Author's Accepted Manuscript

Efficacy and Safety of Desmopressin “Add-On” Therapy in Men with Persistent

Nocturia Under Alpha Blocker Monotherapy for Lower Urinary Tract Symptoms: A
Randomized, Double-Blind, Placebo-Controlled Study

Joon Chul Kim , Kang Jun Cho , Jeong Gu Lee , Ju Tae Seo , Duk Yoon Kim ,
Seung-June Oh , Kyu-Sung Lee , Myung-Soo Choo , Jeong Zoo Lee

PII: S0022-5347(16)31228-9
DOI: 10.1016/j.juro.2016.08.116
Reference: JURO 13997

To appear in: The Journal of Urology

Accepted Date: 31 August 2016

Please cite this article as: Kim JC, Cho KJ, Lee JG, Seo JT, Kim DY, Oh SJ, Lee KS, Choo MS, Lee
JZ, Efficacy and Safety of Desmopressin “Add-On” Therapy in Men with Persistent Nocturia Under
Alpha Blocker Monotherapy for Lower Urinary Tract Symptoms: A Randomized, Double-Blind, Placebo-
Controlled Study, The Journal of Urology® (2016), doi: 10.1016/j.juro.2016.08.116.

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1 -Title Page_

3 Efficacy and Safety of Desmopressin “Add-On” Therapy in Men with Persistent

4 Nocturia Under Alpha Blocker Monotherapy for Lower Urinary Tract Symptoms: A

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5 Randomized, Double-Blind, Placebo-Controlled Study

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7 Joon Chul Kima, Kang Jun Choa, Jeong Gu Leeb, Ju Tae Seoc, Duk Yoon Kimd, Seung-June

Ohe, Kyu-Sung Leef, Myung-Soo Choog, Jeong Zoo Leeh,*

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8

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a
10 Department of Urology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic
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11 University of Korea, Seoul, Korea; bDepartment of Urology, College of Medicine, Korea

12 University, Seoul, Korea; cDepartment of Urology, Cheil General Hospital and Women’s
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13 Healthcare Center, Dankook University College of Medicine, Seoul, Korea; dDepartment of

14 Urology, Daegu Catholic University, College of Medicine, Daegu, Korea; eDepartment of

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15 Urology, Seoul National University Hospital, Seoul National University College of Medicine,
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16 Seoul, Korea; fDepartment of Urology, Samsung Medical Center, Sungkyunkwan University

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17 School of Medicine, Seoul, Korea; gDepartment of Urology, Asan Medical Center, University

18 of Ulsan College of Medicine, Seoul, Korea; hDepartment of Urology, Pusan National

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19 University, School of Medicine, Busan, Korea

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21 Running head: Efficacy of desmopressin add on in persistent nocturia under alpha blocker

22

*
23 Corresponding author. Jeong Zoo Lee, Professor, M.D., Ph.D,

24 Department of Urology, Pusan National University, School of Medicine, 179 Gudeok-ro,

25 Seo-gu, Busan, Republic of Korea

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26 Postal code: 49241

27 Tel. +82-51-240-7351; FAX. +82-51-254-0192

28 E-mail address: toohotman@hanmail.net

29

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30 Keywords: Alpha adrenergic blockers, Desmopressin, Lower urinary tract symptoms,

31 Nocturia

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32 Abstract

33 Purpose: We investigated the efficacy and safety of desmopressin add-on therapy in men

34 with persistent nocturia on alpha-blocker for lower urinary tract symptoms (LUTS) with

35 placebo-controlled study.

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36 Materials and Methods: The study included men aged 40–65 years with LUTS and persistent

37 nocturia despite alpha-blocker for at least 8 weeks. The patients were randomized to once-

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38 daily placebo or desmopressin 0.2 mg for 8 weeks. The primary end point was to assess

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39 changes in the mean number of nocturia episodes from the baseline to the final assessment.

40 Other secondary end points and adverse events were evaluated.

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41 Results and limitation: In all, 86 patients were randomized to receive placebo (n = 39) or
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42 desmopressin 0.2 mg (n = 47). Baseline characteristics were similar between the two groups.

43 Desmopressin add-on group was significantly superior to placebo in terms of the change from
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44 baseline in the mean number of nocturia episodes (-1.13 ± 0.92 vs -0.68 ± 0.79, p = 0.034)

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change in nocturnal urine volume (p <0.001), change in total International Prostate Symptom

46 Score (p = 0.041), change in nocturnal polyuria index (p = 0.001), change in International

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47 Consultation on Incontinence Questionnaire-Nocturia (p = 0.001), and willingness to

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48 continue (p = 0.025). The incidence of adverse events in desmopressin add-on group was

49 similar to that in placebo group. Most adverse events were mild.

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50 Conclusion: Desmopressin add-on therapy in men aged 40–65 years with persistent nocturia
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51 on alpha-blocker monotherapy for LUTS is effective and well tolerated.

52
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53 Introduction

54 Nocturia is one of the most distressing lower urinary tract symptoms (LUTS) in men, and its

55 prevalence in a population-based survey was reported to be up to 65% in men aged ≥40 years
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56 . Nocturia shows a strong association with decreased quality of life (QoL) for men resulting

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57 from sleep disruption, daytime tiredness, and mood disturbance . Men with nocturia may

58 also have other storage or voiding symptoms. Nocturia in men has been regarded as a storage

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59 symptom related with bladder outlet obstruction (BOO) or detrusor overactivity. In practice,

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60 many physicians have started management of nocturia with pharmacotherapy with alpha-

61 blockers in men to relieve BOO. The efficacy of alpha-blockers for nocturia associated with

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62 LUTS suggestive of benign prostatic hyperplasia (BPH) has been reported in some studies 4-6.
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63 However, nocturia has a multifactorial pathogenesis. The pathophysiology of nocturia is

64 classified as reduced bladder capacity, nocturnal polyuria, 24-h polyuria, and sleep
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65 disturbance 7. Thus, merely relieving BOO with alpha-blockers has been shown to produce

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less than satisfactory results for nocturia at times.

67 Desmopressin, a synthetic analogue of arginine vasopressin, has antidiuretic effects and

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68 leads to a significant decrease in nocturnal urine output as well as the number of nocturia
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69 episodes in nocturnal polyuria 8. A combination of desmopressin and alpha-blockers could be

70 considered in men with nocturia who fail to respond with alpha-blocker monotherapy. Some
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71 studies have reported the effectiveness of desmopressin addition to alpha-blockers for

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72 nocturia in men . However, they were not placebo-controlled studies. Nocturia can be

73 alleviated by behavioral modifications such as fluid restriction after dinner or night time.

74 Thus, the effects of pharmacologic treatment for nocturia could be affected by non-

75 pharmacological factors and studies related to pharmacotherapy for nocturia require a

76 placebo control.

77 The aim of this study was to investigate the efficacy and safety of desmopressin add-on
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78 therapy in men with persistent nocturia already using alpha-blocker monotherapy for LUTS

79 with a placebo control group for comparison.

80

81 Materials and Methods

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82 Study population

83 We screened men aged 40–65 years with LUTS, International Prostatic Symptom Score

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84 (IPSS) ≥13, and persistent nocturia (≥2/night) and a nocturia index score ≥1 despite use of

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85 alpha-blocker treatment for at least 8 weeks for study enrollment in 8 centers in South Korea.

86 Nocturnal polyuria was defined as nocturnal polyuria index (NPI) >33% in this study. Those

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87 with a total daily urine volume ≥ 3,000 mL, diabetes insipidus, a history of prostate surgery in
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88 the past 6 months, cardiac failure, serum sodium <135 mM/L, clinically significant

89 abnormalities of serum potassium or creatinine, current treatment for insomnia, desmopressin

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90 treatment in the past 1 month, uncontrolled hypertension, urgency urinary incontinence,

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significant anatomical abnormalities in urinary tract, use of other drugs that could influence

92 desmopressin (diuretics, tricyclic antidepressants, indomethacin, carbamazepine,

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93 chlorpropamide), or use of anticholinergics or 5 alpha reductase inhibitor in the past 3 months

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94 were excluded. All patients gave written informed consent prior to enrollment. The present

95 study followed the Declaration of Helsinki and was approved by the ethics committee and the
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96 institutional review board at each center.

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98 Study design

99 This was an 8-week, multicenter, randomized, double-blind, placebo-controlled study.

100 Enrolled patients received either oral desmopressin 0.2mg or matching placebo at bedtime for

101 8 weeks and continued to take the alpha-blocker in the same dose and way as before. They

102 were given explanation about behavioral therapy such as night time restriction. Patients were
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103 required to visit the outpatient clinic at the first visit and after 1, 4, and 8 weeks. All patients

104 recorded in a voiding diary for 3 consecutive days at baseline and again at 8 weeks.

105 Laboratory data including serum sodium were checked at baseline and at 1 and 8 weeks. All

106 patients fulfilled the IPSS, nocturnal hesitancy scores, International Consultation on

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107 Incontinence Questionnaire-Nocturia (ICIQ-N) at baseline and at 4 and 8 weeks.

108 The primary end point of this study was to assess changes in the mean number of nocturia

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109 episodes in a voiding diary from the baseline to the final assessment. Secondary end points

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110 included the proportion of patients with a decreased number of nocturia episodes by ≥50%,

111 changes in nocturnal urine volume, NPI, IPSS, and nocturnal hesitancy score. QoL was

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112 evaluated based on changes in ICIQ-N and IPSS QoL scores. Evaluation of patient’s
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113 perception of treatment was performed with the Benefit, Satisfaction, and Willingness to

114 continue questionnaire at week 8. Safety assessments included adverse events, vital signs,
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115 and laboratory data. Adverse events reported in response to general questioning by the

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investigator or self-reported by the patient were recorded with the severity and likely

117 causality to study medication. Patient-reported medication compliance was also evaluated.
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118
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119 Statistical analysis

120 Statistical analyses were performed using IBM® SPSS® 20.0. The mean ± SD is reported for
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121 continuous variables and the frequency and percentage are reported for categorical variables.
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122 Continuous variable comparisons were performed with paired t-test or Wilcoxon’s signed

123 rank test and categorical variables were evaluated with Pearson’s chi-square test or Fisher’s

124 exact test. A two-sided p <0.05 indicated statistical significance.

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126 Results

127 In total, 121 patients were screened. Of these, 109 patients were randomized and received at
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128 least one dose of study medication. Of the randomized patients, 86 completed the study (Fig.

129 1). Baseline clinical characteristics are presented in Table 1 and there were no relevant

130 differences between control and desmopressin add-on groups. Patient-reported medication

131 compliance was 90.8% in the desmopressin add-on group and 90.0% in placebo.

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132 Efficacy results are presented as the intent-to-treat (ITT), i.e. all patients (n = 86) who

133 took study medication and provided primary efficacy data. The mean change in the number of

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134 nocturia episodes in the voiding diary from the baseline to the final assessment in the

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135 desmopressin add-on group was significantly superior to that seen with placebo (-1.13 ± 0.92

136 vs. -0.68 ± 0.79, p = 0.034) (Fig. 2). Some secondary end points showed significant

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137 improvement in the desmopressin add-on group compared to placebo, too (Table 2).
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138 Nocturnal urine volume and NPI were decreased significantly in the desmopressin add-on

139 group compared to placebo. IPSS total score including nocturia was decreased significantly
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140 in the desmopressin add-on group compared to placebo. In the aspect of QoL, the change in

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IPSS QoL score was not significantly different between the two groups, but ICIQ-N was

142 significantly improved in the desmopressin add-on group compared to the placebo group. The
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143 proportion of patients achieving a ≥50% reduction in the mean number of nocturia was 46.8%
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144 (22/47) in the desmopressin add-on group and 28.2% (11/39) in the placebo group (p = 0.077).

145 The percentage of patients who reported ‘much benefit’ was 89.4% in the desmopressin add-
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146 on group and 79.5% in the placebo group (p = 0.203). The proportion of patients who
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147 reported being ‘very satisfied’ was 80.9% in the desmopressin add-on group and 69.2% in the

148 placebo group (p = 0.212). The percentage of patients who reported being ‘very willing to

149 continue treatment’ was 82.9% in the desmopressin add-on group and 61.5% in the placebo

150 group (p = 0.025).

151 Safety assessments are presented for the safety set, i.e. all patients (n = 109) who received

152 at least one dose of study medication. The incidence of adverse events was similar for both
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153 treatment groups, with 9 (15.8%) patients having an adverse event in the desmopressin add-

154 on group and 11 (21.1%) patients in the placebo group. Of these patients, 7 (12.3%) in the

155 desmopressin add-on group and 5 (9.6%) in the placebo group were considered to be

156 possibly/probably related to the study medication. Most adverse events were mild, and only

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157 one serious event was recorded in the placebo group although it was not considered to be

158 possibly/probably related to the study medication (Table 3). One patient in the desmopressin

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159 add-on group had hyponatremia, serum sodium level of 122 mmol/L. It was asymptomatic

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160 and detected at the one week follow up. The medication was stopped and the patient

161 recovered without any intervention.

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162
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163 Discussion
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164 This study lends support to the findings of other results showing that adding
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165 desmopressin to alpha-blocker treatment is effective and well tolerated in the treatment of
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166 nocturia in men aged 40 65 with LUTS. In this study, the mean number of nocturia episodes
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167 in a voiding diary decreased from 2.5 ± 0.8 to 1.3 ± 0.8 in the desmopressin add-on group and

168 from 2.4 ± 0.6 to 1.6 ± 0.9 in the placebo add-on group. A significant difference in this
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169 change was found between the two groups.

170 Some studies showed relationships between alpha-blocker monotherapy and nocturia in men
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171
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with LUTS/BPH. Tamsulosin treatment for 8 weeks in LUTS/BPH patients with nocturnal

172 frequency ≥2 times per day significantly improved nocturia in about 60% of the analyzed

173 patients, nocturnal voiding frequency was decreased from 3.1 ± 1.0 to 1.7 ± 1.0, and NPI was

174 decreased from 41.9 ± 11.0% to 33.8 ± 10.9% 4. Silodosin treatment for 12 weeks in men

175 with LUTS/BPH resulted in more patients experiencing improvement in nocturia compared

176 to placebo (53.4% vs. 42.8%), and nocturia episodes were decreased from 3.0 ± 0.9 to 2.2 ±
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177 1.1 in patients with ≥2 nocturnal voids 5. Efficacy of silodosin monotherapy in improving

178 nocturnal polyuria was reported in men with BPH too 6. However, some patients who

179 received alpha-blocker monotherapy for nocturia did not improve and some worsened.

180 Although alpha-blockers can decrease nocturnal urine volume and NPI, NPI remained > 33%

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181 . The main cause of failure in nocturia treatment with alpha-blocker monotherapy in

182 patients with LUTS/BPH is nocturnal polyuria 10, 11. Although we did not analyze the data of

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183 BOO such as urodynamic parameters in this study, enrolled patients had severe LUTS, the

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184 baseline mean total IPSS was 24.9 ± 8.2 in the desmopressin add-on group and 23.2 ± 6.4 in

185 the placebo group. Thus, these patients had persistent voiding and storage symptoms in spite

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186 of alpha-blocker treatment. We also excluded patients with urgency urinary incontinence,
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187 which required anticholinergic treatment. In this study, men with LUTS and persistent

188 nocturia despite alpha-blocker treatment had a baseline mean NPI > 33%. Therefore, one of
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189 the remaining treatment options in this study population was the add-on of desmopressin to

190
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decrease nocturnal urine volume. The mean changes of nocturnal urine volume and NPI were

191 significantly different between the desmopressin add-on group and the placebo add-on group.
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192 In particular, NPI after 8 weeks of treatment was 30.7 ± 10.7 in the desmopressin add-on
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193 group but 36.9 ± 11.6 in the placebo group. The finding means that add-on desmopressin was

194 effective in treating nocturia, which has a multifactorial pathogenesis and would remain
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195 untreated by the merely relieving of BOO with alpha-blockers, by reducing the excessive
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196 urine volume produced during sleep. In addition, desmopressin add-on decreased the mean

197 total IPSS from 24.9 ± 8.2 to 19.7 ± 7.2. Although the final mean total IPSS after treatment

198 was not a relatively low level, the mean change of total IPSS was significantly different
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199 between the desmopressin add-on and placebo groups. Berges et al. reported that

200 desmopressin was effective for nocturia because nocturnal polyuria in men with LUTS/BPH

201 and total IPSS was significantly decreased by desmopressin treatment, regardless of
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202 concomitant alpha-blocker use.

203 In this study, the change of IPSS QoL score did not differ significantly between the two

204 groups. Although we did not check voiding symptoms or parameters after treatment, voiding

205 symptoms related with baseline high total IPSS could affect IPSS QoL score. However, the

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206 change in the ICIQ-N bother scale was significantly different between the two groups. Thus

207 QoL related with nocturia could be improved by desmopressin add-on. Weiss et al. 13 reported

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208 that low dose desmopressin treatment made significant improvements in health-related QoL

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209 and sleep quality compared to placebo in men with nocturia. The patient’s perception of

210 treatment, including treatment benefit and satisfaction, did not differ significantly between

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211 the two groups in this study. The patient’s perception of treatment was evaluated using the
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212 subjective tools. Thus, these results would differ from those using objective tools. Also, the

213 two groups were given behavioral therapy, which would affect the results of patient’s
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214 perception of treatment.

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A serious potential adverse event associated with using desmopressin is hyponatremia,

14, 15
216 and its risk grows with increasing age, especially in patients aged >65 yr . However, the
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217 incidence of hyponatremia in this study was 1.7% in the desmopressin add-on group. The
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218 reason for the low incidence of hyponatremia may have been related the cohort of men

219 studied were age 40–65 and older men were excluded from this study. There were no other
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220 serious adverse events related to study medication in the desmopressin add-on and placebo
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221 groups in this study. Thus, the safety of desmopressin add-on in men with persistent nocturnal

222 polyuria on alpha-blocker for LUTS was supported by this placebo-controlled study.

223 However, monitoring of serum sodium is recommended.

224 The present study had several limitations. The main outcome was a reduction in nocturia

225 episodes of -0.45. It would make diminish the clinical significance of desmopressin add-on in

226 nocturia. However, considering improvement of QoL and satisfaction with less adverse
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227 events in desmopressin add-on group, slight decrease in nocturia episodes could be relevant

228 clinically. We did not investigate or classify the type of alpha-blockers used in this study.

229 Because of the different pharmacokinetic and concentrations during the night with differences

230 in types of alpha-blockers, efficacy of alpha-blockers on nocturia might differ 16, 17. However,

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231 we enrolled patients with persistent nocturia of 2 times or more despite treatment with any

232 type of alpha-blocker for at least 8 weeks, and enrolled patients showing nocturnal polyuria

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233 by voiding diary. Thus, the type of alpha-blockers would not be expected to affect the results

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234 of desmopressin add-on therapy. We included patients younger than 65 years for safety reason,

235 thus there could be a limit to apply our results to the aspect of safety of desmopressin add-on

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236 in men > 65 years old with nocturia. Another limitation of this study was that our results were
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237 based on a relatively short duration of treatment and a small sample size. Kojima et al.

238 reported that alpha blocker treatment for 24 months reduced nighttime urine production in
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239 correlation with an increase in daytime urine production in BPH patients with nocturnal

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polyuria. Thus, further study with more patients and long-term follow-up will be needed.

241
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242 Conclusions
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243 Oral desmopressin add-on therapy can be considered for men aged 40 65 with persistent

244 nocturia on alpha-blocker monotherapy for LUTS. This placebo-controlled randomized study
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245
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demonstrated the efficacy and safety of desmopressin add-on therapy for persistent nocturia

246 in men aged 40 65 taking alpha-blockers for LUTS.

247

248

249 Conflicts of interest

250 The authors have nothing to disclose.

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251 References

252 1. Kim, T. H., Han, D. H., Lee, K. S.: The prevalence of lower urinary tract symptoms in

253 korean men aged 40 years or older: a population-based survey. Int Neurourol J, 18:

254 126, 2014

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255 2. Kupelian, V., Wei, J. T., O'Leary, M. P. et al.: Nocturia and quality of life: results from

256 the Boston area community health survey. Eur Urol, 61: 78, 2012

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257 3. Miranda Ede, P., Gomes, C. M., Torricelli, F. C. et al.: Nocturia is the Lower Urinary

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258 Tract Symptom With Greatest Impact on Quality of Life of Men From a Community

259 Setting. Int Neurourol J, 18: 86, 2014

260 4.
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Yoshida, M., Inadome, A., Masunaga, K. et al.: Effectiveness of tamsulosin
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261 hydrochloride and its mechanism in improving nocturia associated with lower urinary

262 tract symptoms/benign prostatic hyperplasia. Neurourol Urodyn, 29: 1276, 2010
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263 5. Eisenhardt, A., Schneider, T., Cruz, F. et al.: Consistent and significant improvement
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264 of nighttime voiding frequency (nocturia) with silodosin in men with LUTS
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265 suggestive of BPH: pooled analysis of three randomized, placebo-controlled, double-

266 blind phase III studies. World J Urol, 32: 1119, 2014
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267 6. Kim, Y. W., Park, J., Chung, H. et al.: The Effectiveness of Silodosin for Nocturnal

268 Polyuria in Elderly Men With Benign Prostatic Hyperplasia: A Multicenter Study. Int
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269 Neurourol J, 19: 190, 2015

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270 7. Van Kerrebroeck, P., Andersson, K. E.: Terminology, epidemiology, etiology, and

271 pathophysiology of nocturia. Neurourol Urodyn, 33 Suppl 1: S2, 2014

272 8. Wang, C. J., Lin, Y. N., Huang, S. W. et al.: Low dose oral desmopressin for nocturnal

273 polyuria in patients with benign prostatic hyperplasia: a double-blind, placebo

274 controlled, randomized study. J Urol, 185: 219, 2011

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275 9. Ahmed, A. F., Maarouf, A., Shalaby, E. et al.: The impact of adding low-dose oral

276 desmopressin therapy to tamsulosin therapy for treatment of nocturia owing to benign

277 prostatic hyperplasia. World J Urol, 33: 649, 2015

278 10. Bae, W. J., Bae, J. H., Kim, S. W. et al.: Desmopressin add-on therapy for refractory

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279 nocturia in men receiving alpha-blockers for lower urinary tract symptoms. J Urol,

280 190: 180, 2013

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281 11. Yoong, H. F., Sundaram, M. B., Aida, Z.: Prevalence of nocturnal polyuria in patients

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282 with benign prostatic hyperplasia. Med J Malaysia, 60: 294, 2005

283 12. Berges, R., Hofner, K., Gedamke, M. et al.: Impact of desmopressin on nocturia due

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284 to nocturnal polyuria in men with lower urinary tract symptoms suggestive of benign
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285 prostatic hyperplasia (LUTS/BPH). World J Urol, 32: 1163, 2014

286 13. Weiss, J. P., Herschorn, S., Albei, C. D. et al.: Efficacy and safety of low dose
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287 desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter,

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randomized, double-blind, placebo controlled, parallel group study. J Urol, 190: 965,

289 2013
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290 14. van Kerrebroeck, P., Rezapour, M., Cortesse, A. et al.: Desmopressin in the treatment
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291 of nocturia: a double-blind, placebo-controlled study. Eur Urol, 52: 221, 2007

292 15. Rembratt, A., Riis, A., Norgaard, J. P.: Desmopressin treatment in nocturia; an
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293 analysis of risk factors for hyponatremia. Neurourol Urodyn, 25: 105, 2006
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294 16. Zhang, K., Yu, W., Jin, J. et al.: Effect of doxazosin gastrointestinal therapeutic system

295 4 mg vs tamsulosin 0.2 mg on nocturia in Chinese men with lower urinary tract

296 symptoms: a prospective, multicenter, randomized, open, parallel study. Urology, 78:

297 636, 2011

298 17. Nishino, Y., Masue, T., Miwa, K. et al.: Comparison of two alpha1-adrenoceptor

299 antagonists, naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary
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300 tract symptoms with benign prostatic hyperplasia: a randomized crossover study. BJU

301 Int, 97: 747, 2006

302 18. Kojima, Y., Sasaki, S., Imura, M. et al.: Tamsulosin reduces nighttime urine

303 production in benign prostatic hyperplasia patients with nocturnal polyuria: a

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305 Urodyn, 31: 80, 2012

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306 Figure Legends

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308 Fig. 1 - Disposition of patients. ITT: intention to treat

309 Fig. 2 - Mean change in number of nocturia events in the voiding diary from baseline to

310 final assessment

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Table 1. Baseline clinical characteristic of studied patients

Desmopressin add on Placebo add on p-value

(n = 47) (n = 39)

Age (years) 59.2 ± 5.1 60.3 ± 4.5 0.675

Height (cm) 169.8 ± 4.6 168.1 ± 3.9 0.654

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Weight (kg) 68.8 ± 8.1 66.3 ± 8.1 0.161
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BMI (kig/m ) 23.9 ± 2.6 23.4 ± 2.5 0.463

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Laboratory data

Serum Sodium (mmol/L) 141.3 ± 2.4 140.8 ± 1.9 0.270

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Serum Potassium, (mmol/L) 4.4 ± 0.3 4.2 ± 0.4 0.129

Serum Creatinine (mg/dL) 0.94 ± 0.11 0.99 ± 0.16 0.308

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IPSS
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Total score 24.9 ± 8.2 23.2 ± 6.4 0.532

Nocturia (Q7) 4.3 ± 1.1 4.1 ± 1.1 0.458

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QoL score 5.0 ± 1.1 5.1 ± 0.9 0.623

Voiding diary
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Number of nocturia 2.5 ± 0.8 2.4 ± 0.6 0.429

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Nocturnal urine volume (ml) 780.3 ± 234.2 723.8 ± 229.3 0.105

NPI (%) 44.6 ± 8.9 42.1 ± 9.8 0.528

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BMI: body mass index, IPSS: international prostate symptom score, QoL: quality of life, NPI:

nocturnal polyuria index

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Table 2. Secondary end points

Desmopressin add on Placebo add on p-value

baseline 8 weeks Change baseline 8 weeks Change

PT
*
Nocturnal urine 780.3 ± 234.2 496.7 ± 205.7 -283.6 ± 217.7 723.8 ± 229.3 611.2 ± 270.3 -112.6 ± 231.1 <0.001

RI
volume (ml)

SC
*
NPI (%) 44.6 ± 8.9 30.7 ± 10.7 -13.9 ± 13.0 42.1 ± 9.8 36.9 ± 11.6 -5.1 ± 11.4 0.001

IPSS

U
*
Total score 24.9 ± 8.2 19.7 ± 7.2 -5.2 ± 6.7 23.2 ± 6.4 20.6 ± 7.5 -2.5 ± 5.0 0.042

AN
*
Nocturia (Q7) 4.3 ± 1.1 2.9 ± 1.3 -1.4 ± 1.2 4.1 ± 1.1 3.5 ± 1.4 -0.6 ± 1.4 0.004

QoL score 5.0 ± 1.1 3.8 ± 1.2 -1.2 ± 1.1 5.1 ± 0.9 4.4 ± 1.3 -0.7 ± 1.1 0.070

M
ICIQ-N

D
*
Nocturia 3.7 ± 0.7 2.5 ± 1.0 -1.1 ± 0.7 3.6 ± 0.6 2.9 ± 0.8 -0.7 ± 0.7 0.013

TE
*
Bother scale 6.7 ± 2.1 3.3 ± 2.6 -3.3 ± 2.4 6.6 ± 2.6 5.0 ± 2.8 -1.6 ± 2.7 0.001

Nocturnal
EP
3.3 ± 1.5 2.5 ± 1.2 -0.8 ± 1.2 3.2 ± 1.8 2.8 ± 1.7 -0.4 ± 1.2 0.226
hesitancy score
C

NPI: nocturnal polyuria index, IPSS: international prostate symptom score, QoL: quality of life, ICIQ-N: International Consultation on Incontinence
AC

*
Questionnaire-Nocturia, : statistically significant
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Table 3. Adverse events in safety set

Desmopressin add on Placebo add on p-value

(n = 57) (n = 52)

Total patients with AEs 9 (15.8%) 11 (21.1%) 0.469

Serious AE

PT
Rib fracture 0 (0.0%) 1 (1.9%)

AEs related to study medication 7 (12.3%) 5 (9.6%) 0.657

RI
Serious AE 0 0

Mild AE

SC
Dyspepsia 1 (1.7%) 2 (3.8%)

Nausea 3 (5.3%) 0 (0.0%)

U
Abdominal discomfort 0 (0.0%) 1 (1.9%)
AN
Dry mouth 0 (0.0%) 1 (1.9%)

Hyponatremia 1 (1.7%) 0 (0.0%)

M

Dysuria 1 (1.7%) 1 (1.7%)

Urinary hesitation 1 (1.7%) 0 (0.0%)

D

Dizziness 1 (1.7%) 0 (0.0%)

TE

Headache 1 (1.7%) 0 (0.0%)

Motion thickness 1 (1.7%) 0 (0.0%)

EP

Erectile dysfunction 1 (1.7%) 0 (0.0%)

Fatigue 0 (0.0%) 1 (1.9%)

C

Acne 0 (0.0%) 1 (1.9%)

AE: adverse event

AC
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PT
RI
U SC
AN
M
D
TE
EP
C
AC
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PT
RI
U SC
AN
M
D
TE
EP
C
AC
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Key of definition for abbreviations

LUTS, lower urinary tract symptoms

BPH, benign prostatic hyperplasia

PT
QoL, quality of life

BOO, bladder outlet obstruction

RI
IPSS, International Prostatic Symptom Score

SC
ICIQ-N, International Consultation on Incontinence Questionnaire-Nocturia

U
NPI, nocturnal polyuria index
AN
ITT, intent-to-treat
M
D
TE
C EP
AC