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

Abstract

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 0.4 mg; 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.

Introduction

Lower urinary tract symptoms (LUTS) can be categorised into three groups: storage (eg, urgency, daytime frequency, nocturia), voiding (eg, hesitancy, weak stream, intermittency), and postmicturition (feeling of incomplete bladder emptying and postmicturition dribble) [1], [2]. These subgroups frequently overlap, with around two-thirds of patients experiencing LUTS from more than one group, and one-third from all three subgroups [3].

Voiding symptoms are typically managed with α-blockers (α₁-adrenoceptor antagonists) [4], while storage symptoms are usually treated with antimuscarinics [5]. However, storage symptoms, which patients often find more bothersome, are typically undertreated in men, owing to a perceived increased risk of acute urinary retention (AUR) with antimuscarinic agents [6], [7]. Evidence from clinical trials lasting 4–12 wk with antimuscarinic plus α-blocker combinations suggests that the risk of AUR is low in men with LUTS [8]; thus, a combination of these two classes of agents appears to be a feasible treatment for men with both storage and voiding LUTS.

Combination therapy with solifenacin (Soli) and the oral controlled absorption system formulation of tamsulosin (TOCAS) has been assessed in clinical studies for the treatment of storage and voiding LUTS. These include two phase 2 studies [9], [10], in which the two agents were coadministered, and the phase 3 Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS (oral controlled absorption system) in Males with Lower Urinary Tract Symptoms (NEPTUNE) study [11], in which the active ingredients were combined in a once-daily, modified-release, fixed-dose combination (FDC) tablet [11]. In these studies, doses of 6 mg and 9 mg Soli in combination with TOCAS 0.4 mg were well tolerated and offered treatment benefits compared with placebo or TOCAS monotherapy in patients with moderate to severe storage and voiding symptoms.

Patients completing the 12-wk NEPTUNE study were invited to continue into the open-label, 40-wk NEPTUNE II extension study, the only study to date to evaluate the long-term (up to 52 wk in total) safety and efficacy of Soli plus TOCAS combination therapy in male patients with both storage and voiding LUTS.