Tolvaptan for In-hospital Hyponatremia (INSERT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01386372
Recruitment Status : Terminated (futility)
First Posted : July 1, 2011
Last Update Posted : December 15, 2016
A.O. Ospedale Papa Giovanni XXIII
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research

Brief Summary:
Hyponatremia is a common electrolyte disorder encountered in hospitalized patients. A preliminary, observational, feasibility analysis finalized to assess retrospectively the incidence of hyponatremia (Serum sodium < 135 mEq/L) in a general medical-surgical hospital and the distribution of the cases of hyponatremia among different referral units showed that over one year observation there were more than 1500 cases of hyponatremia. Conventional therapy for hyponatremia depends on its causes, speed of onset, extracellular fluid volume status, and severity. Treatment consists in fluid restriction, normal or hypertonic saline, furosemide. Recent development of arginine vasopressin antagonists has provided a new therapeutic option for treatment of hyponatremia.Tolvaptan, an orally administered, nonpeptide, selective vasopressin V2 receptor antagonist reported to increase free water clearance and limit fluid retention in subjects with congestive heart failure or liver cirrhosis, has been also shown to be effective in the treatment of chronic hyponatremia in patients with SIADH, chronic heart failure, liver cirrhosis. Thus the investigators designed a clinical study to explore the incidence of severe hyponatremia in hospitalized patients in the setting of large general hospital and to evaluate whether tolvaptan is effective and safe in increasing serum sodium concentration in patients with normovolemic and hypervolemic hyponatremia in the setting of daily clinical practice. Moreover this study may help understand the cost-effectiveness of tolvaptan therapy compared to traditional treatments of hyponatremia.

Condition or disease Intervention/treatment Phase
Hyponatremia Drug: Tolvaptan Other: Standard therapy Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study To Evaluate The Incidence Of Hyponatremia In A Medical-Surgical Hospital And To Explore The Efficacy And Safety Of Tolvaptan In The Clinical Practice
Study Start Date : June 2011
Actual Primary Completion Date : November 2012
Actual Study Completion Date : November 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Tolvaptan

Arm Intervention/treatment
Experimental: Tolvaptan Drug: Tolvaptan
Patients will receive full-dose oral tolvaptan therapy up to 1 month after randomization. During the initial 4 days of therapy, the dose of the study drug will be increased from 15 to 30 mg or from 30 to 60 mg according to a regimen designed for slow correction of serum sodium concentrations to 135 mEq/L or more Depending on the serum sodium concentration the dose will be increased or decreased. Patients will then be continued on their maintenance therapy with adjustments allowed to prevent hyponatremia and avoiding hypernatremia. As soon as normal serum sodium levels are achieved in at least two consecutive measurements the dose of the study drug will be progressively tapered according to an individually tailored weaning program

Active Comparator: standard therapy Other: Standard therapy
Fluid restriction, normal or hypertonic saline, furosemide.

Primary Outcome Measures :
  1. Changes from baseline in proportion of subjects with normonatremia at 6 month. [ Time Frame: At 1,2,3,4 and 10 day, and at 1,2,4 and 6 month.. ]
  2. Changes from baseline in serum sodium levels from basal at 6 months. [ Time Frame: At 1,2,3,4, 10 day and at 1,2,4 and 6 month.. ]

Secondary Outcome Measures :
  1. Proportion of subjects achieving normonatremia at discharge and at predefined time-points. [ Time Frame: 8 hours, 1, 2, 3, and 10 days and 1, 2, 4 and 6 months after randomization ]
  2. Absolute changes in serum sodium levels vs baseline at predefined time-points. [ Time Frame: 8 hours, 1, 2, 3, and 10 days and 1, 2, 4 and 6 months after randomization ]

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Non artifactual hyponatremia in euvolemic or hypervolemic states, defined as serum sodium <135 mEq/L confirmed in at least 2 consecutive evaluations;
  • 18 years of age or older;
  • Able to give written Informed Consent.

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01386372

OO.RR., Bergamo - Unit of Nephrology and Dialisis
Bergamo, Italy, 24128
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
A.O. Ospedale Papa Giovanni XXIII

Responsible Party: Mario Negri Institute for Pharmacological Research Identifier: NCT01386372     History of Changes
Other Study ID Numbers: INSERT
2010-024431-17 ( EudraCT Number )
First Posted: July 1, 2011    Key Record Dates
Last Update Posted: December 15, 2016
Last Verified: February 2013

Keywords provided by Mario Negri Institute for Pharmacological Research:

Additional relevant MeSH terms:
Water-Electrolyte Imbalance
Metabolic Diseases
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Physiological Effects of Drugs