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.


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.
Reported AUR rates in clinical trials with antimuscarinics and α 1 -blockers in men with LUTS associated with benign prostatic hyperplasia (LUTS/BPH) vary between studies and range from 0% to 1.9%, corresponding to an incidence rate of 0-78.2/1000 man-years [6]. The majority of trials evaluating antimuscarinics and α 1 -blocker combination therapy in men with LUTS/BPH are of short duration ( 12 weeks). The 12-week NEPTUNE [7] and 40-week NEP-TUNE II [8] studies assessed men with storage and voiding LUTS/BPH treated with two fixeddose combinations (FDCs) of the antimuscarinic solifenacin (Soli) and an oral-controlled absorption system formulation of the α 1 -blocker tamsulosin (TOCAS). To our knowledge, these are the only clinical trials that have studied the combination of an antimuscarinic and an α 1 -blocker for a period of up to 52 weeks. Thereby, the studies provide important new information regarding the long-term efficacy and tolerability of combined use of antimuscarinics and α 1 -blockers in men with LUTS. The aim of the current analysis was to evaluate the rate and time of onset of UR and the incidence of AUR cases (defined as those cases of UR that required catheterization) occurring over a period of up to 1 year. Furthermore, we assessed the relationship between the development of AUR and several baseline characteristics of the NEP-TUNE study population that are known risk factors.

Patients and methods
Patient characteristics and study results for the NEPTUNE studies have been published previously [7]. In brief, men aged !45 years were eligible to enter the studies if they had a diagnosis of LUTS/BPH for at least 3 months, a total International Prostate Symptom Score (IPSS) !13, !2 urgency episodes/24 h with Patient Perception of Intensity of Urgency Scale (PPIUS) grade 3 or 4 (i.e., severe urgency or urgency incontinence), and !8 micturitions/24 h, as well as an ultrasound-estimated prostate volume <75 mL, a maximum urinary flow rate (Q max ) of 4.0-12.0 mL/s, and a post-void residual (PVR) volume of 150 mL.
The NEPTUNE study (ClinicalTrials.gov identifier: NCT01018511, https://clinicaltrials. gov/ct2/show/NCT01018511?term=NCT01018511&rank=1) was a 12-week, randomized, double-blind, placebo-controlled, phase 3 trial that investigated the efficacy and safety of a  [8]. Patients were permitted to switch between doses at each subsequent 3-monthly visit (Fig 1). Data on FDC treatment from the NEPTUNE and NEPTUNE II studies have been combined to cover the period of potential drug exposure of up to 52 weeks. The NEPTUNE studies were approved by independent ethics committees and were conducted in accordance with the Declaration of Helsinki; written informed consent was obtained from all patients. The safety analysis set (SAF) included all patients who received !1 dose of FDC in NEP-TUNE and/or NEPTUNE II and who had any safety data reported after the first dose. Adverse events (AEs) were coded using MedDRA (Version 12.1) preferred terms. All cases of AUR, a subgroup of UR cases that required catheterization, were reported as serious AEs. No specific definitions for UR were provided. Analyses were performed according to exposure to FDC (up to 52 weeks).
The occurrence of AUR/UR during the 1-year treatment period is illustrated in cumulative incidence plots. A Cox-regression model was used to evaluate whether specific patient and baseline disease characteristics (i.e., prostate-specific antigen [PSA], prostate volume, Q max , total IPSS, PVR, bladder voiding efficiency [calculated as voided volume/(voided volume + PVR)], age) were associated with an increase in the risk of developing AUR/UR; Pearson correlation coefficients were derived between all characteristics of interest to understand the relationship between the potential risk factors. All 95% confidence intervals for proportions were calculated using the exact method.

Urinary retention rates in NEPTUNE and NEPTUNE II
During the placebo run-in period, four men experienced UR, three cases of which were AUR and led to discontinuation from the study. Across both NEPTUNE and NEPTUNE II, 14 men experienced episodes of UR: 13 of the 1208 men (1.1%; 95% CI, 0.6%-1.8%) who received FDC Soli 6 mg or 9 mg + TOCAS ( Table 1) and one man who received TOCAS monotherapy. For 10 of the 13 patients experiencing UR while on FDC, the investigator judged the events to be possibly or probably related to study medication. Of these 13 men, eight (0.7%; 95% CI, 0.3%-1.3%; incidence 7/1000 man-years) developed AUR, four cases of which required hospitalization. Detailed information about each individual who experienced UR or AUR can be found in Table 2.
Additionally, six men experienced UR, four of which were AUR, during the 40-week, openlabel NEPTUNE II study. Three men experienced the event onset of UR (two of which were AUR) while receiving FDC Soli 6 mg + TOCAS. Similarly, three men experienced the event onset of UR (two of which were AUR) while receiving FDC Soli 9 mg + TOCAS ( Table 1). Two men who experienced UR in NEPTUNE continued into the NEPTUNE II extension study and did not experience any further episodes. None of the men experiencing UR in NEP-TUNE II had prior episodes in the 12-week double-blind NEPTUNE study.

FDC dose duration at onset of urinary retention
The duration of FDC exposure at the time of onset of UR varied considerably (median 77 days, range 6-347 days); however, the majority of patients developed UR within the first 4 months of treatment (9 of 13, 69.2%). Four men (30.8%) had UR after at least 4 months of treatment, one on Soli 6 mg + TOCAS and three on Soli 9 mg + TOCAS. Cumulative incidence plots for AUR and UR (Fig 2A and 2B) were developed to illustrate the timing of their occurrence in relation to the duration of treatment with FDC Soli 6 mg or 9 mg + TOCAS.

Baseline risk factors for acute urinary retention
The mean baseline values for potential risk factors for AUR of patients with UR or AUR on FDC Soli + TOCAS (NEPTUNE/NEPTUNE II) and of the total NEPTUNE SAF population are presented in S1 Table. As some of these risk factors were found to be highly correlated with each other (S2 Table), a post-hoc Cox-regression model, assessing risk of developing UR or AUR, was derived separately for each potential risk factor ( Table 3). The results of the Coxregression analysis indicated that decreased bladder voiding efficiency (BVE) and increased PSA concentration, PVR volume, and prostate volume at baseline were associated with an increased risk of developing AUR and UR; other risk factors tested (i.e., Q max , total IPSS, age) did not show evidence for an increased risk of AUR or UR.
Although an association between prostate volume and increased AUR/UR was determined, the overall rates of UR and AUR were low in all patients regardless of prostate volume. In the 12-week double-blind study, the AUR rates on the FDC of Soli 6 mg + TOCAS were 0% (0/ 203) and 0.7% (1/134) for patients with a prostate volume of 40 mL and >40 mL, respectively. The AUR rates on the FDC of Soli 9 mg + TOCAS were 0.5% (1/185) and 1.4% (2/138) for patients with a prostate volume of 40 mL and >40 mL, respectively.

Discussion
Traditionally, the use of antimuscarinics in men with LUTS/BPH, benign prostatic enlargement, and/or benign prostatic obstruction has been limited owing to fears of AUR [3]. This belief, however, has been questioned by a number of studies performed over the past decade demonstrating promising efficacy and safety of combination therapy using antimuscarinics and α 1 -blockers [5]. The vast majority of data are from short-term studies ( 12 weeks), even though treatment with antimuscarinics and α 1 -blockers combination therapy is a long-term option. NEPTUNE II, together with NEPTUNE, is the only long-term study to assess the efficacy and safety of 52 weeks of treatment with antimuscarinic and α 1 -blocker combination therapy. Patients with storage and voiding LUTS, Q max <12 mL/s, PVR volume 150 mL, and prostate volume <75 mL were eligible for inclusion. We consider that these patients are typical candidates for combination therapy in routine clinical practice. In NEPTUNE and NEPTUNE II, treatment with FDC Soli + TOCAS therapy for up to 52 weeks was associated with low rates of UR (1.1%) and AUR (0.7%, corresponding to an incidence of 7/1000 man-years). Most cases occurred within the first 4 months after treatment initiation, and only one patient experienced UR after this period with the now-approved FDC dosage (Soli 6 mg + TOCAS 0.4 mg). These results are in agreement with those of The Health Improvement Network (THIN) database analysis, which reported the incidence of AUR in men treated with oral antimuscarinics. This analysis found that the relative risk of AUR was highest in early treatment (first 30 days) and lowered with time [9]. Consequently, patients at risk for UR should be initially treated with caution and counselled for the symptoms and signs of UR [10]. The long-term incidence of AUR on the FDC Soli 6 mg + TOCAS dose cannot be calculated owing to the permitted dose changes during the 40-week open-label period; however, the total incidence in the patient population studied was low (7/1000 man-years) despite the inclusion of cases reported while on the higher Soli 9 mg + TOCAS dose.
Rates of UR and AUR were similarly low during the first 12 weeks of the double-blind NEP-TUNE study. Events of UR were reported in only 7 of 661 patients receiving FDC: three events (0.9%) occurred with FDC 6 mg and four events (1.2%) occurred with FDC 9 mg. Four of these UR events were AUR: one (0.3%, incidence 13/1000 man-years) occurred with FDC 6 mg and three (0.9%, incidence 40/1000 man-years) occurred with FDC 9 mg. These data are consistent with previously published AUR rates and incidences for treatment with Soli + TOCAS [6,[11][12][13]. The AUR rates reported here are also consistent with other 12-week studies evaluating tolterodine (another antimuscarinic) in combination with tamsulosin in men with LUTS (0-0.9%) [14][15][16]. The AUR incidence in the NEPTUNE studies, regardless of FDC dose, is also in the same range as the incidence of AUR reported for the general, symptomatic, but untreated male LUTS population (18.3-35.9/1000 man-years) [6]. However, it should be noted that inclusion and exclusion criteria varied between different clinical trials, and thus populations are likely to have different propensities for UR.
Rates of UR and AUR in the NEPTUNE and NEPTUNE II studies may have been affected by the inclusion and exclusion criteria: for example, patients with a PVR >150 mL were excluded from the study, potentially lowering the overall risk of retention in this population. In most other studies with antimuscarinics, baseline PVR volume was also restricted, typically to 200 mL. Thus, additional research would be required to comment on the use of combination therapy in men with higher baseline PVR volumes. Despite the exclusion of patients with a prostate volume !75 mL at baseline, mean/median prostate volume at baseline was 38.1/36.0 mL (range: 9-74 mL), which is comparable with patients investigated in the Medical Therapy of Prostatic Symptoms (MTOPS) study (mean prostate volume of 36.3 mL [17]), indicating that prostate volume was clearly increased for the majority of patients in this study, although not typical for patients with LUTS/BPH.
A number of known risk factors for UR, as described in the MTOPS and Olmsted County studies [17,18], were present in the total NEPTUNE population at baseline, suggesting a propensity for UR in this population. While age and total IPSS were not shown to be associated with risk for AUR, decreased BVE, and increased PSA, PVR, and prostate volume at baseline were significantly associated with increasing risk of developing AUR/UR by cox-regression analysis. Although more men with prostate volume >40 mL experienced AUR than men whose baseline prostate volume was 40 mL, the overall rate of AUR across the entire study was low. As the low rates of AUR may impact the ability to accurately assess risk factors, the results of this post-hoc analysis should therefore be interpreted with caution. Following this clinical trial program, the FDC tablet of Soli 6 mg + TOCAS 0.4 mg has been registered in 42 countries (Vesomni™ or Urizia™), in most cases for the treatment of moderate to severe storage (urgency, increased micturition frequency) and voiding LUTS associated with BPH in men who are not adequately responding to treatment with monotherapy. Registration procedures in other countries are ongoing.

Conclusions
Results from the NEPTUNE and NEPTUNE II studies suggest that treatment for up to 52 weeks with an FDC tablet containing Soli 6 mg or 9 mg with TOCAS 0.4 mg was well tolerated and associated with low rates of UR and AUR in men with LUTS. The overall incidence of UR was low, occurring in only 13 of 1208 patients (1.1%) receiving FDC Soli + TOCAS in either NEPTUNE or NEPTUNE II, with eight of those patients (0.7%, incidence 7/1000 man-years) requiring catheterization (AUR). Decreased BVE and increased PSA, PVR, and prostate volume at baseline were associated with an increased risk of developing AUR/UR. However, it should be noted that the low rates of AUR/UR observed in this study limit the accuracy of risk assessment. Most cases occurred within 4 months of treatment initiation, suggesting no increase in the risk of AUR with long-term treatment compared with 12 weeks of treatment.
Supporting information S1