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.

Study Overview

• Status: Completed
• Conditions: Hypovolemic Hyponatremia
• Intervention / Treatment: Drug: Tolvaptan; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 241
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Cardiology / Endocrinology, Peking Union Medical College Hospital
  • Beijing, China
    • Cardiology / Hepatology, Beijing Friendship Hospital
  • Beijing, China
    • Cardiology/Endocrinology/Infection, Beijing University First Hospital
  • Beijing, China
    • Endocrinology, No. 301 hospital
  • Beijing, China
    • Hepatology, Beijing Renmin Hospital
  • Chongqing, China
    • Hepatology/Endocrinology, Chongqing Medical University Second Hospital
  • Shanghai, China
    • Hepatology / Endocrinology, Shanghai Changzheng Hospital
  • Tianjin, China
    • Cardiology, Tianjin Medical University Second Hospital
  • Tianjin, China
    • Endocrinology, Tianjin General Hospital
  • Hunan
    • Changsha, Hunan, China
      • Department of Cardiology, Xiangya Hospital, Central South University
    • Changsha, Hunan, China
      • Department of Cardiology, the Third Xiangya Hospital, Central South University
  • Jilin
    • Changchun, Jilin, China
      • Cardiology, Jilin University Second Hospital
  • Sichuan
    • Chengdu, Sichuan, China
      • Endocrinology, West China Hospital Sichuan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Informed consent.
2. Age:18～75 (when informed consent is obtained)，male or female.
3. 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)
4. In-patient subjects.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; placebo plus conventional therapy according to each patient's underlying disease, such as congestive heart failure, hepatic cirrhosis and SIADH or others.
Experimental: Tolvaptan	Drug: Tolvaptan; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	4 and 7 days

Secondary Outcome Measures

Outcome Measure	Time Frame
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.	4 or 7 days

Collaborators and Investigators

• Sponsor: Otsuka Beijing Research Institute
• Collaborators: Otsuka Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Wenling Zhu, Peking Union Medical College Hospital; Principal Investigator: Feng Gu, Peking Union Medical College Hospital; Principal Investigator: Jidong Jia, Beijing Friendship Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: April 14, 2008
• First Submitted That Met QC Criteria: April 21, 2008
• First Posted (Estimated): April 22, 2008

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 24, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: hyponatremia; Non-acute and non hypovolemic hyponatremia
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Water-Electrolyte Imbalance; Hypovolemia; Hyponatremia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: 156-07-802-01