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| Name | Class |
|---|---|
| Otsuka Pharmaceutical Co., Ltd. | INDUSTRY |
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.
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.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| tolvaptan | Drug |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
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Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Nestor Molfino, MD | Otsuka Pharmaceutical Development & Commercialization, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA Greater Los Angeles Health Care Ctr | Los Angeles | California | 90073 | United States | ||
| UCLA |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25151571 | Derived | 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. | |
| 22027579 | Derived | 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. |
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| 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. |
| Los Angeles |
| California |
| 93552 |
| United States |
| UCSF Medical Center | San Francisco | California | 94143 | United States |
| Aurora Denver Cardiology Association | Denver | Colorado | 80218 | United States |
| University of Colorado Heath Science Center | Denver | Colorado | 80262 | United States |
| University of Florida Gainesville | Gainesville | Florida | 32610 | United States |
| Charlotte Heart Group Research Ctr | Port Charlotte | Florida | 33952 | United States |
| Medical College of Georgia | Augusta | Georgia | 30912 | United States |
| Northwestern University | Chicago | Illinois | 60611 | United States |
| University of Chicago | Chicago | Illinois | 60637 | United States |
| University of Iowa Hospital | Iowa City | Iowa | 52242 | United States |
| Minneapolis VA Medical Center | Minneapolis | Minnesota | 55417 | United States |
| Washington University Ctr for Clinical Studies | St Louis | Missouri | 63110 | United States |
| Mercury Street Medical | Butte | Montana | 59701 | United States |
| Northshore University Hospital | Great Neck | New York | United States |
| New York | New York | 10010 | United States |
| University of North Carolina, Div. of Cardiology | Chapel Hill | North Carolina | 27599 | United States |
| University Hospitals of Cleveland | Cleveland | Ohio | 44106 | United States |
| Ohio State University Medical Center | Columbus | Ohio | 43210 | United States |
| The Arthur P. Noyes Research Foundation | Norristown | Pennsylvania | 19401 | United States |
| University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | 15213 | United States |
| Baptist Clinical Research Ctr | Memphis | Tennessee | 38120 | United States |
| Tennessee Center for Clinical Trials | Tullahoma | Tennessee | 37388 | United States |
| 17105757 | Derived | 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. |
| ID | Term |
|---|---|
| D007010 | Hyponatremia |
| D014869 | Water Intoxication |
| D007177 | Inappropriate ADH Syndrome |
| D014883 | Water-Electrolyte Imbalance |
| D003919 | Diabetes Insipidus |
| D005355 | Fibrosis |
| ID | Term |
|---|---|
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D011041 | Poisoning |
| D064419 | Chemically-Induced Disorders |
| D010900 | Pituitary Diseases |
| D007027 | Hypothalamic Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D004700 | Endocrine System Diseases |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077602 | Tolvaptan |
| ID | Term |
|---|---|
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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