VPA 985 DOSING OF PATIENTS W/ HYPONATREMIA

Virginia Commonwealth University, Richmond VA

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Abstract

A trial to determine the effects of three dose levels of VPA-985 and placebo in the treatment of patients with a deficiency of sodium in the blood. Vasopressin (VP), also known as antidiuretic hormone (ADH), plays a primary role in the regulation of renal water excretion in mammals. This drug might be useful in treating disease states associated with vasopressin-induced impairment of water metabolism such as congestive heart failure, advanced liver disease and the syndrome of inapropriate andidiuretic hormone secretion. Experimental, preclinical and clinical evidence demonstrates that VPA-985 is an orally active, competitive, nonpeptide vasopressin antagonist. VPA-985 produces dose-related increases in urine flow and free water clearance with prelongation of effect at higher doses and corresponding increases in serum sodium. This randomized, double-blind, parallel group, placebo-controlled study will have at least 200 subjects who are male or female, not pregnant, having a stable regimen of any incidental medications for a minimum of three days prior to the study medication administration, a paticular serum sodium level, and able to give signed and dated informed consent. Subjects will participate for approximately 30 days, the first 3-5 used for screening purposes. After the screening, the subjects will be admitted to the clinic for up to nine days and then studied outside the clinic for up to 16 days. Screening will consist of a medical history, a physical exam including assessment of fatigue, fluid under the skin, appetite, blood pressure, heart rate, height, weight, blood and urine collections, pregnancy test and lab work. Subjects will remain on a fixed salt diet until the last day that medication is given. Daily intake of liquid will be measured. The subjects will be randomly assigned to receive either the study drug or the placebo. The drug will be given at three different doses, twice daily. Urine output will be collected for measurement every time it takes place. While admitted, subjects will undergo the following tests: Daily physical exams, frequent measures of lying and standing blood pressure, heart rate, daily weights, frequent blood and urine samples, several electrocardiograms, assessments of thirst, and tests for mental function. Out-of-clinic days will include four visits, and the subjects will have been advised on daily amounts of liquid to consume. Doses of the study medication will be taken on specific days and several tests will take place. Physical exams, lying and standing blood pressures, heart rates, body weight, assessment of thirst, blood and urine samples, two electrocardiograms, and a series of tests to measure the mental function will be done. There will be one final day of study after the outpatient period where a physical exam , lying and standing blood pressure, heart rate, weight, ECG, blood and urine tests and assessment of thirst will be done.