Healthy
Conditions
Keywords
Tolvaptan, Aquaretic Efficacy
Brief summary
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. 1. The variable effect on urine output is due to individual differences in blood vasopressin which counteracts the effects of tolvaptan. 2. The differences in blood vasopressin are due to individual differences in the amount secreted in response to a rise in blood sodium. 3. 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. 1. 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. 2. 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.
Detailed description
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. 1. 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. 2. 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: 1. weight in kg to the nearest 0.1 kg 2. thirst intensity as rated by the subject on a scale of 1 to 10. 3. pulse and blood pressure recumbent 4. urine volume to the nearest 5 mL 5. urine osmolarity by freezing point depression in Clinical Research Unit Core Laboratory 6. urine creatinine in clinical chemistry laboratory of Northwestern Memorial Hospital 7. blood placed on ice, centrifuged immediately at 4 C, plasma removed for: 1. osmolarity by freezing point depression in Clinical Research Unit Core Lab (STAT) 2. sodium by ion specific electrode in Northwestern Memorial Hospital chemistry laboratory after sealed storage at 4 degrees C for 2-16 hours 3. vasopressin by radioimmunoassay in Clinical Research Unit Core Laboratory after sealed storage at -4 C for approximately 6 months 4. tolvaptan (first study only) by reverse phase, high performance liquid chromatography at ICON Labs (Dublin) after storage at -20 C for approximately 6 months. DATA analysis and interpretation will be as follows: 1. To test the hypothesis that the variable effect of tolvaptan on urine concentration and flow depends on the level of plasma vasopressin as well as plasma tolvaptan, the relationship between the osmolarity of the first 9 urine collections after treatment to the area under the curve (AUC) for plasma vasopressin, for plasma tolvaptan and for the ratio of plasma tolvaptan/plasma vasopressin during the concurrent time periods will be determined by regression analysis in each of the 12 subjects. The same analysis will be performed using urine volume instead of urine osmolarity. Hypothesis 1 predicts that in all subjects, the best correlation (r value)will be between urine osmolarity and the ratio of tolvaptan/vasopressin. It also predicts that the slopes of every individual regression line will be negative (i.e. the higher the ratio of tolvaptan to vasopressin)the lower the urine osmolarity). However, the slopes may differ between subjects owing to individual differences in the concentrating capacity of the kidneys. 2. To test the hypothesis that the individual differences in plasma vasopressin during treatment are due to the inherent,genetically determined differences in the secretory response to osmotic (sodium) stimuli that are known to exist in humans, the relationship of plasma vasopressin to plasma sodium (or osmolarity)during the first 6 hours of treatment with tolvaptan or 3% saline will be determined separately by regression analysis and compared. Based on previous findings, the correlation of plasma vasopressin to plasma sodium (or osmolarity) should be very high (r\>0.9) in every subject during 3% saline infusion but the slopes will vary markedly between subjects. The hypothesis predicts that these correlations and marked differences in slopes will not differ after tolvaptan treatment. This prediction will be tested by regressing the slope during tolvaptan against the slope in the same subject during 3% saline infusion in all 12 subjects. If the hypothesis is correct, the correlation coefficient between the individual slopes will be greater than 0.8 and the line describing the relation will have a slope approximating 1 with an intercept near zero on both axes. 3. To test the hypothesis that the variable effect of tolvaptan on plasma sodium can be reduced by continuously adjusting fluid intake to a level below urine output by a constant amount (5 mL/kg each hour), the relation of plasma sodium to elapsed time over the 6 hour period after tolvaptan and during saline infusion will be calculated separately for each subject by regression analysis and compared. If the hypothesis is correct, the correlation coefficients for the tolvaptan and saline treatments should be uniformly high e.g. greater than 0.9 in all subject even though the slopes of the lines describing these relationships may differ.
Interventions
DRUGTolvaptan
Adult male volunteers will be given a given a 60mg or a 30 mg dose of tolvaptan. Blood and urine samples will be collected at specified time points for the next 24 hours.
A week after the first intervention(tolvaptan), the subjects will undergo a hypertonic saline infusion for 6 hours. Blood and urine samples will be collected at specified time points until 4hour hours after the infusion.
Sponsors
Northwestern University
Otsuka America Pharmaceutical
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Males * 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
Exclusion criteria
* Females * Body weight \> or \< 15% of ideal * Known allergy to tolvaptan * Participation in another research study in previous 2 months * Inability to sense thirst
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Osmolarity With Tolvaptan | 22 hours | Blood samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. Plasma osmolarity was measured from the blood samples. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Plasma Osmolarity With 3% Saline Infusion | 10 hours | Baseline data for visit 1 and visit 2 were collected separately at the start of each visit, this Outcome Measure is reporting data from the baseline collected at visit 2. Samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, and 10 hours post baseline. Plasma osmolarity was measured from the blood samples. |
| Change in Plasma Sodium With Tolvaptan | 22 hours | Blood samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. Plasma sodium was measured from the blood samples. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Plasma Sodium With 3% Saline Infusion | 10 hours | Blood samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, and 10 hours post baseline. Plasma sodium was measured from the blood samples. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Vasopressin With Tolvaptan | 22 hours | Blood samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. Plasma vasopressin was measured from the blood samples. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Plasma Vasopressin With 3% Saline Infusion | 10 hours | Blood samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, and 10 hours post baseline. Plasma vasopressin was measured from the blood samples. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
| Change in Urine Osmolarity With Tolvaptan | 22 hours | Urine samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. Urine osmolarity was measured from the urine samples. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Urine Osmolarity With 3% Saline Infusion | 10 hours | Urine samples were collected at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, and 10 hours post baseline. Urine osmolarity was measured from the urine samples. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
| Change in Thirst Ratings With Tolvaptan | 6 hours | Participants were asked to rate their thirst at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, and 6 hours post baseline. The participants were instructed to rate their thirst on a scale from 0-10 with a higher number indicating a higher level of thirst. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Thirst Ratings With 3% Saline Infusion | 6 hours | Participants were asked to rate their thirst at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, and 6 hours post baseline. The participants were instructed to rate their thirst on a scale from 0-10 with a higher number indicating a higher level of thirst. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
| Change in Fluid Intake Volume With Tolvaptan | 22 hours | For the first six hours, participants ingested water in prescribed amounts. For the remaining 16 hours, fluid intake was unrestricted but the volumes of fluids ingested was recorded. Fluid intake was recorded 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Fluid Intake Volume With 3% Saline Infusion | 10 hours | Subjects were not allowed to drink until the end of the 6-hour infusion. After that time, they were allowed to drink freely, and intake was recorded as volume each hour for the next 4 hours. So, the values recorded at 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, and 6 hours post baseline are the volume of the infusion, while the values recorded at 8 hours post baseline and 10 hours post baseline are the volumes the participants chose to drink freely. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
| Change in Fluid Intake Volume Per kg Body Weight With Tolvaptan | 22 hours | For the first six hours, participants ingested water in prescribed amounts. For the remaining 16 hours, fluid intake was unrestricted but the volumes of fluids ingested and weight was recorded. Volume of fluids ingested and weight was recorded 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Fluid Intake Volume Per kg Body Weight With 3% Saline Infusion | 6 hours | Subjects were not allowed to drink until the end of the 6 hour infusion and were weighed each hour. So, the values recorded at 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, and 6 hours post baseline are the volume of the infusion per kg of body weight. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
| Change in Urine Volume With Tolvaptan | 22 hours | For the first six hours, participants ingested water in prescribed amounts. For the remaining 16 hours, fluid intake was unrestricted. The volume of urine was recorded at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Urine Volume With 3% Saline Infusion | 10 hours | Subjects were not allowed to drink until the end of the 6 hour infusion. After that time, they were allowed to drink freely. Urine was recorded as volume each hour at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, and 10 hours post baseline. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
| Change in Urine Volume Per kg Body Weight With Tolvaptan | 22 hours | For the first six hours, participants ingested water in prescribed amounts. For the remaining 16 hours, fluid intake was unrestricted. The volume of urine and weight were recorded at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Urine Volume Per kg Body Weight With 3% Saline Infusion | 6 hours | Subjects were not allowed to drink until the end of the 6-hour infusion. Urine volume and weight were recorded at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, and 6 hours post baseline. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
| Change in Body Weight With Tolvaptan | 22 hours | For the first six hours, participants ingested water in prescribed amounts. For the remaining 16 hours, fluid intake was unrestricted. The participant's weight was recorded at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, 6 hours post baseline, 8 hours post baseline, 10 hours post baseline, 14 hours post baseline, and 22 hours post baseline. This Outcome Measure is reporting the data from the first visit when participants were given tolvaptan. |
| Change in Body Weight With 3% Saline Infusion | 6 hours | Subjects were not allowed to drink until the end of the 6-hour infusion. After that time, they were allowed to drink freely. Participant's weight was recorded at baseline, 1 hour post baseline, 2 hours post baseline, 3 hours post baseline, 4 hours post baseline, 5 hours post baseline, and 6 hours post baseline. This Outcome Measure is reporting the data from the second visit when participants were given 3% saline infusion. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORGary L Robertson, MD
Northwestern University
Participant flow
Recruitment details
Subjects were recruited through Clinicaltrials.gov, on-campus advertising via flyers and through the services of the NUCATS (Northwestern University Center for Translational Studies) General Research Registry. Subjects in the registry had previously agreed to be contacted regarding future research projects at Northwestern University.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 36.8 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 10 |
| other Total, other adverse events | 0 / 7 | 3 / 10 |
| serious Total, serious adverse events | 0 / 7 | 0 / 10 |
Outcome results
None listed