Efficacy and Safety of Intravenous OPC-61815 Compared with Oral Tolvaptan in Patients with Congestive Heart Failure

AIMS: This multicentre, randomized, controlled, double-blind, parallel-group Phase III study was conducted to confirm the non-inferiority of OPC-61815 (tolvaptan sodium phosphate) intravenous injections to oral tolvaptan tablets in patients with congestive heart failure and volume overload despite receiving diuretics other than vasopressin antagonists. METHODS AND RESULTS: Congestive heart failure patients with volume overload despite receiving diuretics other than vasopressin antagonists were randomly assigned (1:1) to receive OPC-61815 (16-mg injection; n = 149) or oral tolvaptan (15-mg tablet; n = 145) once daily for 5 days. Most patients were male; the mean age and weight were 74.7 years and 62.1 kg, respectively; other demographic and clinical characteristics were similar between groups. In this study, the primary endpoint was the change in body weight from baseline to the day after the last dose. Secondary endpoints included improvement from baseline in congestive findings and New York Heart Association classification. The change in body weight was -1.67 kg [95% confidence interval (CI): -1.93, -1.41] and -1.36 kg (95% CI: -1.62, -1.10) in the OPC-61815 group and tolvaptan group, respectively; the difference in the least squares mean between the groups was -0.31 kg (95% CI: -0.68, 0.06). Given the upper CI did not exceed the pre-specified limit of 0.48, this confirmed the non-inferiority of injectable OPC-61815 to oral tolvaptan. Daily urine volume and daily fluid intake increased, and daily fluid balance was negative throughout the treatment period; changes were similar for both groups. All evaluated congestive symptoms and New York Heart Association classifications showed improvement and safety findings were similar between the groups. The incidence of hyperkalaemia was higher in the OPC-61815 group, and the incidence of thirst and dry mouth was higher in the tolvaptan group. Most treatment-emergent adverse events were mild to moderate; one serious treatment-emergent adverse event of hyperkalaemia in the OPC-61815 group was considered treatment related. CONCLUSIONS: OPC-61815 (16-mg injection) was confirmed as non-inferior to oral tolvaptan (15-mg tablet) in patients with congestive heart failure and inadequate response to diuretics; no new safety concerns were observed.