A Phase 2 Efficacy and Safety Study of the Tolvaptan Tablets in Patients With Non-hypovolemic Non-acute Hyponatremia

A Phase 2 Efficacy and Safety Study of the Tolvaptan Tablets in Patients With Non-hypovolemic Non-acute Hyponatremia

Randomized, Double-blind, Multicenter, Placebo-controlled (Standard Therapy + Placebo), Phase 2 Efficacy and Safety Study of the Tolvaptan Tablets in Patients With Non-hypovolemic Non-acute Hyponatremia

This is a randomized, double-blind, multicenter, placebo-controlled (standard therapy + placebo), phase 2 efficacy and safety study of the Tolvaptan tablets in treatment of patients with non-hypovolemic non-acute hyponatremia arising from a variety of etiologies. 240 (120 in each group) patients are to be enrolled randomly into Tolvaptan group or placebo group. Subjects in Tolvaptan group will receive standard therapy + Tolvaptan (15-60mg/day), while those in control group receiving standard therapy + placebo. The starting dose of tolvaptan is 15mg and it could be titrated up to 30mg and then,if necessary, to the maximum of 60mg according to a certain titration scheme based on patients' response of serum sodium level. The study includes a 2-day screening period from day -2 to day -1, 7-day inpatient study treatment (day 1 to day 7 ). After study treatment, subjects will be Followed-up on safety events on day 14 - 16. The Primary Efficacy Variable is the change of serum sodium from baseline. For patients with Congestive Heart Failure (CHF) or hepatic cirrhosis, change of body weight, fluid balance and symptoms improvement of CHF and hepatic edema will be assessed as secondary efficacy variables.

Tablet;15mg/tab;15/30/60mg/day for 7days Plus conventional therapy according to each patient's underlying disease, such as congestive heart failure, hepatic cirrhosis and SIADH or others.

placebo plus conventional therapy according to each patient's underlying disease, such as congestive heart failure, hepatic cirrhosis and SIADH or others.

The change of average daily Area Under the Curve (AUC) of serum sodium by day 4 and 7 comparing with baseline serum sodium level within the double-blind therapy period.

For CHF and hepatic edema patients, improvement of symptoms and relevant physical examination measures or ultrasound test findings . Other secondary efficacy variables on blood serum sodium, fluid balance or body weight change.

Inclusion Criteria: Informed consent. Age:18～75 (when informed consent is obtained)，male or female. Non-hypovolemic and non acute hyponatremia with a Serum sodium < 135mEq/L before randomization. (main underlying diseases include CHF, hepatic cirrhosis with edema, SIADH and others) In-patient subjects.

Wang S, Zhang X, Han T, Xie W, Li Y, Ma H, Liebe R, Weng H, Ding HG. Tolvaptan treatment improves survival of cirrhotic patients with ascites and hyponatremia. BMC Gastroenterol. 2018 Sep 4;18(1):137. doi: 10.1186/s12876-018-0857-0.

Chen S, Zhao JJ, Tong NW, Guo XH, Qiu MC, Yang GY, Liu ZM, Ma JH, Zhang ZW, Gu F. Randomized, double blinded, placebo-controlled trial to evaluate the efficacy and safety of tolvaptan in Chinese patients with hyponatremia caused by SIADH. J Clin Pharmacol. 2014 Dec;54(12):1362-7. doi: 10.1002/jcph.342.