Efficacy and safety of 25 and 50 μg desmopressin orally disintegrating tablets in Japanese patients with nocturia due to nocturnal polyuria: Results from two phase 3 studies of a multicenter randomized double‐blind placebo‐controlled parallel‐group development program

Abstract This study assessed the efficacy and safety of desmopressin orally disintegrating tablets (ODTs) in Japanese males (50 and 25 μg) and females (25 μg) with nocturia due to nocturnal polyuria (NP). Two Phase 3 randomized double‐blind placebo‐controlled studies of 342 males and 190 females with nocturia due to NP were conducted. The primary endpoint was change from baseline in mean number of nocturnal voids. In addition, time to first awakening to void, nocturnal urine volume, NP index (NPI), and quality of life were assessed during a 12‐week treatment period. In males, 50 and 25 μg desmopressin ODTs significantly reduced the number of nocturnal voids by −1.21 (P < .0001) and − 0.96 (P = .0143), respectively, and significantly prolonged the time to first awakening to void by 117.60 minutes (P < .0001) and 93.37 minute (P = .0009), respectively, with no safety concerns. In females, 25 μg desmopressin ODT significantly prolonged the time to first awakening to void by 116.11 minutes (P = .0257), with no safety concerns. The reduction in the number of nocturnal voids (−1.11) was not significantly different compared with placebo (P = .0975). Desmopressin ODTs (50 and 25 μg) were an effective and well‐tolerated treatment for nocturia due to NP in Japanese males, and desmopressin ODT 50 μg is an appropriate dose in these patients. For patients who are likely to experience hyponatremia, such as elderly males, starting with 25 μg desmopressin ODT should be considered.


| INTRODUCTION
Nocturia is a lower urinary tract symptom that occurs more frequently in both males and females with aging. It was defined as "Waking to pass urine during the main sleep period" by the International Continence Society (ICS) in 2018. 1,2 Nocturia is thought to be primarily caused by nocturnal polyuria (NP), which is the excretion of an excessive amount of urine while sleeping despite 24-hour urine volume being normal. However, the ICS Standardisation Committee defined nocturia more specifically as nocturnal urine volume that exceeds 33% of the total 24-hour urine volume for elderly patients, and 20% for younger patients. 2 Repeatedly waking up at night to void due to NP causes lack of sleep and reduced sleep quality, which markedly reduces a patient's quality of life (QoL), interfering with daily life. Therefore, appropriate treatment is needed. Nocturia associated with NP has been reported to be related to decreased secretion of the antidiuretic hormone arginine vasopressin (AVP). 3 Desmopressin acetate, a synthetic AVP analog, has proven to be an effective and well-tolerated treatment in both male 4 and female 5 patients with nocturia. An orally disintegrating tablet (ODT) containing desmopressin quickly disintegrates when placed under the tongue and can be taken without water, simplifying administration.
At the present time, 60, 120, and 240 μg desmopressin ODTs (daily doses of 60, 120 and 240 μg, respectively) and 100 and 200 μg desmopressin tablets (daily doses of 100, 200 and 400 μg) have been approved in over 80 countries worldwide for the indication "nocturia associated with idiopathic NP in adults", and 25 μg desmopressin ODT for women and 50 μg desmopressin ODT for men have been approved in over 35 countries worldwide that can be used more safely, especially by patients who are likely to experience hyponatremia. The efficacy of desmopressin ODT 25 μg desmopressin ODT for women and 50 μg desmopressin ODT for men was confirmed as statistically superior to placebo in all efficacy endpoints in global studies. 6,7 In Japan, a Phase 2 study suggested a lower dose of desmopressin ODT may be effective in Japanese male and female patients with nocturia. 8 The study also confirmed a sex difference in sensitivity to desmopressin, and that the optimum dose for NP treatment is lower in females than in males. 8 Herein we report the results of two separate clinical studies (NCT02904759 and NCT02905682) of the efficacy and safety of 25 and 50 μg desmopressin ODTs in male patients and 25 μg desmopressin ODT in female patients versus placebo. The primary efficacy endpoint was change from baseline in the mean number of nocturnal voids during 12 weeks of treatment. Other secondary endpoints, namely time to first awakening to void, nocturnal urine volume, NP index (NPI), and patient-reported outcomes, and safety were also evaluated.

| Study design
The clinical program comprised two separate clinical studies in male and female patients with nocturia (two or more nocturnal voids) due to NP defined as an NPI ≥33%. During the 12-week treatment period randomized double-blind parallel group studies, desmopressin was compared to placebo at 57 (NCT02904759) and 50 (NCT02905682) sites in Japan from September 2016 to September 2017. The studies were approved by the institutional review board for each site and were conducted in accordance with the Declaration of Helsinki, Good Clinical Practice of International Conference on Harmonisation, Good Clinical Practice in Japan, and applicable regulatory requirements. All patients provided written informed consent before participating in the studies.

| Patients
For screening, eligible patients in both studies were male or female aged ≥20 years with at least two nocturnal voids for 6 months or more. Prior to the randomization, a 1-week placebo run-in/lifestyle change was conducted. During this period, patients were instructed to follow the water consumption and voiding guidance. Subsequently, the eligibility criteria were two or more nocturnal voids (average of 3 days); NP, defined as an NPI ≥33%; and bothered by nocturia, defined as a score ≥ 2 on the Hsu five-point Likert bother scale (moderate to extremely bothered). 9 Patients with interstitial cystitis (IC), overactive bladder (OAB), or benign prostatic hyperplasia (BPH) exceeding the stipulated criteria, urinary disorders (eg, severe stress incontinence, heart disease, and uncontrolled hypertension or diabetes) were excluded to eliminate the effects of these conditions on the efficacy evaluation of desmopressin ODT for nocturia associated with NP. Patients with coexisting psychogenic or habitual polydipsia (24-hour urine output >2.8 L), hyponatremia (serum sodium concentration < 135 mEq/L), or syndrome of inappropriate antidiuretic hormone secretion (SIADH) were excluded to avoid the risk of onset of hyponatremia.
Sample size was based on the hypothesis of demonstrating superiority of 25 μg desmopressin ODT in female patients and superiority of 50 and 25 μg desmopressin ODTs in male patients when tested against placebo on the primary endpoint, with an overall power of 90% and an overall Type I error rate of 5% (two-sided). Therefore, 89 patients for each group in the female study and 100 patients for each group in the male study were required to demonstrate superiority of desmopressin ODT.

| Study treatment and procedures
The studies were comprised of placebo run-in/lifestyle changes and double-blind periods. During the placebo run-in/lifestyle changes period, patients took one placebo ODT every night approximately 1 hour prior to bedtime for 1 week. All subjects were given instructions regarding lifestyle changes (eg, limiting fluid intake and emptying the bladder before going to bed) throughout the entire duration of the trial (including the placebo run-in/lifestyle changes period). Subsequently, patients who satisfied the inclusion and exclusion criteria were randomized to one of two treatment groups (25 μg desmopressin ODT, placebo) in a 1: 1 ratio for females and three treatment groups (50 or 25 μg desmopressin ODT, placebo) in a 1: 1: 1 ratio for males, stratified by age (<65 and ≥65 years).
In the 12-week double-blind period, patients took the investigational product every night approximately 1 hour prior to bedtime for 12 weeks. In addition, subjects recorded nocturnal voiding information and sleep status using a voiding diary for three consecutive days immediately before each scheduled visit, and completed the Nocturia Quality-of-Life (N-QoL) questionnaire to assess the effect of nocturia on health-related QoL. [10][11][12] The N-QoL has been translated and culturally validated to a Japanese setting. 13 The quality of sleep was evaluated using the Insomnia Severity Index (ISI), 14 and the bothersomeness of nocturia was assessed using the Hsu fivepoint Likert bother scale. 9 To monitor hyponatremia, patients with a serum sodium concentration <135 mM at screening were excluded from the studies, and serum sodium concentrations were measured on Days 3 and Weeks 1,2,4,8 and 12, or post-dose for discontinued subject. Subjects were asked to come to the hospital for additional tests and examinations if the serum sodium concentration was ≤130 mM. Subjects were instructed to stop taking the investigational product if their serum sodium concentration was ≤125 mM. In addition, subjects were withdrawn from the study if they were diagnosed with water intoxication, if B-type natriuretic peptide (BNP) exceeded 100 pg/mL, or if 24-hour urine volume exceeded 2.8 L due to psychogenic or habitual polydipsia during the trial period.

| Study endpoints
The primary efficacy endpoint was change from baseline in the mean number of nocturnal voids during 12 weeks of treatment, which has been the standard primary efficacy endpoint in multiple clinical trials of nocturia since overseas clinical trials began in the early 2000s. 15 The secondary efficacy endpoints were: he safety and tolerability of desmopressin ODT treatment were evaluated by the monitoring of adverse events (AEs) based on hematology, blood chemistry, urinalysis, vital signs, and physical findings. AEs were coded to system organ class (SOC) and preferred term (PT) using Medical Dictionary for Regulatory Activities (MedDRA/J), https://www. meddra.org/how-to-use/support-documentation/japanese.

| Statistical analysis
The primary efficacy endpoint was assessed for the full analysis set (FAS), which consisted of all randomized (as planned) patients who had at least one post-baseline measurement for the mean number of nocturnal voids. Analysis was performed based on the planned (randomly assigned) treatment. Desmopressin ODT groups were compared with the placebo group with regard to change from baseline in efficacy variables using longitudinal analysis by repeated-measures analysis of covariance (ANCOVA), with baseline value as a covariate and treatment, visit, age group, and interaction between treatment and visit as fixed effects.
In the male study where multiple doses were evaluated, the overall significance level was controlled at 5% with a closed testing procedure where the superiority of the low dose was tested against placebo using a two-sided test at a 5% significance level after superiority of the high dose was established against placebo using a twosided test at a 5% significance level.

| Study population
In the male study, 342 male patients were randomized: 109 and 115 in the 50 and 25 μg desmopressin ODT groups, respectively, and 118 patients to the placebo group. Of the randomized subjects, 338 male patients were included in the FAS because all data from the double registration subjects were excluded from the FAS. Finally, 318 patients (93.0%) completed the study, and 24 (7%) withdrew, primarily because of onset of an AE and withdrawal of consent. In the female study, 190 patients were randomized (92 and 98 in the 25 μg and placebo groups, respectively) and 187 female subjects were included in the FAS.
Finally, 185 patients (97.4%) completed the trial, and 5 (2.6%) withdrew primarily because of onset of an AE. The number of subjects who withdrew from the study because of an AE was 4 (3.5%) and 2 (1.8%) in the 25 and 50 μg desmopressin ODT groups in the male study and 2 (2.2%) in the 25 μg desmopressin ODT group in the female study.
Patient demographics and characteristics are given in Table 1.
There were no differences of note between the treatment groups with regard to demographic data and baseline voiding parameters in both studies ( Table 2). The mean number of nocturnal voids at baseline was similar across treatment groups (2.41-2.53 voids in males; 2.41-2.46 in females). The mean time to first void at baseline was 152 to 158 minutes in males and 144 to 150 minutes in females.

| Efficacy
Results of the efficacy endpoints are given in Tables 3 and 4.

| Number of nocturnal voids
In males, the change from baseline in the mean number of nocturnal voids during 12 weeks of treatment, as a primary endpoint, in the 50 and 25 μg desmopressin ODT and placebo groups was −1.21, −0.96, and − 0.76, respectively. A significant reduction compared with the placebo group was found in both treatment groups (P < .0001 and P = .0143, respectively), confirming that 50 and 25 μg desmopressin ODTs are effective in the treatment of nocturia in male patients (Table 3; Figure 1). The absolute change from baseline in the 50 μg desmopressin ODT group was 26% larger than that in the 25 μg desmopressin ODT group.
In females, the change from baseline in the mean number of nocturnal voids in the 25 μg desmopressin ODT and placebo groups was −1.11 and − 0.95, respectively. No significant reduction compared with the placebo group was observed in the 25 μg desmopressin ODT group, but the reduction was numerically greater in the latter group compared with the placebo group (P = .0975; Table 3; Figure 2).   Figure 4).

| Safety and tolerability
The safety results are summarized in  Because of the pharmacological effect of desmopressin, hyponatremia was an AE of special interest. According to MedDRA PT, hyponatremia could be reported as an AE of either hyponatremia or blood sodium decrease. In females, no hyponatremia or blood sodium decrease was reported as an AE throughout the 12-week treatment period. In males, hyponatremia and blood sodium decrease, as related AEs, were reported by 1.8% and 0.9% of subjects in the 50 μg and 25 μg groups, respectively; all three subjects were ≥65 years of age.
There were two AEs of mild intensity, namely hyponatremia in two male subjects receiving 50 μg desmopressin ODT; both these subjects were aged ≥65 years. One of these two subjects was withdrawn from the trial due to the AE; in this subject, serum sodium concentrations were 134 and 133 mM at follow-up after discontinuation of treatment. The other subject recovered from the AE after the completion of treatment. There was one AE of mild intensity, namely blood sodium decrease, which was reported in one male subject receiving 50 μg desmopressin ODT. This subject was also >65 years of age, and recovered from the AE after the completion of desmopressin administration. The AE of blood sodium decrease was assessed by the investigator to have a reasonable possibility to be related to the desmopressin.  16 In Japanese females, the decrease from baseline in the mean number of nocturnal voids in the 25 μg desmopressin ODT group was numerically greater than that in the placebo group (−1.11 and −0.95, respectively). In addition, 25 μg desmopressin ODT significantly improved secondary efficacy endpoints compared with placebo. A statistically significant difference compared with placebo was not found in the change in the mean number of nocturnal voids throughout the 12-week treatment period. Weiss et al. 16 reported that 25 μg desmopressin ODT was statistically superior to placebo in all efficacy endpoints in a global female study.

| DISCUSSION
The lack of a significant difference in Japanese females in the change in the mean number of nocturnal voids between the 25 μg desmopressin ODT and placebo groups could be due to several reasons. First, an evident placebo effect was seen in females. A numerically greater placebo effect was observed in key efficacy endpoints in females receiving placebo compared with males. This effect was also seen in Japanese patients in the early Phase II study. 8  F I G U R E 4 Change from baseline in the mean time to first awakening to void throughout the 12-week treatment in females (full analysis set). ODT, orally dissolving tablet medication effects ( Figure 5). To avoid the placebo effect we set a 1 week placebo run-in/lifestyle change period. A longer placebo run-in period, such as ≥2 weeks, is preferable, such as in recent randomized control trials for lower urinary tract symptoms, 17 but at this moment there is no clear evidence and general consensus on the optimal length of lifestyle change. In addition, the 1-week run-in period allowed the investigator to ascertain which subjects would be most likely to comply with the treatment.
However, it should be noted that the efficacy of 25 μg desmopressin ODT for females has been confirmed as statistically superior to placebo for the change in the mean number of nocturnal voids in global studies. 6,7 The higher reactions of females in the Japanese study to placebo have also been reported in the development of therapeutic products for patients with irritable bowel syndrome (IBS). 18,19 In addition, the lifestyle modifications and behavioral reinforcement during the study (through the large num-  In male patients with nocturia due to NP who were treated with 50 and 25 μg desmopressin ODTs throughout the 12 weeks, the primary objective was achieved and efficacy was consistently observed in time to first awakening to void, nocturnal urine volume, and NPI as secondary endpoints. These results indicate the clinical benefits of desmopressin ODT that include not only a reduction in nocturnal voids, but also an effective prolongation in the time to first awakening to void, which had the greatest effect on improving sleep quality, and represented the true aim of nocturia treatment. The effects of desmopressin ODT were statistically significant. Furthermore, the treatment improved health-related QoL in nocturia patients. In males, 50 μg desmopressin had higher efficacy than did 25 μg desmopressin and there were no safety issues.
The findings above confirm the superiority of 50 and 25 μg desmopressin ODTs compared with placebo for Japanese males.
Therefore, we determined that 50 μg desmopressin ODT is an appropriate dose for males with nocturia due to NP. For patients who are more likely to experience hyponatremia, especially elderly male patients with low body weight (<50 kg), low body mass index (<18.5 kg/m 2 ), poor physiological status, or impaired renal function, 25 μg desmopressin ODT should be considered as a starting dose and the patients should be frequently monitored for hyponatremia.
In summary, the results of this study demonstrate that 50 and 25 μg desmopressin ODTs were efficacious in treating Japanese male patients with nocturia due to NP. In addition, 50 and 25 μg desmopressin ODTs were determined to be safe and well tolerated; therefore, it can be concluded that the risk-benefit profiles for 50 and 25 μg desmopressin ODTs are favorable for treating male patients with nocturia due to NP. In particular, the findings also determined that 50 μg desmopressin ODT is the optimal dose for males, providing clinically meaningful benefits. For elderly patients who are more likely to experience hyponatremia, 25 μg desmopressin ODT should be con-