Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial
Division of LUTS Research, Nihon University School of Engineering, Koriyama, Japan
What's known on the subject? and What does the study add?
Desmopressin orally disintegrating tablet (ODT) 60–240 μg has proved an effective and well-tolerated antidiuretic treatment in male and female patients with nocturia. The main adverse event is hyponatraemia. Recent studies suggest that female patients are more sensitive to desmopressin ODT, achieving the same efficacy at lower doses than male patients.
The study demonstrates the efficacy of desmopressin ODT in male and female Japanese patients with nocturia. It provides further evidence that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males. Tailoring the dose according to gender provides an improved therapeutic window with the benefits of a decreased risk of hyponatraemia without compromising efficacy.
To establish the dose–response efficacy of desmopressin in a Japanese patient population for the treatment of nocturia.
To explore gender differences in sensitivity to desmopressin in Japanese patients with nocturia.
Patients and Methods
A phase II multicentre, randomized, placebo-controlled, double-blind, parallel-group, comparative clinical trial was conducted.
Subjects aged 55–75 years, with a mean of ≥2 voids per night, were included and randomized to receive placebo or one of four doses of desmopressin orally disintegrating tablet (ODT): 10 μg, 25 μg, 50 μg or 100 μg.
The dose–response relationship of pharmacodynamic variables measured after a single dose of desmopressin administered to water-loaded subjects (treatment period 1) was compared with the primary clinical endpoint of change from baseline in mean number of nocturnal voids, after 28 days of desmopressin treatment (treatment period 2).
A total of 116 patients were treated in treatment period 1 of whom 113 qualified for treatment period 2, and 111 completed the study.
In treatment period 1 a dose–response relationship was observed, both overall and in each gender group. Overall, the duration of antidiuretic action (DOA; time with urine osmolality >200 mOsm/kg) for the 25, 50 and 100 μg doses was 2 h (P = 0.010), 3.45 h (P < 0.001) and 5.74 h (P < 0.001), respectively; all statistically significant compared with placebo.
Female patients were found to be more sensitive to desmopressin; DOA in female patients was longer than in male patients after desmopressin 25 and 50 μg. Extrapolation suggests that male patients require ∼58 μg to achieve similar DOA to females receiving 25 μg.
A dose–response relationship was also seen in treatment period 2 for the group overall with a greater reduction in mean number of nocturnal voids from baseline to day 28 at higher doses, and with significant reductions in the 25- (P = 0.015) 50- (P < 0.001) and 100-μg (P = 0.001) dose groups compared with placebo. Similar dose–response relationships were also seen when the data were analysed by gender.
Desmopressin ODT was well tolerated with no serious or severe adverse events.
A dose–response relationship for desmopressin ODT was shown in a population of Japanese patients with nocturia.
The study suggests that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males, indicating a gender-specific therapeutic window with a decreased risk of hyponatraemia without compromising efficacy on reduction of nocturnal voids.
Further dose-finding studies are planned to confirm the recommended dose for the treatment of nocturia in a Japanese patient population.
Nocturia, the need to wake to void during the night , has long been considered to be one of the symptoms of BPH; however, epidemiological data show that the overall prevalence of nocturia is similar in both sexes and focus has therefore shifted to consider nocturia as an independent LUTS .
Treating nocturia symptoms with the traditional approaches used for BPH and overactive bladder, such as α-blockers and antimuscarinic agents, has provided only marginal therapeutic impact and the clinical significance of these changes has been considered doubtful [3, 4]. The majority of patients with nocturia have nocturnal polyuria (NP) [5-10], an overproduction of urine at night . NP is linked with decreased secretion of the antidiuretic hormone arginine vasopressin (AVP) [11-15], and there is clinical evidence that antidiuretic treatment provides a clinically significant reduction in nocturia symptoms . Desmopressin acetate, a synthetic analogue of AVP, has proved an effective and well-tolerated treatment in both male  and female  patients with nocturia.
An orally disintegrating tablet (ODT) containing desmopressin (MINIRIN® Melt, Ferring Pharmaceuticals, Saint-Prex, Switzerland), which is administered sublingually without water, has been available since 2005 and is now approved for the treatment of nocturia in 57 countries. This formulation is associated with increased bioavailability, allowing lower dosing than with the original solid tablets .
In Japan, desmopressin is indicated for central diabetes insipidus and nocturnal enuresis, but is not yet indicated for nocturia . The overall purpose of the current trial was to characterize the dose–response relationship of desmopressin ODT in Japanese patients with nocturia in order to establish correct dose recommendations in the Japanese patient population.
Recently, significant gender differences were shown in the antidiuretic response to desmopressin; with a higher median effective dose value reported for reduction in nocturnal urine volume in male compared with female patients with nocturia, suggesting a greater renal sensitivity to desmopressin in males ; therefore, the present trial was also designed to explore gender differences in sensitivity to desmopressin in Japanese patients with nocturia.
Patients and Methods
Adults aged 55–75 years, with a mean of ≥2 voids/night in a 3-day frequency–volume chart during screening were included. A total of 10 patients of each gender were recruited to each dose level to provide an estimate of dose response to desmopressin ODT. Key exclusion criteria were: bladder obstruction or a urine flow <5 mL/s, surgical treatment of bladder obstruction or prostatic hyperplasia ≤6 months before the study, patients showing symptoms of BPH, overactive bladder or interstitial cystitis, patients with a mean number of nocturnal voids >4 per night in a consecutive 3-day period during the screening, or hyponatraemia (serum sodium <135 mEq/L) after desmopressin administration. All patients provided written informed consent. The study aimed to recruit 10 patients of each gender to all treatment groups to estimate the response to desmopressin. No formal power calculations were performed.
The study was approved by the institutional review board or ethics committee for each site. The study was registered on http://www.clinicaltrials.gov (NCT01184859).
Study Design and Procedures
We conducted a two-part, phase II, randomized, double-blind, placebo-controlled, parallel group study at 36 sites in Japan from July 2010 to April 2011. The trial comprised one screening (observation) period and two treatment periods for each randomized subject.
Screening period: Within 21 days of randomization, records of nocturnal voiding and sleep over a consecutive 3-day period were kept in a voiding and sleep diary.
Treatment period 1: Eligible subjects were randomized to one of the five treatment cohorts (placebo or desmopressin ODT 10, 25, 50 or 100 μg), according to a computer-generated randomization list and stratified by age and gender to ensure balanced groups (Fig. 1). Desmopressin ODT and placebo were supplied by Ferring Pharmaceuticals A/S and were indistinguishable with respect to appearance, smell, taste and packaging. Treatments were packaged according to the computer-generated randomization code to ensure that patients, investigators and the sponsor remained fully blinded.
All dose levels were investigated by administering a single dose on day 1. Water-loading to suppress the endogenous release of AVP and ensure that all antidiuretic activity was related to desmopressin administration was initiated 2 h before dosing on day 1. A single dose of randomized treatment was then administered to determine the antidiuretic effect. Urine volume was measured and samples were taken to determine urine osmolality every 30 min for the duration of urine production <0.12 mL/kg/min. Water loading was terminated if no antidiuretic effect was observed within 3 h of dosing. Otherwise, hydration continued until urine production returned to >0.12 mL/kg/min, or for a maximum of 12 h after dosing.
Treatment period 2: After a washout period of 2–4 days, patients received their randomized treatment 1 h before bedtime for a period of 28 days to evaluate the clinical effect of desmopressin. Patients were instructed to empty their bladder before bed and drink only to satisfy thirst. Evening intake of diuretic fluids was especially discouraged. Subjects attended regular study visits during this period.
Diaries and Questionnaires
During screening and treatment period 2, patients completed voiding and sleep diaries over three consecutive days to record the time and volume of voids, and the initial period of undisturbed sleep (time from falling asleep to first nocturnal void). To evaluate the impact of treatment on quality of life (QoL), patients were asked to respond to two QoL questionnaires at baseline and day 28; the Pittsburgh Sleep Quality Index (PSQI) and the nocturia QoL (N-QoL) questionnaire (13 statements in two domains: sleep/energy and bother/concern). Patients rated each statement from 0 (lowest QoL) to 4 (highest QoL). The raw scores were then transformed into a standardized score out of 100.
The primary endpoint in treatment period 1 was the duration of antidiuretic action (DOA), defined as the time period with urine osmolality >200 mOsm/kg (maximum 12 h). Secondary endpoints included the time period with urine production <0.12 mL/kg/min, the area under the urine osmolality–time curve (AUCosm), and the area under the urine production–time curve (AUCurine prod).
The primary endpoint in treatment period 2 was change in mean number of nocturnal voids from baseline to day 28. Secondary endpoints included change in initial period of undisturbed sleep from baseline, change in diuresis (nocturnal urine volume) from baseline, change in NP index (NPI; nocturnal urine volume/24-h urine volume [%]) from baseline and change in QoL from baseline.
Safety and Tolerability
Safety and tolerability were monitored via observation and assessment of adverse events (AEs). AEs were coded by the system organ class and preferred terms using MedDRA (Medical Dictionary for Regulatory Activities), and categorized by severity, seriousness and likelihood of causal relationship to study medication as rated by the investigator. AEs were monitored at each visit using a standard non-leading question such as ‘How do you feel since your last visit?’.
Serum sodium was measured at baseline and on all study visits. During the first treatment period, serum sodium was measured pre-dose and at discharge from the trial site. Randomization was stratified by gender and age (≥/<65 years) to ensure that risk for hyponatraemia would be balanced among the groups. If serum sodium was ≤130 mEq/L, the patient was asked to visit the trial site as soon as possible for further evaluation.
Additional safety measurements included clinical laboratory results (haematology, serum chemistry and urine analysis), vital signs (diastolic blood pressure, systolic blood pressure, heart rate and body temperature) and physical examinations. All patients who received ≥1 dose of the study drug or placebo and had ≥1 safety assessment were included in the safety analyses.
We analysed the per-protocol (PP) dataset, which included all randomized and exposed patients, except those excluded as a result of major protocol violations and those with <80% compliance. The analysis was based on the PP analysis dataset using observed cases only. Missing values, excluding the number of nocturnal voids after treatment, were treated as missing. Missing nocturnal voids after treatment were imputed using last observation carried forward, assuming at least one post-baseline measurement was available from before the missing observation.
Data from treatment period 1 were tabulated and analysed using summary statistics (mean [sd] values). Data were plotted against dose for patients overall and by gender, to determine if there was a gender difference in response to desmopressin. A t-test was performed to compare DOA for each active treatment group with placebo.
Data from all endpoints from treatment period 2 were tabulated overall and by gender as change from baseline to day 28 and summarized as mean (sd) values or 95% CIs. The change from baseline to day 28 in mean number of nocturnal voids in the overall population was analysed using ancova with the change in number of nocturnal voids from baseline to day 28 as a dependent variable, and gender, baseline number of nocturnal voids, DOA, and treatment groups as explanatory variables. The change from baseline to day 28 in mean number of nocturnal voids in the male and female populations was analysed using a t-test. The relationship between DOA and change from baseline to day 28 in mean number of nocturnal voids was modelled using linear regression, including data from all treatment groups and placebo, and not correcting for other covariates.
Patient Disposition and Demographics
Patient disposition throughout the study is shown in Fig. 1. Overall, 177 patients entered screening and 139 patients were randomized to treatment. Across treatment groups, 23 patients discontinued before dosing in treatment period 1 (22 patients owing to urine production during water loading pre-dose not reaching >0.12 mL/kg/min within 2 h and one because of not meeting inclusion/exclusion criteria). Three patients withdrew after dosing in treatment period 1 (one owing to onset of AEs, one owing to urine production not reaching >0.12 mL/kg/min within 2 h before dosing and one owing to non-compliance with trial protocol). Two subjects discontinued in treatment period 2 (one through patient choice and one because of onset of AEs).
Baseline demographics of the PP population are shown in Table 1. Overall, groups were well balanced. The mean number of nocturnal voids at baseline was similar across treatment groups (2.16–2.45). Mean nocturnal urine volume was ∼600 mL and more than half the patients had a NPI of >33%, with an overall population mean NPI of 35%.
Table 1. Baseline demographics (PP population)
Placebo, n = 23
10 μg, n = 23
25 μg, n = 22
50 μg, n = 21
100 μg, n = 23
Age, n (%)
55 ≤ × <65 years
65 ≤ × <76 years
Gender, n (%)
Baseline no. of nocturnal voids
Baseline number of daytime voids
Nocturnal urine volume, mL
24-h urine volume, mL
NPI, n (%)
Treatment Period 1 (Single Dose in Water-Loaded Patients)
There was an increase in the DOA with increasing dose (Table 2). Urine osmolality was >200 mOsm/kg in the overall population for 2 h (P = 0.010), 3.45 h (P < 0.001) and 5.74 h (P < 0.001), after desmopressin 25, 50 and 100 μg, respectively; all significant compared with placebo.
Table 2. Pharmacodynamic characteristics after a single dose of treatment: treatment period 1 (PP population)
In male patients, the DOA of the 50 and 100 μg doses was 2.4 h (P = 0.018) and 5.9 h (P < 0.001), respectively; both significant compared with placebo (Table 2). In female patients the DOA for the 25, 50 and 100 μg doses was 3 h (P = 0.010), 4.41 h (P < 0.001) and 5.59 h (P < 0.001), respectively; all significant compared with placebo. Comparison of DOA in male and female patients suggested that male patients require ∼58 μg desmopressin to achieve an equivalent DOA to that achieved in females receiving 25 μg desmopressin (Fig. 2). This yields an effective male/female dose ratio of 2.3, suggesting female patients are more sensitive to desmopressin.
The secondary endpoints, time with urine production <0.12 mL/kg/min, AUCosm and AUCurine prod, all increased with increasing desmopressin dose in all patients (Table 2). There was a greater increase in time with urine production <0.12 mL/kg/min for female vs male patients in the 10-, 25- and 50-μg treatment groups. There was a greater increase in AUCosm after desmopressin 25, 50 and 100 μg and AUCurine prod after desmopressin 10 and 25 μg in female vs male patients.
A dose–response relationship was observed for all pharmacodynamic (PD) endpoints in the overall patient population and in each gender group. Greater responses were observed in females for all PD endpoints at lower doses, indicating a gender difference in sensitivity to desmopressin.
Treatment Period 2 (Baseline–Day 28, Multiple dose Parallel Study)
Results from the ancova analysis of change in mean nocturnal voids from baseline to day 28 are shown in Table 3. A significant reduction was seen in the 25-, 50- and 100-μg dose groups compared with placebo. Similar results were seen for both male and female patients.
Table 3. Efficacy results in treatment period 2 (PP population)
Change from baseline to day 28
Mean (95% CI or sd)
*Significant difference vs placebo, P ≤ 0.05, analysed using ancova with the change in number of nocturnal voids from baseline to day 28 as a dependent variable, and gender, baseline number of nocturnal voids, DOA, and treatment groups as explanatory variables. †Significant difference vs placebo, P ≤ 0.05, analysed using a t-test.
In the overall patient population, the change in initial period of undisturbed sleep from baseline to day 28 increased with increasing desmopressin dose. The first period of undisturbed sleep was prolonged by ∼3 h in males receiving 50 and 100 μg and females receiving 25, 50 and 100 μg desmopressin (Table 3). Total sleep time was similar between all groups (data not shown).
Nocturnal urine volume and the NPI (change from baseline) decreased with increasing desmopressin dose compared with placebo in the overall patient population. The maximum change in NPI from baseline was seen in the 100-μg treatment group in males (−18.39 ± 6.08), and in the 25-μg treatment group in females (−14.81 ± 7.58) [Table 3].
Nocturia and Sleep-Related Qol
The change from baseline in total N-QoL score and in the sleep/energy and bother/concern domain scores was greater in all desmopressin treatment groups compared with placebo (Table 4). The maximum change from baseline in total N-QoL score and sleep/energy and bother/concern domain scores was achieved in the 25-μg treatment group. The change from baseline in the global PSQI score was greater in the 25-, 50- and 100-μg treatment groups compared with placebo (Table 4). The maximum change from baseline in PSQI global score was achieved in the 25-μg treatment group.
Table 4. Impact of treatment on QoL (PP population)
n = 22
n = 23
n = 22
n = 21
n = 22
Mean (sd) change from baseline in total score
Mean (sd) change from baseline in sleep/energy score
Mean (sd) change from baseline in bother/concern score
Placebo n = 22
10 μg n = 23
25 μg n = 21
50 μg n = 21
100 μg n = 21
Mean (sd) change from baseline in global score
Relationship between DOA of Desmopressin (Treatment Period 1) and Change from Baseline to Day 28 in Number of Nocturnal Voids (Treatment Period 2)
Based on an analysis of individual patient data, the decrease from baseline to day 28 in the number of nocturnal voids was significantly associated with increasing DOA of desmopressin in the same patient measured in treatment period 1 (R2 = 0.0561; P = 0.011, not correcting for other covariates) [Fig. 3].
Safety and Tolerability
Adverse events were reported by 47.8% of patients receiving placebo and 43.0% of patients receiving desmopressin. Adverse drug reactions (AEs probably associated with treatment) were reported by 8.7% of patients receiving placebo and 11.8% of patient receiving desmopressin. AEs led to two patients discontinuing treatment, one patient receiving 100 μg during treatment period 1 and one receiving placebo during treatment period 2. The most common AE in treatment period 1 was serum sodium decrease, which was experienced by nine patients (9.7%) (one patient in the 10 μg group, three patients in the 50 μg group and five patients in the 100 μg group [Table 5]). The most common AE in treatment period 2 in the desmopressin groups was nasopharyngitis (5.3%).
Table 5. Summary of AEs in overall patient population in treatment periods 1 and 2 in all treatment groups
Treatment period 1
Safety dataset, total
All AEs, n (%)
Serum sodium decreased
Treatment period 2
Safety dataset, total
All AEs, n (%)
Brain natriuretic peptide increased
The minimum serum sodium level in each patient in treatment period 1 and treatment period 2 is shown in Fig. 4. No patients on active treatment had serum sodium <130 mEq/L during any treatment period. Only two patients had serum sodium levels below 135 mEq /L, both of whom were male and >65 years of age. The remaining fluctuations in serum sodium concentration during the trial were moderate.
The majority of haematology, clinical chemistry and urine test results were within reference intervals throughout the study. Changes in blood pressure, pulse rate and weight during the trial were unremarkable. There were no notable changes in laboratory variables, vital signs or weight during the trial. No serious or severe AEs were observed during the trial.
The objectives of this phase II randomized trial were to investigate the dose response of four different dose levels of desmopressin ODT and placebo in water-loaded male and female Japanese patients with nocturia after a single dose, and to evaluate the clinical efficacy and safety of the same dose levels after 28 days of dosing.
Overall, a clear dose–response relationship was observed in the total patient population and in each gender group for DOA of desmopressin ODT. A low dose of 25 μg desmopressin ODT increased urine osmolality >200 mOsm/kg for a significant time period compared with placebo in female but not male patients with nocturia. Statistical significance was achieved with 50–100 μg desmopressin ODT in male patients. Further analysis suggested that to achieve the same DOA in males as that achieved after administration of 25 μg in females (3 h) would require 58 μg desmopressin ODT; thus, a gender difference in PD and greater sensitivity to desmopressin in females than males was clearly demonstrated with lower doses in the present study. This is consistent with that reported in a recent trial in patients with nocturia in Europe and the USA, which explored lower doses of desmopressin to evaluate therapeutic effect vs tolerability . The relative male/female desmopressin dose ratio of 2.3 in the present study, is consistent with a previous estimate of 2.7 reported by Juul et al. . The authors of that study estimated the median effective dose of desmopressin (change in nocturnal urine volume) in women and men to be 16.1 and 43.2 μg, respectively.
The reasons for this gender difference in renal sensitivity to desmopressin, observed in two nocturia trials, are under investigation. As the vasopressin receptor gene (AVPR2) is located on the X chromosome, in an area with a particularly high probability of escaping X inactivation , females may have higher levels of vasopressin receptor (V2) expression than males for genetic reasons. For a number of genetic renal diseases attributed to X-inactivation, males have been shown to be more vulnerable to mutations in their single copy of X-linked genes than females . Furthermore, some evidence suggests that oestrogens lower the plasma osmotic threshold for vasopressin release and consequently increase renal sensitivity in females .
Based on these phase II findings, lower doses of desmopressin in female patients with nocturia provide a shorter DOA and thus minimize the risk of hyponatraemia by ensuring an antidiuresis-free window and thereby allowing compensatory diuresis during daytime between doses. Our findings support a recommended dose of desmopressin ODT of 25 μg for women and between 50 and 75 μg for men for the treatment of nocturia in Japanese patients; however, dose recommendation will be confirmed in further Japanese phase II and III studies.
Nocturia is a condition that severely affects the sleep patterns of a large proportion of patients aged > 50 years [26, 27]. In the present study, we found that the change from baseline in initial period of undisturbed sleep increased with increasing desmopressin dose in both male and female patients, with a prolongation of the initial period of undisturbed sleep of ∼3 h at the therapeutic dose levels. These results confirm the findings of previous studies of desmopressin's efficacy in improving duration of sleep [16, 17].
The data demonstrate a dose–response relationship overall and the 25–100 μg doses produced significant reductions in mean number of nocturnal voids from baseline compared with placebo. Furthermore, a gender difference in the response to desmopressin was observed in the primary efficacy endpoint (change in mean number of nocturnal voids). In male patients, the change from baseline in mean number of nocturnal voids decreased with increasing desmopressin dose, with no plateau in response observed, whereas in female patients the response reached a plateau at 25 ug desmopressin ODT. Higher doses (50 and 100 μg) did not provide any further reduction in mean number of nocturnal voids. The response to 10 μg desmopressin ODT was not significantly different from placebo. These findings are consistent with those of Juul et al. , who reported responses to 25 μg desmopressin ODT in female nocturia patients to be at the upper plateau phase of the S-formed dose–response curve, and increasing doses of desmopressin did not provide additional clinical efficacy.
No placebo effect was seen in the PD endpoint DOA in treatment period 1, but all endpoints in treatment period 2 for the placebo group showed greater increases in females compared with males (Table 3). It is speculated that this substantial placebo effect may be linked to advice on fluid restriction given during screening or some as yet unknown gender-specific lifestyle modification affecting nocturia placebo response.
The DOA measured in treatment period 1 correlated with the change from baseline to day 28 in the mean number of nocturnal voids (Fig. 3). Considering the mode of action of desmopressin as an antidiuretic drug, this correlation was not unexpected. Although the correlation was weak, to our knowledge this is the first direct evidence for such a correlation between PD and clinical endpoints in nocturia.
Desmopressin was well tolerated. The proportion of patients reporting AEs and the incidence of individual events were similar in all treatment groups with the exception of the desmopressin 100-μg treatment group in treatment period 1 where more AEs were reported compared with placebo and other desmopressin treatment groups. All AEs were mild or moderate and most were considered unrelated to desmopressin. To date, the only serious potential AEs that have been identified with use of desmopressin are water intoxication and hyponatraemia . In the present study, there were no reports of hyponatraemia, (serum sodium <130 mEq/L) during 28 days of daily dosing with desmopressin ODT.
The present study has some limitations. It only assessed the short-term efficacy of desmopressin; long-term studies would be of value to assess efficacy in the Japanese population for this chronic condition. Further larger trials are planned to support dose recommendations in Japanese patients with nocturia as the present study was not designed using formal power calculations.
In summary, results from this phase II trial have shown a dose–response relationship to desmopressin ODT in patients with nocturia with regard to PD and clinical endpoints, established a significant correlation between DOA and reduction in nocturnal voids and re-confirmed the magnitude of gender difference in renal sensitivity to desmopressin. Our findings have implications for future gender-specific desmopressin doses for the treatment of nocturia; however, dose selection awaits further confirmation in larger Japanese phase II and III studies.
The authors would like to thank all the investigators involved in the study. Medical writing assistance was provided by Dr Kerry af Forselles, ApotheCom ScopeMedical Ltd, funded by Ferring Pharmaceuticals A/S.
Conflict of Interest
Osamu Yamaguchi and Osamu Nishizawa are consultants to Ferring Pharmaceuticals. Osamu Nishizawa, Kristian Vinter Juul and Jens Peter Nørgaard are employees of Ferring Pharmaceuticals.
The study was sponsored by Ferring Pharmaceuticals A/S.