Tolvaptan Sodium Phosphate

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.

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.

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.

OPC-61815, a prodrug of tolvaptan, is an injectable aquaretic drug. This study evaluated the tolerability of OPC-61815 in patients with congestive heart failure (CHF) who had difficulty with, or were incapable of, oral intake in a multicenter, uncontrolled, open-label Phase III study.Methods and Results: Forty-five patients were enrolled at 30 Japanese sites. OPC-61815 infusion was administered once daily; the 8 mg initial dose could be increased to 16 mg if the dose escalation criteria were met. Patients were treated for up to 5 days. Thirty-eight patients maintained the 8-mg dose and 7 had a dose increase to 16 mg; 41 completed the trial (34 completed early). One patient had mild hypernatremia. No significant safety concerns were observed with OPC-61815 administration at a starting dose of 8 mg and with dose escalation in accordance with the protocol-specified criteria. Treatment resulted in weight decrease (-3.01 kg); improvement or disappearance rates for other CHF symptoms (including edema, dyspnea, orthopnea, pulmonary congestion, and rales) indicated that treatment was effective. Urine excretion was increased 0-1 h after OPC-61815 administration and reached a maximum level at 1-2 h.

The tolerability of once daily (up to 5 days) intravenous OPC-61815 (8 mg or 16 mg) was confirmed in patients with CHF who had difficulty with, or were incapable of, oral intake.