Back to results"SALT Trial" Study of Ascending Levels of Tolvaptan in Hyponatremia
Primary Purpose
Hyponatremias, Water Intoxication, Inappropriate ADH Syndrome
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
tolvaptan
Sponsored by
About this trial
This is an interventional treatment trial for Hyponatremias focused on measuring Sodium, SIADH, Vasopressin, CHF, Cirrhosis, salt, water, electrolyte
Eligibility Criteria
Inclusion Criteria Hyponatremia in euvolemic or hypervolemic states, defined as serum sodium <135 mEq/L prior to randomization. Able to give 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 of potential study enrollment, excluding percutaneous coronary interventions. History of a myocardial infarction within 30 days of potential study enrollment. History of sustained ventricular tachycardia or ventricular fibrillation within 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. 10) 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. Previous participation in another clinical drug trial within the past 30 days. Previous participation in this or any other tolvaptan clinical trial. 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
Sites / Locations
- VA Greater Los Angeles Health Care Ctr
- UCLA
- UCSF Medical Center
- Aurora Denver Cardiology Association
- University of Colorado Heath Science Center
- University of Florida Gainesville
- Charlotte Heart Group Research Ctr
- Medical College of Georgia
- Northwestern University
- University of Chicago
- University of Iowa Hospital
- Minneapolis VA Medical Center
- Washington University Ctr for Clinical Studies
- Mercury Street Medical
- Northshore University Hospital
- University of North Carolina, Div. of Cardiology
- University Hospitals of Cleveland
- Ohio State University Medical Center
- The Arthur P. Noyes Research Foundation
- University of Pittsburgh Medical Center
- Baptist Clinical Research Ctr
- Tennessee Center for Clinical Trials
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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.
Percentage of patients with normalized serum sodium at Day 30.
Time to first normalization in serum sodium.
Change from baseline in serum sodium at Day 4.
Change from baseline in serum sodium at Day 30.
Percentage of patients requiring fluid restriction at any time during the double-blind on therapy period of the study.
Urine output at Day 1.
Change from baseline in body weight at Day 1 (hypervolemic patients only).
Fluid balance at Day 1 (hypervolemic patients only).
Change from baseline in the SF-12 (health survey)Physical Component Summary (PCS)and Mental Component Summary (MCS)scales at Week 1 and Day 30.
Categorical change in serum sodium at Day 4 and Day 30 for patients with baseline serum sodium <130 mEq/L.
Categorical change in serum sodium at Day 4 and Day 30 for patients with baseline serum sodium ≥130 mEq/L.
The percentage of patients who are designated as treatment failure due to the need for saline infusion,with or without fluid restriction.
Safety:Adverse events,vital signs,clinical laboratory tests,12- lead electrocardiograms.
PK:Plasma tolvaptan and DM-4103 concentrations.
Full Information
NCT ID
NCT00072683
First Posted
November 7, 2003
Last Updated
January 24, 2007
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
Otsuka Pharmaceutical Co., Ltd.
1. Study Identification
Unique Protocol Identification Number
NCT00072683
Brief Title
"SALT Trial" Study of Ascending Levels of Tolvaptan in Hyponatremia
Official Title
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of the Effects of Titrated Oral Tolvaptan Tablets in Patients With Hyponatremia
Study Type
Interventional
2. Study Status
Record Verification Date
January 2007
Overall Recruitment Status
Completed
Study Start Date
April 2003 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
February 2006 (undefined)
3. Sponsor/Collaborators
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
Otsuka Pharmaceutical Co., Ltd.
4. Oversight
5. Study Description
Brief Summary
This study's purpose is 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.
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 hypoosmolality. 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 is being undertaken in order to evaluate whether tolvaptan, an oral AVP inhibitor, will be effective in correcting mild to moderate hyponatremia, and to elucidate the effect of this correction on the subject's well-being.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyponatremias, Water Intoxication, Inappropriate ADH Syndrome, Water-Electrolyte Imbalances
Keywords
Sodium, SIADH, Vasopressin, CHF, Cirrhosis, salt, water, electrolyte
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Double
Allocation
Randomized
Enrollment
240 (false)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
tolvaptan
Primary Outcome Measure Information:
Title
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
Title
The average daily area under the curve of change from baseline in serum sodium level up to Day 30 within
Secondary Outcome Measure Information:
Title
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).
Title
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).
Title
Percentage of patients with normalized serum sodium at Day 4.
Title
Percentage of patients with normalized serum sodium at Day 30.
Title
Time to first normalization in serum sodium.
Title
Change from baseline in serum sodium at Day 4.
Title
Change from baseline in serum sodium at Day 30.
Title
Percentage of patients requiring fluid restriction at any time during the double-blind on therapy period of the study.
Title
Urine output at Day 1.
Title
Change from baseline in body weight at Day 1 (hypervolemic patients only).
Title
Fluid balance at Day 1 (hypervolemic patients only).
Title
Change from baseline in the SF-12 (health survey)Physical Component Summary (PCS)and Mental Component Summary (MCS)scales at Week 1 and Day 30.
Title
Categorical change in serum sodium at Day 4 and Day 30 for patients with baseline serum sodium <130 mEq/L.
Title
Categorical change in serum sodium at Day 4 and Day 30 for patients with baseline serum sodium ≥130 mEq/L.
Title
The percentage of patients who are designated as treatment failure due to the need for saline infusion,with or without fluid restriction.
Title
Safety:Adverse events,vital signs,clinical laboratory tests,12- lead electrocardiograms.
Title
PK:Plasma tolvaptan and DM-4103 concentrations.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria
Hyponatremia in euvolemic or hypervolemic states, defined as serum sodium <135 mEq/L prior to randomization.
Able to give 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 of potential study enrollment, excluding percutaneous coronary interventions.
History of a myocardial infarction within 30 days of potential study enrollment.
History of sustained ventricular tachycardia or ventricular fibrillation within 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. 10) 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.
Previous participation in another clinical drug trial within the past 30 days.
Previous participation in this or any other tolvaptan clinical trial.
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nestor Molfino, MD
Organizational Affiliation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
VA Greater Los Angeles Health Care Ctr
City
Los Angeles
State/Province
California
ZIP/Postal Code
90073
Country
United States
Facility Name
UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
93552
Country
United States
Facility Name
UCSF Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Aurora Denver Cardiology Association
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
University of Colorado Heath Science Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80262
Country
United States
Facility Name
University of Florida Gainesville
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Charlotte Heart Group Research Ctr
City
Port Charlotte
State/Province
Florida
ZIP/Postal Code
33952
Country
United States
Facility Name
Medical College of Georgia
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Iowa Hospital
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Minneapolis VA Medical Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55417
Country
United States
Facility Name
Washington University Ctr for Clinical Studies
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Mercury Street Medical
City
Butte
State/Province
Montana
ZIP/Postal Code
59701
Country
United States
Facility Name
Northshore University Hospital
City
Great Neck
State/Province
New York
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10010
Country
United States
Facility Name
University of North Carolina, Div. of Cardiology
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
University Hospitals of Cleveland
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
The Arthur P. Noyes Research Foundation
City
Norristown
State/Province
Pennsylvania
ZIP/Postal Code
19401
Country
United States
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Baptist Clinical Research Ctr
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38120
Country
United States
Facility Name
Tennessee Center for Clinical Trials
City
Tullahoma
State/Province
Tennessee
ZIP/Postal Code
37388
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
25151571
Citation
Lee MY, Kang HJ, Park SY, Kim HL, Han E, Lee EK. Cost-effectiveness of tolvaptan for euvolemic or hypervolemic hyponatremia. Clin Ther. 2014 Sep 1;36(9):1183-94. doi: 10.1016/j.clinthera.2014.07.010. Epub 2014 Aug 21.
Results Reference
derived
PubMed Identifier
22027579
Citation
Cardenas A, Gines P, Marotta P, Czerwiec F, Oyuang J, Guevara M, Afdhal NH. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol. 2012 Mar;56(3):571-8. doi: 10.1016/j.jhep.2011.08.020. Epub 2011 Oct 23.
Results Reference
derived
PubMed Identifier
17105757
Citation
Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112. doi: 10.1056/NEJMoa065181. Epub 2006 Nov 14.
Results Reference
derived
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"SALT Trial" Study of Ascending Levels of Tolvaptan in Hyponatremia
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