoid residuals ≤ 150 ml, who completed the 12-wk, double-blind NEPTUNE study could continue in the 40-wk, open-label NEPTUNE II study. INTERVENTION FDC of Soli 6 mg plus TOCAS 0.4 mg, or Soli 9 mg plus TOCAS 0.4mg; patients could switch between doses in NEPTUNE II. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Safety and efficacy data from NEPTUNE and NEPTUNE II were combined to cover a 52-wk period. Primary efficacy end points were total International Prostate Symptom Score (IPSS) and total urgency and frequency score (TUFS); secondary end points included IPSS storage and voiding subscores, micturition diary variables, and quality of life parameters. RESULTS In all, 1066 men completed NEPTUNE and received one dose or more of study medication in NEPTUNE II. Treatment-emergent adverse events were reported in 499 (46.8%) patients who participated in NEPTUNE II; most were mild or moderate. Urinary retention occurred in 13 of 1208 (1.1%) patients receiving one or more FDCs in NEPTUNE and/or NEPTUNE II; 8 (0.7%) required catheterisation (acute urinary retention [AUR]). Reductions in total IPSS and TUFS during NEPTUNE were maintained for up to 52 wk of FDC treatment, with mean reductions of 9.0 (standard deviation [SD]: 5.7) and 10.1 (SD: 9.2), respectively, from baseline to end of treatment. Clinically relevant improvements were also observed for secondary efficacy end points. CONCLUSIONS Long-term treatment with FDC Soli plus TOCAS was well tolerated and efficacious in men with storage and voiding LUTS, with a low incidence of AUR. PATIENT SUMMARY Treatment with solifenacin plus tamsulosin in a fixed-dose combination tablet was well tolerated by men with lower urinary tract symptoms. Improvements in symptoms were achieved after 4 wk of treatment, with further improvements at week 16 maintained for up to 52 wk throughout the study.

Total urgency and frequency score as a measure of urgency and frequency in overactive bladder and storage lower urinary tract symptoms.

The term lower urinary tract symptoms (LUTS) encompasses a range of urinary symptoms, including storage symptoms (e.g. overactive bladder [OAB]) as well as voiding and post‐micturition symptoms. Although treatment of male LUTS tends to focus on voiding symptoms, patients typically find storage symptoms the most bothersome. The core storage symptom is urgency, which drives the other main storage symptoms of increased daytime frequency, nocturia and incontinence. Although several validated questionnaires have been widely used to study urgency, few measure the two important storage parameters, urgency and frequency, in a single assessment. The total urgency and frequency score (TUFS) is a new validated tool that captures both variables and is derived from the Patient Perception of Intensity of Urgency Scale, which has been validated in patients with OAB and LUTS. The TUFS was first validated in OAB in the phase IIa BLOSSOM study, which was designed to assess the efficacy and safety of mirabegron, a β3‐adrenoceptor agonist, in 260 patients. The responsiveness of the TUFS to treatment has been confirmed in a further three large‐scale randomized controlled trials of solifenacin in patients with OAB or LUTS. Changes in TUFS from baseline to end of treatment were consistent with changes in micturition diary variables in all four studies. Furthermore, the TUFS was significantly correlated with several health‐related quality‐of‐life variables in the phase III NEPTUNE study. Thus, the TUFS appears to be useful for assessing improvements in major storage symptoms (urgency and frequency) in clinical trials.

Qualitative Exploration of the Patient Experience of Underactive Bladder

BACKGROUND Underactive bladder (UAB) is considered the symptom complex associated with the urodynamic diagnosis of detrusor underactivity. OBJECTIVE The aim of this research was to investigate the patient reported experience of the symptoms, signs, and impact of UAB. This research is also part of the initial qualitative phase for the development of a new patient reported outcome measure for the assessment of UAB. DESIGN, SETTING, AND PARTICIPANTS Qualitative methods were used to understand the experience of UAB from a patient perspective, in a purposive sample of male (n=29) and female (n=15) patients aged 27-88 yr (mean: 64 yr), diagnosed with a primary diagnosis of detrusor underactivity, with or without coexisting urological conditions. Semistructured interviews were conducted in Bristol, UK. RESULTS Male and female patients reported a variety of lower urinary tract symptoms and associated impact on quality of life. Storage symptoms of nocturia, increased daytime frequency, and urgency, and the voiding symptoms of slow stream, hesitancy, and straining were reported by over half of the patients. A sensation of incomplete emptying and postmicturition dribble were also frequently described. Most had a post void residual >30ml (n=34, 77%, median: 199ml) with many reporting urinary tract infections, a history of self-catheterisation, and some experiencing occasional acute retention episodes. These symptoms and signs can have a broad impact on quality of life including having to plan their daily activities around the location of toilets, disruption to sleep, social life, and associated effect on family and friends. CONCLUSIONS Knowledge of the lived experience of UAB obtained in the current study will be used for the development of a new patient reported outcome measure and help inform the current working definition of UAB. PATIENT SUMMARY The symptoms, signs, and impact on quality of life of underactive bladder are described by patients with the condition.

Responder and health-related quality of life analyses in men with lower urinary tract symptoms treated with a fixed-dose combination of solifenacin and tamsulosin oral- controlled absorption system: results from the NEPTUNE study

To evaluate the effect of a fixed‐dose combination (FDC) of solifenacin and an oral‐controlled absorption system (OCAS™) formulation of tamsulosin (TOCAS) on health‐related quality of life (HRQoL) in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH).

Validation of the Patient Perception of Intensity of Urgency Scale in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia

OBJECTIVE To assess the reliability and validity of scores derived from the Patient Perception of Intensity of Urgency Scale (PPIUS) in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). METHODS A post hoc analysis of the phase II Solifenacin and Tamsulosin in Males with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia trial (NCT00510406), a 12-week clinical trial in men with LUTS associated with BPH, assessed the measurement properties of six PPIUS-derived scores: mean score; maximum urgency score; total urgency and frequency score (TUFS; average sum of urgency scores over 3 days); and numbers of urgency episodes, urgency episodes of grade 3 or 4, and urgency incontinence episodes. Test-retest reliability, presence of floor/ceiling effects, responsiveness to change, known-group validity, and concurrent validity were assessed for each score. RESULTS A total of 901 patients had at least one valid PPIUS assessment after baseline. TUFS demonstrated good test-retest reliability (intraclass correlation coefficient >0.8), discriminated between groups defined based on International Prostate Symptom Score storage score severity (known-groups validity), had high concurrent validity, and had high responsiveness to change (Guyatts responsiveness statistic 0.88), with an absence of floor or ceiling effects. The psychometric properties of other PPIUS-derived scores were not as consistently robust and showed either low-to-moderate responsiveness, presence of a floor or ceiling effect, or low-to-moderate test-retest reliability. CONCLUSIONS This study shows that the PPIUS is reliable and valid in patients with LUTS associated with BPH. TUFS provided the best combination of psychometric properties of the six scores derived from the PPIUS and appeared to be an appropriate measure of urgency and frequency.

Reply to Bora Lee and Jae Heon Kim's Letter to the Editor re: Alan D. Uren, Nikki Cotterill, Christopher Harding, et al. Qualitative Exploration of the Patient Experience of Underactive Bladder. Eur Urol 2017;72:402–7

We thank the authors for their letter on our article [1] and provide the following clarifications in response. A patientreported outcome (PRO) measure was not used as part of the methodology in this study. Indeed, PRO measure development requires a lengthy validation process, of which this was the initial phase. The findings support the development of a new PRO measure for the assessment of the signs, symptoms, and impact of underactive bladder (UAB). The study used qualitative methodology to explore the experience of UAB from a patient perspective using semistructured interviews, guided by an interview schedule. Patients were encouraged to talk in an open-ended manner about their experiences, using prompts from the interview schedule to “guide” discussion. A well-designed interview guide is important in order to help avoid possible interviewer bias or unintentional influence of the researcher on the type of responses from the subject. Exploratory qualitative interviews are particularly useful to explore around a topic for which little may be understood, as is the case with UAB. Direct patient input using qualitative research methodology is important for the demonstration of content validity when developing a new instrument [2,3]. Although the underlying aetiology of the presenting detrusor underactivity (DU) in the sample was not assessed, neurological patients were excluded. However, as UAB was the symptom complex under investigation, it was not necessary to ascertain the underlying aetiology of the DU at this stage. Indeed, there is a lack of evidence for the symptomatic presentation of its various aetiological origins, which requires further study. We took the pragmatic decision to categorise our sample by those with DU only and those with DU and coexisting conditions. This allowed the notable reporting of incontinence to be mainly associated with the inclusion of the group with those who demonstrated DU and coexisting detrusor

Incidence of urinary retention during treatment with single tablet combinations of solifenacin+tamsulosin OCAS™ for up to 1 year in adult men with both storage and voiding LUTS: A subanalysis of the NEPTUNE/NEPTUNE II randomized controlled studies

Introduction The emergence of urinary retention (UR), specifically acute urinary retention (AUR), has been a concern when treating men with lower urinary tract symptoms (LUTS) with antimuscarinic drugs. Materials and methods In NEPTUNE (12-week, double-blind), men (≥45 years) with LUTS were randomized to receive tamsulosin oral-controlled absorption system (TOCAS) 0.4 mg, fixed-dose combination (FDC) of solifenacin (Soli) 6 mg + TOCAS 0.4 mg, FDC Soli 9 mg + TOCAS 0.4 mg, or placebo. In NEPTUNE II (40-week, open-label extension of NEPTUNE), continuing patients received 4-week FDC Soli 6 mg + TOCAS, then FDC Soli 6 mg or 9 mg + TOCAS for the remainder of the study, switchable every 3 months. Results Across both studies, 1208 men received ≥1 dose of FDC Soli 6 mg or 9 mg + TOCAS for up to 52 weeks; 1199 men completed NEPTUNE and 1066 received ≥1 dose in NEPTUNE II. In total, 13 men (1.1%; 95% CI, 0.6%–1.8%) reported a UR event while receiving FDC, eight of which were AUR (0.7%; 95% CI, 0.3%–1.3%, incidence 7/1000 man-years). Six men reported UR events while taking Soli 6 mg + TOCAS (three AUR), and seven men reported a UR event while taking Soli 9 mg + TOCAS (five AUR). One man developed AUR while taking TOCAS alone and four reported UR (three AUR) during placebo run-in. Most AUR/UR events occurred within 4 months of treatment initiation. Conclusions FDC Soli and TOCAS was associated with a low rate of UR and AUR in men with LUTS.

Platinum PriorityReply from Authors re: Mikkel Fode, Jens Sønksen. Towards a Greater Understanding of Underactive Bladder. Eur Urol 2017;72:408–9

The editorial comments by Fode and Sønksen [1] on our study [2] are most welcome and raise a number of challenging issues. They are correct in suggesting that the strands of our underactive bladder (UAB)/detrusor underactivity (DU) research programme is work in progress. Further work is ongoing to develop the ICIQ-UAB patientreported outcome measure, noninvasive methods of diagnosing DU, and a more precise way of defining DU. For the modified definition proposed by Fode and Sønksen, we would like to draw attention to the recently published symptomatic definition proposed by the standardisation subcommittee of the International Continence Society included in a recent book by Chapple et al [3]: ‘‘Underactive bladder is characterised by a slow urinary stream, hesitancy and straining to void, with or without a feeling of incomplete bladder emptying and dribbling, often with storage symptoms’’. However, we would suggest that the current proposed definition above, which we support at this stage, is unlikely to be the definitive one in view of the ongoing research efforts of many. The editorial also raises further discussion as to how closely linked DU is to what has become termed UAB. This raises the question of whether all patients with a urodynamically confirmed diagnosis of DU are considered to have UAB, or only when such patients demonstrate symptoms such as slow flow, hesitancy, and straining. Our qualitative exploration of the reported symptoms [2] demonstrates that in patients with confirmed DU, the actual subjective