- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01227512
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
Study Overview
Status
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Alabama
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Birmingham, Alabama, United States, 35216
- Otsuka Investigational Site
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Birmingham, Alabama, United States, 35242
- Otsuka Investigational Site
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Mobile, Alabama, United States, 36608
- Otsuka Investigational Site
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California
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Azusa, California, United States, 91702
- Otsuka Investigational Site
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Banning, California, United States, 92220
- Otsuka Investigational Site
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Culver City, California, United States, 90232
- Otsuka Investigational Site
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Fountain Valley, California, United States, 92708
- Otsuka Investigational Site
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Los Angeles, California, United States, 90025
- Otsuka Investigational Site
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Los Angeles, California, United States, 90033
- Otsuka Investigational Site
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Northridge, California, United States, 91324
- Otsuka Investigational Site
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Orange, California, United States, 92868
- Otuska Investigational Site
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Yorba Linda, California, United States, 92886
- Otsuka Investigational Site
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Colorado
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Denver, Colorado, United States, 80210
- Otsuka Investigational Site
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District of Columbia
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Washington, District of Columbia, United States, 20010
- Otsuka Investigational Site
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Florida
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Jacksonville, Florida, United States, 32216
- Otsuka Investigational Site
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Jacksonville, Florida, United States, 32209
- Otsuka Investigational Site
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Jacksonville, Florida, United States, 32207
- Otsuka Investigational Site
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Orlando, Florida, United States, 32803
- Otsuka Investigational Site
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Port Charlotte, Florida, United States, 33952
- Otsuka Investigational Site
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Georgia
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Savannah, Georgia, United States, 31405
- Otsuka Investigational Site
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Kentucky
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Elizabethtown, Kentucky, United States, 42701
- Otsuka Investigational Site
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Maryland
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Baltimore, Maryland, United States, 21215
- Otsuka Investigational Site
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Massachusetts
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Springfield, Massachusetts, United States, 01107
- Otsuka Investigational Site
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Michigan
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Saginaw, Michigan, United States, 48602
- Otsuka Investigational Site
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Southfield, Michigan, United States, 48075
- Otsuka Investigational Site
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Minnesota
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Minneapolis, Minnesota, United States, 55455
- Otsuka Investigational Site
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Rochester, Minnesota, United States, 55905
- Otsuka Investigational Site
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Mississippi
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Jackson, Mississippi, United States, 39216
- Otsuka Investigational Site
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Missouri
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St. Louis, Missouri, United States, 63110
- Otsuka Investigational Site
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Nebraska
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Grand Island, Nebraska, United States, 68803
- Otsuka Investigational Site
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Omaha, Nebraska, United States, 68131
- Otsuka Investigational Site
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New Jersey
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Haddon Heights, New Jersey, United States, 08035
- Otsuka Investigational Site
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Newark, New Jersey, United States, 07103
- Otsuka Investigational Site
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New York
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Bronx, New York, United States, 10461
- Otsuka Investigational Site
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Buffalo, New York, United States, 14215
- Otsuka Investigational Site
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Buffalo, New York, United States, 14203
- Otsuka Investigational Site
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Jamaica, New York, United States, 11418
- Otsuka Investigational Site
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New York, New York, United States, 10032
- Otsuka Investigational Site
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Ohio
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Cincinnati, Ohio, United States, 45267
- Otsuka Investigational Site
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Cleveland, Ohio, United States, 44195
- Otsuka Investigational Site
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Columbus, Ohio, United States, 43212
- Otsuka Investigational Site
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Fairfield, Ohio, United States, 45014
- Otsuka Investigational Site
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Toledo, Ohio, United States, 43560
- Otsuka Investigational Site
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Oklahoma
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Oklahoma City, Oklahoma, United States, 73120
- Otsuka Investigational Site
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Pennsylvania
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Bethleham, Pennsylvania, United States, 18017
- Otsuka Investigational Site
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Philadelphia, Pennsylvania, United States, 19102
- Otsuka Investigational Site
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Philadelphia, Pennsylvania, United States, 19140
- Otsuka Investigational Site
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West Reading, Pennsylvania, United States, 19611
- Otsuka Investigational Site
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Rhode Island
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Providence, Rhode Island, United States, 02903
- Otsuka Investigational Site
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Texas
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Galveston, Texas, United States, 77555
- Otsuka Investigational Site
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Houston, Texas, United States, 77030
- Otsuka Investigational Site
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Mission, Texas, United States, 78572
- Otsuka Investigational Site
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San Antonio, Texas, United States, 78205
- Otsuka Investigational Site
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San Antonio, Texas, United States, 78229
- Otsuka Investigational Site
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Virginia
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Fairfax, Virginia, United States, 22030
- Otsuka Investigational Site
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Wisconsin
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Madison, Wisconsin, United States, 53705
- Otsuka Investigational Site
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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 |
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Experimental: Tolvaptan 15-60mg
Oral tablet without fluid restriction.
After the initial dose, daily dose may be titrated based on response.
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15 mg titrated to 30 mg then 60 mg once daily as oral tablet for up to 7 days based on response.
Other Names:
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Active Comparator: Fluid Restriction
Placebo tablet with prescribed fluid restriction.
After the initial dose, level of fluid restriction may titrated based response.
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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 |
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Length of Hospital Stay (LoS)
Time Frame: 45 days
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LoS was time to clinically ready to be hospital discharged (CRBD) from study treatment initiation, disregarding prolonged hospitalization due solely to social factors.
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45 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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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
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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
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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
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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
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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
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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
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Change From Baseline in Serum Sodium Concentration (24 Hour Area Under the Curve [AUC]).
Time Frame: 0 to 72 hours
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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
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Time to First 2-point Improvement in CGI-S Score.
Time Frame: Up to 72 hours
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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.
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Up to 72 hours
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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
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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.
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48 hours post dose
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Percentage of Participants Requiring Rescue Therapy for Hyponatremia
Time Frame: 7 days
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Percentage of participants requiring rescue therapy within first 7 days of treatment for hyponatremia.
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7 days
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Collaborators and Investigators
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Metabolic Diseases
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Endocrine System Diseases
- Hypothalamic Diseases
- Pituitary Diseases
- Water-Electrolyte Imbalance
- Hyponatremia
- Inappropriate ADH Syndrome
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Natriuretic Agents
- Antidiuretic Hormone Receptor Antagonists
- Tolvaptan
Other Study ID Numbers
- 156-08-275
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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