Author's Accepted Manuscript

A randomized controlled study to evaluate the efficacy of tamsulosin monotherapy

and its combination with mirabegron on patients with overactive bladder induced by
benign prostatic obstruction

Koji Ichihara, Naoya Masumori, Fumimasa Fukuta, Taiji Tsukamoto, Akihiko

Iwasawa, Yoshinori Tanaka

PII: S0022-5347(14)04488-7
DOI: 10.1016/j.juro.2014.09.091
Reference: JURO 11834

To appear in: The Journal of Urology

Accepted Date: 11 September 2014

Please cite this article as: Ichihara K, Masumori N, Fukuta F, Tsukamoto T, Iwasawa A, Tanaka Y, A
randomized controlled study to evaluate the efficacy of tamsulosin monotherapy and its combination with
mirabegron on patients with overactive bladder induced by benign prostatic obstruction, The Journal of
Urology (2014), doi: 10.1016/j.juro.2014.09.091.

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 ACCEPTED MANUSCRIPT

Original Article: A randomized controlled study to evaluate the efficacy of tamsulosin

monotherapy and its combination with mirabegron on patients with overactive bladder

induced by benign prostatic obstruction

Koji Ichihara (1), Naoya Masumori (1), Fumimasa Fukuta (1), Taiji Tsukamoto (1), Akihiko

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Iwasawa (2) and Yoshinori Tanaka (3)

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(1) Department of Urology, Sapporo Medical University School of Medicine

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(2) Iwasawa Clinic

(3) Department of Urology, Hokkaido Prefectural Esashi Hospital

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Running head: mirabegron and tamsulosin for BPO and OAB
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Key Words: benign prostatic obstruction, alpha-blockers, overactive bladder, beta

adrenoceptor agonist
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Corresponding author:

Naoya Masumori, M.D.

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Department of Urology, Sapporo Medical University School of Medicine

S1, W16, Chuo-ku, Sapporo 060-8543, Japan

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Phone: +81-11-611-2111, EXT. 3474, FAX: +81-11-612-2709

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E-mail: masumori@sapmed.ac.jp
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Abstract

Purpose: To evaluate the efficacy and safety of add-on treatment with a 3-adrenoceptor

agonist (mirabegron) on overactive bladder (OAB) symptoms remaining after 1-blocker

(tamsulosin) treatment in men with benign prostatic obstruction (BPO).

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Materials and Methods: Patients with BPO having urinary urgency at least once per week

and a total OAB symptom score (OABSS) 3 points after 8 weeks treatment with

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tamsulosin were enrolled. They were randomly allocated to receive 0.2 mg of tamsulosin

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daily or 0.2 mg of tamsulosin and 50 mg of mirabegron daily for 8 weeks. The primary

endpoint was the change in the total OABSS. Safety assessments included the change in

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the post-void residual urine volume (PVR) and adverse events (AEs).
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Results: From January 2012 through September 2013, a total of 94 patients were

randomized. Of these, 76 completed the protocol treatment. In the full analysis set, the
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change in the total OABSS during the treatment period was significantly greater in the
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combination group than in the monotherapy group (-2.21 vs. -0.87, p=0.012). The changes
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in the scores for urinary urgency, daytime frequency, and the International Prostate

Symptom Score storage symptom subscore and QOL for 8 weeks were significantly greater in
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the combination group. The change in PVR was significantly greater in the combination

group. Although 6 patients developed AEs in the combination group, urinary retention
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was observed in only 1 patient.

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Conclusion: Combined tamsulosin and mirabegron treatment is effective and safe for

patients with BPO who have OAB symptoms remaining after tamsulosin monotherapy.
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Introduction

In the 2013 EAU guideline for non-neurogenic male LUTS including benign BPO1,

patients having BPO with OAB symptoms and patients with BPO still having OAB symptoms

after -blocker administration are recommended to use anticholinergic agents

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simultaneously or in the add-on setting. The effectiveness of anticholinergic agents was

shown by large scale, well-designed randomized control clinical trials2-8. In real life clinical

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practice, we previously showed the efficacy of the combination therapy using an

anticholinergic agent and -blocker in patients with BPO and remaining OAB symptoms9.

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On the other hand, anticholinergic agents have several adverse effects such as urinary

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retention, dry mouth, blurred vision, and constipation. Moreover, these adverse effects
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make it difficult for patients with OAB to continue the medication10,11.

Beta-adrenoceptors have a role in mediating the relaxation of bladder smooth

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muscle. An important role has been proposed for the 3-adrenoceptor subtype in
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promoting urine storage in the bladder12. Mirabegron, which is a 3-adrenoceptor agonist

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first developed in Japan and launched in 2011, now can be used for the treatment OAB

symptoms. The rate of adverse effects such as dry mouth and constipation with
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mirabegron is lower than that with anticholinergic drugs13. However, there are no

randomized controlled study data about its efficacy and safety for men who received initial
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-blocker treatment for BPO and have remaining OAB symptoms. Therefore, we
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conducted a study to examine the efficacy of add-on treatment with mirabegron compared

with monotherapy with the -blocker tamsulosin. Moreover, we evaluated the safety for

these patients after mirabegron induction.

Material and Methods

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Patient inclusion criteria and study design

This 8-week multicenter randomized open-label controlled trial was conducted at

21 urologic clinics in Hokkaido, Japan. From January 2012 through September 2013, men

aged 50 or older with LUTS most likely secondary to BPO were included. All of them had

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persistent OAB symptoms after 0.2 mg/day -blocker tamsulosin monotherapy for at least 8

weeks. The definition of persistent OAB symptoms is that the total OABSS14 is 3 points or

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more with urinary urgency at least once per week. This study was approved by the

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institutional review board of each study site and conducted in accordance with the ethical

principles that have their origin in the Declaration of Helsinki. The clinical study design is

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posted at https://upload.umin.ac.jp (UMIN 000007269). All participants provided written
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informed consent. Criteria for exclusion from the study were as follows: PVR > 100 ml,

Qmax < 5 ml/s, history of urinary retention, prior diagnosis of neurogenic bladder or
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performance of clean intermittent catheterization, with severe bladder diverticulum or

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urethral stricture, planning to have a child, suspected malignant disease, with previous
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intrapelvic irradiation, suspected urinary infection, with renal or hepatic impairment, taking

medicines contraindicated to combination with mirabegron, or judged to be unsuitable for

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the trial by doctors.

Patients were randomized to either a monotherapy group, which continuously

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received 0.2 mg of tamsulosin daily, or an add-on group, which received 0.2 mg of

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tamsulosin and 50 mg of mirabegron daily. The approved dosage of tamsulosin is 0.2

mg/day and the upper limit dosage of mirabegron is 50 mg/day in Japan. Randomization

was performed through central registration using an allocation table.

Before randomization, the OABSS, IPSS, and IPSS-QOL were evaluated, and PV was

measured by transabdominal or rectal ultrasonography, together with UFM and PVR. Eight

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weeks later the changes from baseline were determined for the OABSS, IPSS, QOL, UFM, and

PVR. We set the treatment duration to 8 weeks in the study since it is thought to be

sufficient for the effectiveness of mirabegron to reach a plateau.

The primary endpoint was the change in the total OABSS. Secondary endpoints

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were the changes in each index of the OABSS, the total IPSS, each index of the IPSS, QOL,

and the Qmax. Safety assessments included the change in PVR and AEs. All AEs were

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closely monitored and details were reported throughout the study period.

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Statistical analysis

To detect a 2-point difference in the change of the OABSS between the two groups

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with a significance level of 5% and a power 99%, at least 38 patients in each group were
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required. Since 20% of the enrolled patients were considered to be withdrawn during the 8

weeks because of self-discontinuation or withdrawal of consent, 50 patients in each group

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were required to evaluate the primary endpoint.

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The differences in the changes of the parameters from baseline to 8 weeks in each
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group were examined using the paired t test. The difference in the parameters between

the 2 groups was examined with the unpaired t test. Safety analysis was performed for all
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treated patients, and treatment efficacy was evaluated in the full analysis set. P < 0.05 was

considered statistically significant.

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Results

Patient population

Ninety-four men were enrolled in the study. Although the number of enrolled

patients was insufficient, the study was closed because of the smaller number of

withdrawals than expected. Analysis for safety was done using 81 patients because 9 men

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were excluded due to protocol violation and 4 never came back to the hospital after the

randomization. Of them, 76 men (n = 38 in the tamsulosin-alone group and n = 38 in the

mirabegron add-on group) completed the protocol treatment and provided a full analysis set.

Five patients withdrew because of adverse events (Figure 1).

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In the full analysis set, the mean ( SD) age was 74.5 8.2 years, the mean duration

of prior tamsulosin treatment was 779 1183 days, and the mean PV was 34.2 16.2 ml.

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Of the 76 patients, 46.1% had comorbidity, including hypertension (n = 20), diabetes mellitus

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(n = 8), ischemic heart disease (n = 5), a history of cerebral infarction (n = 2) and others (n =

11). The patients demographic data and other baseline characteristics are shown in Table

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1. There was no significant difference in the backgrounds between the tamsulosin
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monotherapy and mirabegron add-on groups except for QOL (p = 0.041) and the OABSS

urgency score (p = 0.043).

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Comparison of the mean values of the parameters before and after treatment in each
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group

In the tamsulosin monotherapy group, there was no significant difference in IPSS

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and QOL between before and after treatment (Table 2). On the other hand, there were

significant differences in the total OABSS (p = 0.017), nighttime frequency (OABSS Q2, P =
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0.044) and urgency (OABSS Q3, p = 0.005) after 8 weeks.

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In the mirabegron add-on group, the total OABSS was significantly improved after

treatment (p <0.001). The scores of nighttime frequency (p = 0.010), urgency (p <0.001),

and urgency incontinence (OABSS Q4, p = 0.006) were significantly improved during the 8

weeks. The IPSS, total score (p = 0.011), storage symptom subscore (Q2 + Q4 + Q7, p

<0.001), and QOL (p <0.001) were significantly improved during the study period.

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Comparison of the differences in the parameters between the tamsulosin monotherapy

and mirabegron add-on groups (Table 2)

The mean changes from the baseline total OABSS at 8 weeks were -0.87 in the

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tamsulosin monotherapy group and -2.21 in the mirabegron add-on group. There was a

significant difference between the 2 groups (p = 0.012). In the OABSS, the mean change in

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the urgency score was significantly greater in the mirabegron add-on group than in the

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tamsulosin monotherapy group (-1.34 vs. -0.55, p = 0.006). Moreover, the mean day

frequency score (-0.76 vs. -0.05, p = 0.025), IPSS storage symptom subscore (-2.03 vs. -0.42,

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p = 0.006), and QOL (-0.76 vs. -0.05, p = 0.020) were significantly improved during the study
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period in the add-on group compared with the tamsulosin monotherapy group. The mean

change in Qmax from baseline was not significantly different between the 2 groups.
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Safety analysis
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Safety analysis was performed for all treated patients (n = 38 in monotherapy group

and n = 43 in mirabegron add-on group). In the tamsulosin monotherapy group, the mean
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change in PVR during the study period was not significant and no AEs were observed (Table

2). On the other hand, the mean change in PVR from baseline at 8 weeks was 37.3 ml in
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the mirabegron add-on group, which was significantly greater than in the monotherapy
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group (p = 0.020). Six patients (13.9%) in the mirabegron add-on group had AEs

(constipation in 1, acute urinary retention in 1, increased urgency in 1, dizziness in 1,

heartburn in 1 and elevation of hepatic enzymes in 1). Of these 6, 5 quit mirabegron due to

the AEs. Increased urgency occurred at 2 weeks after medication in a 78-year-old patient

without comorbidity, but having a large prostate (89 ml). Urinary retention occurred in an

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82-year-old patient who had hypertension and diabetes mellitus (baseline PVR 67 ml, PV 32

ml) the day after mirabegron administration. These AEs were improved promptly after

mirabegron withdrawal. On the other hand, the patient with dizziness preferred to

continue mirabegron and the symptom was relieved naturally after several days.

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For subanalysis, the 38 patients who received combination therapy were divided

in 4 groups according to the PV and baseline PVR and the risk factors for increased PVR

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were evaluated (Figure 2). Group a: PV 30 ml and PVR 50 ml (n = 8), Group b: PV 30

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ml and PVR < 50 ml (n = 12), Group c: PV < 30 ml and PVR 50 ml (n = 5), and Group d: PV

<30ml and PVR <50ml (n = 13). The mean SD PVR changes from baseline during the 8

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weeks in the groups (Group a, b, c, and d) were 24.75 59.26 ml, 74.08 101.49 ml, 16.4
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94.55 ml, and 19.15 31.46 ml, respectively. The differences in mean PVR changes among

4 groups were not significant (one-factor ANOVA, p = 0.242). Moreover, there was no
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significant difference in the proportion of the patients who showed a PVR increase to higher
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than the baseline or more than twice the baseline among the groups (chi-square test, p =
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0.686 and 0.306, respectively).

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Discussion

This is the first randomized controlled study demonstrating the efficacy of

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combination therapy using an -blocker and 3-adrenoceptor agonist for patients with BPO
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and OAB. Although -blockers are the first-line treatment modality to reduce OAB

symptoms in male LUTS suggestive of BPO, persisting storage symptoms not responding to

-blockers are frequently observed in daily clinical practice. For these patients, the

administration of anticholinergic agents in the add-on setting is known to be reliable based

on the results of several well-designed randomized studies2-8. One such study, using the

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combination of tamsulosin and solifenacin add-on5 or imidafenacin add-on6, was performed

in Japan using the OABSS as the evaluation tool as in the present study. The mean change

in the OABSS for 8 or 12 weeks in such a study was from 3.1 to 3.7. Although the

improvement in the score of OABSS was relatively mild in our study, the efficacy of the

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mirabegron add-on treatment might not be inferior to that of anticholinergic agent add-on

treatment.

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In the treatment of male LUTS, not only improvement of voiding and storage

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symptoms, but also that of QOL is important. In the present study, the mean change in the

QOL index from the baseline was significantly greater in the mirabegron add-on group than

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for tamsulosin monotherapy. Previous studies of combination therapy using an -blocker
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and anticholinergic agent, (TIMES7, ADAM3 and TAABO8) could not show significant

improvement in the QOL index compared with -blocker monotherapy. Therefore, we

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think the combination therapy using an -blocker and 3-adrenoceptor agonist may be a
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promising option for patients with BPO and OAB from the point of view of QOL.
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Safety is another important aspect in the management of male LUTS. In the

present study, six types of AEs were observed in six patients in the mirabegron add-on group.
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Of these, 5 patients quit the medication and 2 had AEs associated with voiding, i.e.,

increased urgency and urinary retention. The occurrence of urinary retention is a severe
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adverse event because emergent management is needed. It was reported that the
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frequency of urinary retention in patients with BPO and OAB who received anticholinergic

agents ranged from 0.8 to 3.0%15. It is thought that relaxation of the detrusor muscle due

to the antimuscarinic effect is responsible.

On the other hand, 3-adrenoceptor stimulation by mirabegron allows detrusor

relaxation during the storage phase. The bladder relaxation is specific to the storage phase

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of the micturition cycle and is unlikely to inhibit bladder contraction during the voiding

phase16. However, the mean change from the baseline in PVR of the patients with

combination therapy was significantly greater than that of monotherapy in the present study.

Nitti et al.17 conducted a study that evaluated the efficacy and safety of mirabegron for male

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patients with urodynamically proven bladder outlet obstruction. In their study, there was

no decrease in Qmax and detrusor pressure at Qmax during the study period in the patients

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who received monotherapy with 50 mg or 100 mg of mirabegron daily. Although only one

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patient who received 100 mg/day had urinary retention, the occurrence was similar to that

of patients receiving a placebo. These data demonstrated that the administration of

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mirabegron for males having bladder outlet obstruction was safe. However, the mean age
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of the patients in their study cohort was about 10 years younger than in ours. Moreover,

the mean PVR in the patients treated with mirabegron had increased about 20 - 30 ml at 12
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weeks, although there was no significant difference compared with the placebo group.
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Another study, performed by Wada et al.18, showed almost the same result. They
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evaluated urodynamic parameters before and after mirabegron add-on treatment for

Japanese men with persistent OAB symptoms after receiving tamsulosin. The mean
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prostate volume in their cohort was 31 ml. There was no significant difference in PVR after

mirabegron add-on treatment for 8 weeks. However, the mean PVR was increased about
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20 ml from the baseline. Thus, based on these results, we should be aware that the
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administration of mirabegron might have the risk of increasing PVR or deterioration of the

voiding condition like anticholinergic agents, although no factors at baseline to predict the

increasing PVR were identified in our study.

The limitations in this study were that it was open labeled, not placebo-controlled

like the ADDITION study6, and the relatively short treatment duration compared to previous

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studies using anticholinergic drugs. The long-term efficacy and safety of mirabegron

add-on treatment for patients with BPO and OAB thus need to be evaluated in the future.

Conclusion

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The 50 mg/day add-on mirabegron treatment for patients with BPO having

persistent OAB symptoms after tamsulosin treatment is more effective for ameliorating

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storage symptoms than tamsulosin monotherapy. Moreover, this treatment contributes to

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the improvement of QOL. However, we observed several adverse events which, though

they were mostly mild, cannot be ignored. Therefore, we recommend to paying careful

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attention to the possible development of AEs when mirabegron is used for patients with
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BPO and OAB.
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Acknowledgements
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This paper was supported by the following doctors who conducted data collection and case
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report form completion, Fumiyasu Takei, Shuichi Kato, Yohei Matsuda Masahiro Matsuki

(Sunagawa City Hospital), Keisuke Taguchi, Yuichiro Kurimura, Yoshiki Hiyama (Oji General
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Hospital), Noriomi Miyao, Ryuichi Kato (Muroran City General Hospital), Yoshikazu Sato,

Kazunori Haga (Sanjyukai Hospital), Nobukazu Suzuki, Ken-ichi Sunaoshi (Teine Urological
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Clinic), Hiroki Horita (Saiseikai Otaru Hospital), Naoki Itoh, Kohei Hashimoto (NTT East Japan
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Sapporo Hospital), Taketoshi Saka, Seiji Yamazaki (Saka Urological Hospital), Seiji Furuya

(Furuya Urological Clinic), Masanori Shigyo (Kushiro Red Cross Hospital), Yasuharu Kunishima

(Obihiro Kyokai Hospital), Toshiaki Shimizu (Kamui Yawaragi Urological Clinic), and Hitoshi

Tachiki (Steel Memorial Muroran Hospital)

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Conflict of interest

Naoya Masumori declares the financial interest of Astellas Pharma, Inc. and Daiichi Sankyo

Company. The others declare that they have no conflict of interest.

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guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract

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men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int.
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3. Chapple C, Herschorn S, Abrams P et al: Tolterodine treatment improves storage

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symptoms suggestive of overactive bladder in men treated with alpha-blockers. Eur Urol.
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2009;56:534.
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4. Kaplan SA, McCammon K, Fincher R et al: Safety and tolerability of solifenacin add-on

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randomized controlled study. Urology. 2011;78:126.

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7. Kaplan SA, Roehrborn CG, Rovner ES et al: Tolterodine and tamsulosin for treatment of

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men with lower urinary tract symptoms and overactive bladder: a randomized

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anticholinergics. LUTS 2011;3:29.

9. Masumori N, Tsukamoto T, Yanase M et al: The add-on effect of solifenacin for patients

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tract symptoms suggestive of benign prostatic obstruction. Adv Urol. 2010:205251.

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11. Benner JS, Nichol MB, Rovner ES et al: Patient-reported reasons for discontinuing
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overactive bladder medication. BJU Int. 2010;105:1276.

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12. Yamaguchi O. Beta3-adrenoceptors in human detrusor muscle. Urology. 2002;59 Suppl

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1:25.

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systematic review and meta-analysis of phase III trials. Int Urol Nephrol. 2014;46:275.

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syndromeoveractive bladder symptom score. Urology. 2006;68:318.

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15. Fllhase C, Chapple C, Cornu JN et al: Systematic review of combination drug therapy for

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Naunyn Schmiedebergs Arch Pharmacol. 2008;377:449.

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17. Nitti VW, Rosenberg S, Mitcheson DH et al: Urodynamics and safety of the

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#535.

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Figure legends

Figure 1: Disposition of the patients. AEs; adverse events.

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Figure 2: PVR changes over 8 weeks in 38 patients in the mirabegron add-on group, which
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was divided in 4 subgroups according to PV and baseline PVR. The mean SD PVRs at 0w

and 8w were 74.25 17.87 ml and 99.00 62.18 ml in Group a (p = 0.276), 19.92 13.21 ml
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and 94.00 100.15 ml in Group b (p = 0.028), 67.20 10.16 ml and 83.60 91.10 ml in
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Group c (p = 0.718), and 20.69 13.13 ml and 39.84 24.95 ml in Group d (p = 0.049),
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respectively. The number (%) of patients who showed PVR increases to higher than the

baseline or more than twice that of the baseline in each group were as follows: 5 (62.5) and
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3 (37.5) in Group a, 10 (83.3) and 8 (66.7) in Group b, 3 (60) and 1 (20) in Group c, and 9

(69.2) and 6 (46.2) in Group d, respectively. PV: prostate volume, PVR: postvoid residual
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urine volume.
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Abbreviations and Acronyms:

BPO = benign prostatic obstruction

LUTS = lower urinary tract symptoms
OAB = overactive bladder

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OABSS = OAB symptom score
IPSS = International Prostate Symptom Score
Qmax = maximum flow rate

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PV = prostate volume
PVR = post-void residual urine volume

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UFM = uroflowmetry
AEs = adverse events

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Table 1 Baseline characteristics of the full analysis set of patients in the tamsulosin monotherapy and
mirabegron add-on groups

Tamsulosin Tamsulosin + Mirabegron

Monotherapy Combination

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n = 38 n = 38
Study population Mean SD Mean SD p value
Age (year) 73.1 8.7 75.9 7.5 0.145

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Duration of prior tamsulosin 574.4 916.7 983.8 1382.6 0.133
treatment (day)

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Prostate volume (ml) 31.9 15.7 36.5 16.5 0.216
Voided volume (ml) 202.4 106.5 164.2 104.9 0.120
Maximum flow rate (ml/s) 15.4 7.2 13.3 7.6 0.204

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Postvoid residual (ml) 34.7 28.7 37.8 28.1 0.633
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OABSS
Q1 daytime frequency 0.68 0.57 0.68 0.52 -
Q2 nighttime frequency 2.26 0.79 2.34 0.74 0.656
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Q3 urgency 2.97 0.88 3.42 1.00 0.043

Q4 urgency incontinence 1.44 1.40 1.39 1.44 0.873
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Total score 7.34 2.67 7.81 2.48 0.426

IPSS
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Q1 incomplete emptying 1.39 1.51 1.28 1.29 0.746

Q2 day frequency 2.18 1.55 2.63 1.34 0.184
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Q3 intermittency 1.10 1.37 1.34 1.38 0.456

Q4 urgency 2.34 1.59 2.57 1.53 0.512
Q5 weak stream 2.34 1.58 2.26 1.68 0.834
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Q6 straining 1.07 1.26 1.13 1.49 0.869

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Q7 nocturia 2.47 1.10 2.73 1.13 0.309

Voiding symptom subscore 4.52 3.39 4.84 3.34 0.684
Storage symptom subscore 7.00 3.30 7.84 2.73 0.230
Total score 12.94 6.09 13.97 5.52 0.444
QOL index 3.34 1.32 3.97 1.32 0.041
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Table 2 Difference between groups of the mean change from baseline at 8 weeks for each parameter

PT
Tamsulosin Tamsulosin + Mirabegron difference in the
monotherapy combination mean change from

RI
(n = 38) (n = 38) baseline
Variables Mean SD Mean change Mean SD Mean change

SC
baseline 8w from baseline, baseline 8w from baseline, p value
p value p value

U
OABSS

AN
Total score 7.34 2.67 6.47 2.84 -0.87, p = 0.017 7.81 2.48 5.60 2.83 -2.21, p <0.001 0.012
Q1 daytime frequency 0.68 0.57 0.76 0.63 0.08, p = 0.324 0.68 0.52 0.65 0.53 -0.03, p = 0.768 0.377

M
Q2 nighttime frequency 2.26 0.79 2.05 0.76 -0.21, p = 0.044 2.34 0.74 2.05 0.83 -0.29, p = 0.010 0.591
Q3 urgency 2.97 0.88 2.42 1.38 -0.55, p = 0.005 3.42 1.00 2.07 1.56 -1.34, p <0.001 0.006

D
Q4 urgency incontinence 1.44 1.40 1.23 1.21 -0.21, p = 0.300 1.39 1.44 0.81 1.22 -0.58, p = 0.006 0.195

TE
IPSS
Total score 12.94 6.09 12.68 8.13 -0.26, p = 0.770 13.97 5.52 11.63 5.91 -2.34, p = 0.011 0.099
EP
Q1 incomplete emptying 1.39 1.51 1.44 1.63 0.05, p = 0.803 1.28 1.29 1.18 1.37 -0.11, p = 0.644 0.610
Q2 day frequency 2.18 1.55 2.13 1.69 -0.05, p = 0.832 2.63 1.34 1.86 1.33 -0.76, p <0.001 0.025
C

Q3 intermittency 1.10 1.37 1.36 1.74 0.26, p = 0.324 1.34 1.38 1.34 1.54 0.00, - 0.466
AC

Q4 urgency 2.34 1.59 2.13 1.49 -0.21, p = 0.300 2.57 1.53 1.78 1.49 -0.79, p = 0.002 0.069
Q5 weak stream 2.34 1.58 2.00 1.72 -0.34, p = 0.074 2.26 1.68 2.31 1.64 0.05, p = 0.841 0.222
Q6 straining 1.07 1.26 1.28 1.59 0.21, p = 0.440 1.13 1.49 0.89 1.22 -0.24, p = 0.404 0.254
Q7 nocturia 2.47 1.10 2.31 1.14 -0.16, p = 0.225 2.73 1.13 2.26 1.00 -0.47, p = 0.001 0.093
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Voiding symptom subscore 4.52 3.39 4.65 4.14 0.13, p = 0.807 4.84 3.34 4.63 2.69 -0.21, p = 0.686 0.647
Storage symptom subscore 7.00 3.30 6.57 3.57 -0.42, p = 0.266 7.84 2.73 5.81 2.93 -2.03, p <0.001 0.006

PT
QOL index 3.34 1.32 3.28 1.39 -0.05, p = 0.834 3.97 1.32 3.21 1.33 -0.76, p <0.001 0.020
Urine flow

RI
Maximum flow rate 15.4 7.2 14.1 7.0 -1.4, p = 0.267 13.3 7.6 13.0 6.5 -0.4, p = 0.762 0.564
Postvoid residual urine volume 34.7 28.7 38.5 40.8 3.9, p = 0.579 37.8 28.1 75.1 74.1 37.3, p = 0.004 0.020

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Figure 1

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Figure 2

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