Multicenter, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of the Effects of Titrated Oral Tolvaptan Tablets in Patients With Hyponatremia

Brief Summary

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.

Primary Outcomes

Secondary Outcomes

• 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.