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

Objectives 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 mu g, 25 mu g, 50 mu g or 100 mu g. 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). Results 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 mu g 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 mu g. Extrapolation suggests that male patients require similar to 58 mg to achieve similar DOA to females receiving 25 mu g. 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-mu g (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. Conclusions 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.