Variation in the Aquaretic Efficacy of Tolvaptan in Healthy Adults
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Levels of plasma vasopressin, urine osmolarity and plasma tolvaptan
研究概览
简要总结
Tolvaptan is one of new class of medications approved for treatment of low blood sodium (hyponatremia). It works by interfering with the effect of the antidiuretic hormone, vasopressin, thereby increasing urine output and decreasing body water. However, the magnitude of these effects vary from person to person. Thus, the efficacy of tolvaptan is less reliable than an infusion of a concentrated salt solution for emergency, short term treatment of hyponatremia.
This study is designed to test 3 hypotheses about the variable efficacy of tolvaptan.
- The variable effect on urine output is due to individual differences in blood vasopressin which counteracts the effects of tolvaptan.
- The differences in blood vasopressin are due to individual differences in the amount secreted in response to a rise in blood sodium.
- The variable effect on blood sodium is due mainly to the variable effect on urine output and can be corrected by maintaining water intake below urine output.
The study has 2 parts and will be performed in 12 healthy adult males.
- Six subjects will receive tolvaptan at a dose of 60 mg by mouth and six subjects will receive tolvaptan at 30 mg by mouth. Blood and urine will be collected hourly for 6 hours and water will be ingested in prescribed amounts. For the next 16 hours, subjects will drink at will and blood and urine will be collected 4 more times.
- One week later, the same subjects will receive a concentrated salt solution (3% saline) by vein for 6 hours. During this time, blood and urine will be collected hourly but drinking will not be permitted. For the next 4 hours, subjects will be allowed to drink at will while blood and urine are collected twice more.
The volume, concentration and creatinine content of each urine will be determined. Blood will be analyzed for sodium, vasopressin and, in the first study, tolvaptan.
详细描述
Subjects:12 healthy adult males, age 21-55,will be recruited via posters in medical center. They must pass screening history & physical examination and abstain from ingestion of grapefruit products for 3 days prior to study and from all caffeinated beverage for 24 hours before study.
Procedures: Each subject will receive two different treatments one week apart. Each time,they will fast overnight, present to the Northwestern University Clinical Research Unit at Northwestern Memorial Hospital at about 0700 hours and be given a light breakfast. At 0900 hours, staff will collect a completely voided urine (U0)and venous blood sample of 20 mL (B0)then weigh subject to nearest 0.1 kg, record vital signs (pulse rate and blood pressure), obtain a thirst score (rating from 1 to 10)and begin the treatment.
- The treatment on the first admission will be tolvaptan. Six subjects will receive tolvaptan at a dose of 60 mg by mouth and six subjects will receive tolvaptan at 30 mg by mouth. Hourly for the next 6 hours (i.e. until 1500 hours), all the measurements and samples obtained at baseline will be repeated as before. In addition, the subject will drink a volume of water that is 5 mL/kg body weight lower than the volume of urine just voided. This is expected to raise plasma sodium by about 7 millimoles/L in 6 hours. For the next 16 hours, subjects will remain and be allowed to drink at will. In addition, they will be served dinner at approximately 1700 hours and all the measures obtained at baseline will be repeated again at 1700, 1900, 2300 and 0700 hours when subjects will be discharged.
- On the second admission one week later, the procedures will be identical to the first admission with following exceptions: (a) instead of tolvaptan, at 0900 hours, subjects will be started on an infusion of 3% saline at a rate of 0.033 mL/min/kg body weight. This infusion will continue for 6 hours (i.e. until 1500 hours) and is expected to raise plasma sodium about 7 millimoles/L), the same as the tolvaptan treatment;(b) the volume of blood removed each time will be smaller (10 mL) since they will not be assayed for tolvaptan; (c)subjects will not be permitted to drink during the infusion. In addition, subjects will remain in the unit for only 4 more hours (until 1900 hours). During this time, they will be permitted to drink at will, will be served dinner at about 1700 hours and will have all baseline measurements repeated at 1700 and 1900 hours.
The data collected during these two tests will be obtained as follows:
- weight in kg to the nearest 0.1 kg
- thirst intensity as rated by the subject on a scale of 1 to 10.
- pulse and blood pressure recumbent
- urine volume to the nearest 5 mL
- urine osmolarity by freezing point depression in Clinical Research Unit Core Laboratory
- urine creatinine in clinical chemistry laboratory of Northwestern Memorial Hospital
- blood placed on ice, centrifuged immediately at 4 C, plasma removed for:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 盲法
- None
入排标准
- 年龄范围
- 21 Years 至 55 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •21-55 years of age
- •No major health problems or current medications
- •Must be willing/able to avoid grapefruit products for 1 week prior to admission
排除标准
- •Body weight > or < 15% of ideal
- •Known allergy to tolvaptan
- •Participation in another research study in previous 2 months
- •Inability to sense thirst
研究组 & 干预措施
Tolvaptan and Hypertonic saline infusion
Tolvaptan 60 mg or 30 mg tablet by mouth for the first part of the study. A week later, infusion of hypertonic saline.
干预措施: Tolvaptan (Drug)
Tolvaptan and Hypertonic saline infusion
Tolvaptan 60 mg or 30 mg tablet by mouth for the first part of the study. A week later, infusion of hypertonic saline.
干预措施: Hypertonic saline infusion (Drug)
结局指标
主要结局
Levels of plasma vasopressin, urine osmolarity and plasma tolvaptan
时间窗: Throughout the 22 hours of the tolvaptan study .
The relationship of urine osmolarity to each of three variables-plasma vasopressin. plasma tolvaptan and the ratio of plasma vasopressin to plasma tolvaptan- will be compared to determine which correlates best. The hypothesis predicts that the best fit will be between urine osmolarity and the ratio of plasma vasopressin to tolvaptan indicating that the variable effect of tolvaptan on urine output is due to competition with individual differences in plasma vasopressin.
次要结局
- Regression relationship of plasma vasopressin to plasma osmolarity/sodium during tolvaptan and saline infusion studies.(During first 6 hours of each treatment)
研究者
Gary Robertson
Principal Investigator
Northwestern University