Effects of Tolvaptan vs Fluid Restriction in Hospitalized Subjects With Dilutional Hyponatremia (SALACIA)

Phase 3b, Multicenter, Randomized, Single-blind, Parallel Group Trial of the Effects of Titrated Oral SAMSCA(r) (Tolvaptan) 15, 30, or 60 mg QD Compared to Placebo Plus Fluid Restriction on Length of Hospital Stay and Symptoms in Subjects Hospitalized With Dilutional Hyponatremia

The purpose of this study is to determine if hospitalized patients with symptomatic hyponatremia treated with tolvaptan are in the hospital for less time than patients treated with fluid restriction. The study will also test if tolvaptan is better than fluid restriction in treating the symptoms of hyponatremia in hospitalized patients.

Study Overview

Study Type

Interventional

Enrollment (Actual)

124

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

    • Alabama
      • Birmingham, Alabama, United States, 35216
        • Otsuka Investigational Site
      • Birmingham, Alabama, United States, 35242
        • Otsuka Investigational Site
      • Mobile, Alabama, United States, 36608
        • Otsuka Investigational Site
    • California
      • Azusa, California, United States, 91702
        • Otsuka Investigational Site
      • Banning, California, United States, 92220
        • Otsuka Investigational Site
      • Culver City, California, United States, 90232
        • Otsuka Investigational Site
      • Fountain Valley, California, United States, 92708
        • Otsuka Investigational Site
      • Los Angeles, California, United States, 90025
        • Otsuka Investigational Site
      • Los Angeles, California, United States, 90033
        • Otsuka Investigational Site
      • Northridge, California, United States, 91324
        • Otsuka Investigational Site
      • Orange, California, United States, 92868
        • Otuska Investigational Site
      • Yorba Linda, California, United States, 92886
        • Otsuka Investigational Site
    • Colorado
      • Denver, Colorado, United States, 80210
        • Otsuka Investigational Site
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
        • Otsuka Investigational Site
    • Florida
      • Jacksonville, Florida, United States, 32216
        • Otsuka Investigational Site
      • Jacksonville, Florida, United States, 32209
        • Otsuka Investigational Site
      • Jacksonville, Florida, United States, 32207
        • Otsuka Investigational Site
      • Orlando, Florida, United States, 32803
        • Otsuka Investigational Site
      • Port Charlotte, Florida, United States, 33952
        • Otsuka Investigational Site
    • Georgia
      • Savannah, Georgia, United States, 31405
        • Otsuka Investigational Site
    • Kentucky
      • Elizabethtown, Kentucky, United States, 42701
        • Otsuka Investigational Site
    • Maryland
      • Baltimore, Maryland, United States, 21215
        • Otsuka Investigational Site
    • Massachusetts
      • Springfield, Massachusetts, United States, 01107
        • Otsuka Investigational Site
    • Michigan
      • Saginaw, Michigan, United States, 48602
        • Otsuka Investigational Site
      • Southfield, Michigan, United States, 48075
        • Otsuka Investigational Site
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • Otsuka Investigational Site
      • Rochester, Minnesota, United States, 55905
        • Otsuka Investigational Site
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • Otsuka Investigational Site
    • Missouri
      • St. Louis, Missouri, United States, 63110
        • Otsuka Investigational Site
    • Nebraska
      • Grand Island, Nebraska, United States, 68803
        • Otsuka Investigational Site
      • Omaha, Nebraska, United States, 68131
        • Otsuka Investigational Site
    • New Jersey
      • Haddon Heights, New Jersey, United States, 08035
        • Otsuka Investigational Site
      • Newark, New Jersey, United States, 07103
        • Otsuka Investigational Site
    • New York
      • Bronx, New York, United States, 10461
        • Otsuka Investigational Site
      • Buffalo, New York, United States, 14215
        • Otsuka Investigational Site
      • Buffalo, New York, United States, 14203
        • Otsuka Investigational Site
      • Jamaica, New York, United States, 11418
        • Otsuka Investigational Site
      • New York, New York, United States, 10032
        • Otsuka Investigational Site
    • Ohio
      • Cincinnati, Ohio, United States, 45267
        • Otsuka Investigational Site
      • Cleveland, Ohio, United States, 44195
        • Otsuka Investigational Site
      • Columbus, Ohio, United States, 43212
        • Otsuka Investigational Site
      • Fairfield, Ohio, United States, 45014
        • Otsuka Investigational Site
      • Toledo, Ohio, United States, 43560
        • Otsuka Investigational Site
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73120
        • Otsuka Investigational Site
    • Pennsylvania
      • Bethleham, Pennsylvania, United States, 18017
        • Otsuka Investigational Site
      • Philadelphia, Pennsylvania, United States, 19102
        • Otsuka Investigational Site
      • Philadelphia, Pennsylvania, United States, 19140
        • Otsuka Investigational Site
      • West Reading, Pennsylvania, United States, 19611
        • Otsuka Investigational Site
    • Rhode Island
      • Providence, Rhode Island, United States, 02903
        • Otsuka Investigational Site
    • Texas
      • Galveston, Texas, United States, 77555
        • Otsuka Investigational Site
      • Houston, Texas, United States, 77030
        • Otsuka Investigational Site
      • Mission, Texas, United States, 78572
        • Otsuka Investigational Site
      • San Antonio, Texas, United States, 78205
        • Otsuka Investigational Site
      • San Antonio, Texas, United States, 78229
        • Otsuka Investigational Site
    • Virginia
      • Fairfax, Virginia, United States, 22030
        • Otsuka Investigational Site
    • Wisconsin
      • Madison, Wisconsin, United States, 53705
        • Otsuka Investigational Site

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

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Hyponatremia in clinically euvolemic or hypervolemic states, defined as serum sodium < 130 mEq/L prior to randomization
  • Clinically significant symptoms of hyponatremia, defined as a CGI-S score between 3-6, inclusive
  • Female subjects of child bearing potential who agree to remain abstinent or to practice double-barrier forms of birth control from screening through 30 days following first dose on IMP

Exclusion Criteria:

  • Women who are pregnant or breast feeding, and females of childbearing potential who are not using acceptable contraceptive methods (such as barrier contraceptives or methods that result in a failure rate of less than 1%)
  • Hyponatremia in hypovolemic states, defined as the presence of clinical and historical evidence of extracellular fluid volume depletion, including but not limited to skin turgor, orthostatic changes in blood pressure or heart rate, dry mucous membranes, or a response to IV saline challenge
  • Subjects who are likely to require prolonged hospitalization for reasons other than hyponatremia, eg. new femoral fracture, surgeries requiring extended recovery
  • Recent prior treatment for hyponatremia: hypertonic saline (including normal saline challenge) (within 8 hours of baseline) or urea, lithium, demeclocycline, conivaptan or tolvaptan (within 4 days of baseline). Includes any treatment, other than fluid restriction for the purpose of increasing serum sodium.
  • Hyponatremia symptoms of a severity (eg, CGI = 7) such that they require immediate intervention with hypertonic saline; or are expected to require such therapy within 48 hours
  • Causes of neurological symptoms which are attributable to psychological (psychosis), structural (dementia of the Alzheimer's type, stroke, transient ischemic attack, multi-infarct dementia) or other metabolic causes (eg. hyper- or hypo-: oxemia, glycemia, calcemia, ammonemia, etc)
  • Acute and transient hyponatremia associated with head trauma or severe neurological injury (eg. stroke, subdural hematoma)or the use of recreational drugs.
  • History of hyponatremia known to be due to severe, untreated hypothyroidism/adrenal insufficiency
  • Subjects with psychogenic polydipsia
  • Systolic arterial blood pressure < 90 mmHg at screening
  • History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril), or tolvaptan
  • History of drug or medication abuse within the 3 months prior to screening, or current alcohol abuse
  • Uncontrolled diabetes mellitus defined as glucose > 300 mg/dL [16.7 mmol/L]
  • Current urinary tract obstruction (eg, obstructive benign prostatic hypertrophy)
  • Current condition of anuria
  • Serum creatinine > 3.5 mg/dL at screening
  • Terminally ill or moribund condition with little chance of short-term (eg, 30 day) survival
  • Subjects whose hyponatremia is the result of any medication that can safely be withdrawn (examples of drugs often not withdrawn include: anticonvulsants [eg, carbamazepine] and antipsychotics [eg, haloperidol])
  • Patients receiving DDAVP within 2 days of screening
  • Patients with history of active variceal bleeding within the past 30 days, without prior approval from sponsor medical monitor
  • Participation in another investigational drug trial within the past 30 days

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: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tolvaptan 15-60mg
Oral tablet without fluid restriction. After the initial dose, daily dose may be titrated based on response.
15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.
Other Names:
  • OPC-41061
  • SAMSCA
  • OPC-156
Active Comparator: Fluid Restriction
Placebo tablet with prescribed fluid restriction. After the initial dose, level of fluid restriction may titrated based response.

Placebo tablet once daily with prescribed daily fluid intake of 1500 mL, then intensifying to 2 lower volumes of fluid intake for up to 7 days based on response.

Since all particpants were blinded to treatment, titration to stricter fluid restriction followed the same algorithm as tolvaptan, increasing both the level of fluid restriction and increasing the placebo "dose"

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Length of Hospital Stay (LoS)
Time Frame: 45 days
LoS was time to clinically ready to be hospital discharged (CRBD) from study treatment initiation, disregarding prolonged hospitalization due solely to social factors.
45 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline to 48 Hour Post Dose in Clinical Global Impression-Severity (CGI-S) of Hyponatremia Symptoms.
Time Frame: Baseline to 48 hours post dose

Change from baseline in blinded rater assessed CGI-S at 48 hours post-first dose or at discharge/rescue therapy, if earlier was assessed.

The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.

Baseline to 48 hours post dose
Change From Baseline to 24 and 72 Hours Post Dose in CGI-S of Hyponatremia Symptoms.
Time Frame: Baseline to 24 and 72 hours post dose

Change in CGI-S of hyponatremia symptoms from pretreatment baseline at 24 and 72 hours post-first dose, or at discharge/rescue therapy if earlier was assessed.

The CGI-S is a one-question rating scale which was as follows: "Considering your total clinical experience with hyponatremia symptoms in this particular population, how symptomatic is the patient at this time?" 0=not assessed; 1=normal, not at all symtpmatic; 2=borderline symptomatic; 3=mildly symptomatic; 4=moderately symptomatic; 5=markedly symptomatic; 6=severely symptomatic; 7=among the most severly symptomatic patients.

Baseline to 24 and 72 hours post dose
Change From Baseline to 48 Hours Post Dose in Clinical Global Impression - Improvement (CGI-I) Score of Hyponatremia Symptoms.
Time Frame: Baseline to 48 hours post dose

Change in CGI-I score at 48 hours post-first dose or discharge/rescue therapy, if earlier was assessed.

The CGI-I is a one-question rating scale where the participant is asked to rate total improvement whether or not, in their judgment, it is due entirely to trial treatment. Compared to his/her condition at admission to the trial, how much has he/she changed? 0=not assessed; 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse

Baseline to 48 hours post dose
Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]).
Time Frame: 0 to 72 hours

Average 24 hour AUC of serum sodium concentration change from baseline, from Day 1 Hour 0 up to 72 hours post-first dose was assessed.

A serum sodium sample was drawn at pre-treament and 8, 24, 48, and 72 hours post-first dose. Serum sodium was also assessed between 36 and 72 hours after the last dose.

Analysis of AUC was for daily average AUC, hence the units or AUC are mEq/L/24 hours.

0 to 72 hours
Time to First 2-point Improvement in CGI-S Score.
Time Frame: Up to 72 hours
CGI-S data up to 72 hours were used to identify 2-point improvements. Please refer to outcome measure 2 for details on the scale. For the analysis of time to first 2-point improvement in CGI-S, CGI-S data up to Hour 72 were used to identify 2-point improvements. Data for participants who received rescue therapy were censored at the time of receiving rescue therapy. For participants who were discharged before Hour 72 without reaching 2-point improvement in CGI-S, data were censored at the time of discharge. Other participants who did not reach the 2-point improvement during the 72 hours also had their data censored at their last CGI-S observations within 72 hours.
Up to 72 hours
Percentage of Participants With Clinical Global Impression-Improvement (CGI-I) Score Improved to a Score of 1 or 2.
Time Frame: 48 hours post dose
Percentage of responders (defined as CGI-I score of 1 = very much improved or 2 = much improved) at 48 hours post-first dose, or at discharge/rescue therapy, if earlier. Participants given rescue therapy were given a score of 7.
48 hours post dose
Percentage of Participants Requiring Rescue Therapy for Hyponatremia
Time Frame: 7 days
Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia.
7 days

Collaborators and Investigators

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

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

October 1, 2010

Primary Completion (Actual)

May 1, 2013

Study Completion (Actual)

May 1, 2013

Study Registration Dates

First Submitted

October 22, 2010

First Submitted That Met QC Criteria

October 22, 2010

First Posted (Estimate)

October 25, 2010

Study Record Updates

Last Update Posted (Estimate)

October 30, 2014

Last Update Submitted That Met QC Criteria

October 21, 2014

Last Verified

October 1, 2014

More Information

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.

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