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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.
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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.