Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT2)

July 10, 2026 updated by: Otsuka Pharmaceutical Development & Commercialization, Inc.

International, Multicenter, Randomized, Double-blind, Placebo-controlled, Efficacy and Safety Study of the Effects of Titrated Oral Tolvaptan Tablets in Patients With Hyponatremia

The purpose of this study was to determine whether tolvaptan can safely and effectively return the body's balance of sodium and water toward normal and to characterize and quantify the potential clinical benefits of this treatment.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Hyponatremia is defined as a serum sodium concentration below the lower limit of normal and is the most frequently encountered electrolyte abnormality in hospitalized patients. Generally speaking, most cases of hyponatremia are mild. However, as the serum sodium falls below 130 mEq/L, the possibility of significant morbidity and mortality increases, and most clinicians will initiate corrective therapy for serum sodium values approaching 130 mEq/L and lower. The reasons for treating hyponatremia relate both to the symptoms, which may be quite disturbing to patients, as well as to potential outcomes including permanent neurological damage and death. There is also growing awareness of the association between hyponatremia and increased mortality in patients with heart failure.

A common theme underlying the occurrence of hyponatremia, whether in the setting of congestive heart failure, hepatic failure with ascites, or the syndrome of inappropriate anti-diuretic hormone (SIADH), is the non-osmotic secretion of arginine vasopressin (AVP). The presence of excess AVP leads to fluid retention and hyponatremia. Agents that antagonize AVP, causing proportionally more water diuresis than solute excretion, could offer a significant treatment option for patients with hyponatremia, compared to fluid restriction alone. Treatment of hyponatremia, particularly in clinical settings such as decompensated congestive heart failure, is difficult, as conventional diuretics cause neurohormonal activation and further stimulate the inappropriate release of vasopressin, leading to additional retention of free water and aggravation of hypo-osmolality. Similarly, for cirrhosis with ascites and SIADH, conventional diuretics are either minimally effective or completely contraindicated. An alternative approach to symptom relief and treatment of hyponatremia may be the use of vasopressin antagonists, which increase free water clearance with proportionally less effect on sodium excretion. Tolvaptan is an oral vasopressin antagonist with relative affinity for the V2 receptor which has been shown to induce a diuresis with proportionally more free-water than sodium loss.

The current study was conducted to evaluate whether tolvaptan, an oral AVP inhibitor, was effective in correcting mild to moderate hyponatremia and to elucidate the effect of this correction on the subject's well-being.

Study Type

Interventional

Enrollment (Actual)

243

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
    • Dresden
      • Gustav Carus, Dresden, Germany, D-01307
        • Universitatskilinikum Carl

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Hyponatremia in euvolemic or hypervolemic states, defined as serum sodium < 135 mEq/L prior to randomization.
  2. Able to give Informed Consent.

Exclusion Criteria:

  1. Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods.
  2. Hyponatremia in hypovolemic states.
  3. Acute and transient hyponatremia associated with head trauma or post-operative state.
  4. Hyponatremia due to uncontrolled hypothyroidism or uncontrolled adrenal insufficiency.
  5. Cardiac surgery within 30 days of potential study enrollment, excluding percutaneous coronary interventions.
  6. History of a myocardial infarction within 30 days of potential study enrollment.
  7. History of sustained ventricular tachycardia or ventricular fibrillation within 30 days, unless in the presence of an automatic implantable cardioverter defibrillator.
  8. Severe angina including angina at rest or at slight exertion and/or unstable angina.
  9. History of a cerebrovascular accident within the last 30 days.
  10. Subjects with psychogenic polydipsia may not be included, however subjects with other psychiatric illness may be included.
  11. Systolic arterial blood pressure < 90 mmHg.
  12. History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril).
  13. History of drug or medication abuse within the past year,or current alcohol abuse.
  14. Uncontrolled diabetes mellitus defined as fasting glucose > 300mg/dL.
  15. Urinary tract obstruction except benign prostatic hyperplasia (BPH) if non-obstructive.
  16. Previous participation in another clinical drug trial within the past 30 days.
  17. Previous participation in this or any other tolvaptan clinical trial.
  18. Terminally ill or moribund condition with little chance of short term survival.
  19. Serum creatinine > 3.5 mg/dL.
  20. Serum sodium < 120 mEq/L with associated neurologic impairment, ie, symptoms such as apathy, confusion, seizures.
  21. Patients with progressive or episodic neurologic disease such as multiple sclerosis or history of multiple strokes.
  22. Child-Pugh score > 10 (unless approved).
  23. Patients receiving intravenous fluids at a rate greater than KVO (Keep Vein Open).
  24. Hyponatremia due to lab artifacts.
  25. Patients receiving AVP or its analogs for treatment of any condition.
  26. Patients receiving within 7 days of randomization other medications for treatment of hyponatremia specifically: Demeclocycline, lithium carbonate or urea.
  27. Patients likely requiring intravenous (IV) saline for correction of symptomatic or asymptomatic severe hyponatremia during the course of the study.
  28. Severe pulmonary artery hypertension.
  29. Hyponatremia should not be the result of any medication that can safely be withdrawn.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tolvaptan
Participants received tolvaptan orally once a day for 30 days. Initially participants received tolvaptan 15 mg and were forced titrated to 30 mg and 60 mg based on the change in their serum sodium level. Titration occurred if the serum sodium level increased by < 5 mEq/L (mmol/L) from the previous measurement 22-24 hours earlier and was ≤ 135 mEq/L (mmol/L).
Drug: Tolvaptan
Tolvaptan was supplied as tablets.
Other Names:
  • Samsca
  • OPC-41061
Placebo Comparator: Placebo
Participants received placebo orally once a day for 30 days.
Drug: Placebo
Placebo was supplied as tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
The average daily area under the curve of change from baseline in serum sodium level up to Day 4 within the double-blind on therapy period.
and/or
The average daily area under the curve of change from baseline in serum sodium level up to Day 30 within the double-blind on therapy period.

Secondary Outcome Measures

Outcome Measure
The average daily area under the curve of change from baseline in serum sodium level up to Day 4 within the double-blind on therapy period for patients with severe hyponatremia (serum sodium <130 mEq/L at baseline).
The average daily area under the curve of change from baseline in serum sodium level up to Day 30 within the double-blind on therapy period for patients with severe hyponatremia (serum sodium <130 mEq/L at baseline).
Percentage of patients with normalized serum sodium at Day 4.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc.

Collaborators

Otsuka Pharmaceutical Co., Ltd.

Investigators

  • Study Director: Frank Czerwiec, MD, PhD, Otsuka Pharmaceutical Development & Commercialization, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2003

Primary Completion (Actual)

July 1, 2005

Study Completion (Actual)

July 1, 2005

Study Registration Dates

First Submitted

September 13, 2005

First Submitted That Met QC Criteria

September 14, 2005

First Posted (Estimated)

September 20, 2005

Study Record Updates

Last Update Posted (Actual)

July 13, 2026

Last Update Submitted That Met QC Criteria

July 10, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 156-03-238

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.

IPD Sharing Time Frame

Data will be available after marketing approval in global markets or beginning 1-3 years following article publication. There is no end date to the availability of the data.

IPD Sharing Access Criteria

Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe