HealthyPhase 4NCT01973140
Effects of Tolvaptan in Healthy Adults
A Phase 4 study testing Tolvaptan and Hypertonic saline infusion in people with Healthy, run by Northwestern University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 55 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Tolvaptan and Hypertonic saline infusion
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2013to Mar 2016
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 55 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- Females
- Body weight > or < 15% of ideal
- Known allergy to tolvaptan
- Participation in another research study in previous 2 months
- Inability to sense thirst
Trial locations and contacts
1 site in 1 country.
United States1 site
Clinical Research Unit Northwestern Memorial Hospital
Chicago, Illinois, 60611
About this study
Official title: Variation in the Aquaretic Efficacy of Tolvaptan in Healthy Adults
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.
Read more
- 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.
Read the 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.
- 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:
- osmolarity by freezing point depression in Clinical Research Unit Core Lab (STAT)
- sodium by ion specific electrode in Northwestern Memorial Hospital chemistry laboratory after sealed storage at 4 degrees C for 2-16 hours
- vasopressin by radioimmunoassay in Clinical Research Unit Core Laboratory after sealed storage at -4 C for approximately 6 months
- 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:
- 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.
- 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.
- 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.
- Conditions
- Healthy
- Being tested
- Tolvaptan, Hypertonic saline infusion
- Keywords
- Tolvaptan, Aquaretic Efficacy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TolvaptanDrug
Also called Samsca
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.
Hypertonic saline infusionDrug
Also called 3% saline solution
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.
| Study group | Role | What they receive |
|---|---|---|
| 30 mg Tolvaptan and Hypertonic saline infusion | Experimental | Tolvaptan 30 mg tablet by mouth for the first part of the study. A week later, infusion of hypertonic saline. Receives: Drug: Tolvaptan; Drug: Hypertonic saline infusion |
| 60 mg Tolvaptan and Hypertonic saline infusion | Experimental | Tolvaptan 60 mg tablet by mouth for the first part of the study. A week later, infusion of hypertonic saline. Receives: Drug: Tolvaptan; Drug: Hypertonic saline infusion |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Plasma Osmolarity With Tolvaptan
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.
Measured: 22 hours
Change in Plasma Osmolarity With 3% Saline Infusion
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.
Measured: 10 hours
Change in Plasma Sodium With Tolvaptan
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.
Measured: 22 hours
Change in Plasma Sodium With 3% Saline Infusion
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.
Measured: 10 hours
Secondary outcomes (16)
Change in Plasma Vasopressin With Tolvaptan
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.
Measured: 22 hours
Change in Plasma Vasopressin With 3% Saline Infusion
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.
Measured: 10 hours
Change in Urine Osmolarity With Tolvaptan
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.
Measured: 22 hours
Change in Urine Osmolarity With 3% Saline Infusion
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.
Measured: 10 hours
Change in Thirst Ratings With Tolvaptan
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.
Measured: 6 hours
Change in Thirst Ratings With 3% Saline Infusion
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.
Measured: 6 hours
Change in Fluid Intake Volume With Tolvaptan
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.
Measured: 22 hours
Change in Fluid Intake Volume With 3% Saline Infusion
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.
Measured: 10 hours
Change in Fluid Intake Volume Per kg Body Weight With Tolvaptan
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.
Measured: 22 hours
Change in Fluid Intake Volume Per kg Body Weight With 3% Saline Infusion
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.
Measured: 6 hours
Change in Urine Volume With Tolvaptan
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.
Measured: 22 hours
Change in Urine Volume With 3% Saline Infusion
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.
Measured: 10 hours
Change in Urine Volume Per kg Body Weight With Tolvaptan
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.
Measured: 22 hours
Change in Urine Volume Per kg Body Weight With 3% Saline Infusion
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.
Measured: 6 hours
Change in Body Weight With Tolvaptan
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.
Measured: 22 hours
Change in Body Weight With 3% Saline Infusion
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.
Measured: 6 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2013 (estimated)
- Study startNov 2013
- Primary completionDec 2015
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by Northwestern UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Northwestern University
- Sponsor type
- University, hospital or other
- Collaborators
- Otsuka America Pharmaceutical
- Responsible party
- Sponsor
- Investigators
- Gary L Robertson, MD, Principal investigator, Northwestern University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01973140
- Sponsor's protocol ID
- STU00071984
- Status last verified
- Feb 2023
- First submitted
- 19 Sep 2013
- Last updated
- 15 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Robertson GL. Vaptans for the treatment of hyponatremia. Nat Rev Endocrinol. 2011 Mar;7(3):151-61. doi: 10.1038/nrendo.2010.229. Epub 2011 Feb 1.
PubMed 21283124Thompson CA. FDA approves oral vasopressin antagonist. Am J Health Syst Pharm. 2009 Jul 1;66(13):1154. doi: 10.2146/news090054. No abstract available.
PubMed 19535650Cada, DJ, Levien TL, Baker DE. Tolvaptan. Hospital Pharmacy. 2009; 44(1): 998-1009.
Shoaf SE, Wang Z, Bricmont P, Mallikaarjun S. Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending single-dose studies in healthy subjects. J Clin Pharmacol. 2007 Dec;47(12):1498-507. doi: 10.1177/0091270007307877. Epub 2007 Oct 9.
PubMed 17925589Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med. 2006 Jul;119(7 Suppl 1):S36-42. doi: 10.1016/j.amjmed.2006.05.006.
PubMed 16843083Zerbe RL, Miller JZ, Robertson GL. The reproducibility and heritability of individual differences in osmoregulatory function in normal human subjects. J Lab Clin Med. 1991 Jan;117(1):51-9.
PubMed 1987308Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest. 1973 Sep;52(9):2340-52. doi: 10.1172/JCI107423.
PubMed 4727463Robertson GL. Disorders of Thirst in Man. In: Thirst: Physiological and Psychological Aspects. Ed. D Ramsey Springer Verlag, London. 1991; pp 453-475
Study at a glance
From the registry record, last updated by the sponsor on 15 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Variation in the Aquaretic Efficacy of Tolvaptan in Healthy Adults
- ClinicalTrials.gov ID
- NCT01973140
- Acronym / sponsor ID
- STU00071984
- Conditions
- Healthy
- Keywords
- Tolvaptan, Aquaretic Efficacy
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Northwestern UniversityUniversity, hospital or other
- Collaborators
- Otsuka America Pharmaceutical
- Study start
- Nov 2013
- Primary completion
- Dec 2015 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 31 Oct 2013 (estimated)
- Results
- Posted 15 Oct 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
- 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:
- osmolarity by freezing point depression in Clinical Research Unit Core Lab (STAT)
- sodium by ion specific electrode in Northwestern Memorial Hospital chemistry laboratory after sealed storage at 4 degrees C for 2-16 hours
- vasopressin by radioimmunoassay in Clinical Research Unit Core Laboratory after sealed storage at -4 C for approximately 6 months
- 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:
- 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.
- 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.
- 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.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 30 mg Tolvaptan and Hypertonic saline infusion | Experimental | Drug: Tolvaptan, Drug: Hypertonic saline infusionTolvaptan 30 mg tablet by mouth for the first part of the study. A week later, infusion of hypertonic saline. |
| 60 mg Tolvaptan and Hypertonic saline infusion | Experimental | Drug: Tolvaptan, Drug: Hypertonic saline infusionTolvaptan 60 mg tablet by mouth for the first part of the study. A week later, infusion of hypertonic saline. |
Who may qualify
- Ages
- 21 to 55 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (5 listed)
- Females
- Body weight > or < 15% of ideal
- Known allergy to tolvaptan
- Participation in another research study in previous 2 months
- Inability to sense thirst
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TolvaptanAlso: SamscaAdult 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. | Drug | 30 mg Tolvaptan and Hypertonic saline infusion, 60 mg Tolvaptan and Hypertonic saline infusion |
| Hypertonic saline infusionAlso: 3% saline solutionA 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. | Drug | 30 mg Tolvaptan and Hypertonic saline infusion, 60 mg Tolvaptan and Hypertonic saline infusion |
Primary outcome
Change in Plasma Osmolarity With Tolvaptan
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
16 secondary outcomes
Change in Plasma Vasopressin With Tolvaptan
Time frame: 22 hours
Change in Plasma Vasopressin With 3% Saline Infusion
Time frame: 10 hours
Change in Urine Osmolarity With Tolvaptan
Time frame: 22 hours
Change in Urine Osmolarity With 3% Saline Infusion
Time frame: 10 hours
Change in Thirst Ratings With Tolvaptan
Time frame: 6 hours
Change in Thirst Ratings With 3% Saline Infusion
Time frame: 6 hours
Change in Fluid Intake Volume With Tolvaptan
Time frame: 22 hours
Change in Fluid Intake Volume With 3% Saline Infusion
Time frame: 10 hours
Change in Fluid Intake Volume Per kg Body Weight With Tolvaptan
Time frame: 22 hours
Change in Fluid Intake Volume Per kg Body Weight With 3% Saline Infusion
Time frame: 6 hours
Change in Urine Volume With Tolvaptan
Time frame: 22 hours
Change in Urine Volume With 3% Saline Infusion
Time frame: 10 hours
Change in Urine Volume Per kg Body Weight With Tolvaptan
Time frame: 22 hours
Change in Urine Volume Per kg Body Weight With 3% Saline Infusion
Time frame: 6 hours
Change in Body Weight With Tolvaptan
Time frame: 22 hours
Change in Body Weight With 3% Saline Infusion
Time frame: 6 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 21283124Robertson GL. Vaptans for the treatment of hyponatremia. Nat Rev Endocrinol. 2011 Mar;7(3):151-61. doi: 10.1038/nrendo.2010.229. Epub 2011 Feb 1.
- Background: PubMed 19535650Thompson CA. FDA approves oral vasopressin antagonist. Am J Health Syst Pharm. 2009 Jul 1;66(13):1154. doi: 10.2146/news090054. No abstract available.
- BackgroundCada, DJ, Levien TL, Baker DE. Tolvaptan. Hospital Pharmacy. 2009; 44(1): 998-1009.
- Background: PubMed 17925589Shoaf SE, Wang Z, Bricmont P, Mallikaarjun S. Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending single-dose studies in healthy subjects. J Clin Pharmacol. 2007 Dec;47(12):1498-507. doi: 10.1177/0091270007307877. Epub 2007 Oct 9.
- Background: PubMed 16843083Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med. 2006 Jul;119(7 Suppl 1):S36-42. doi: 10.1016/j.amjmed.2006.05.006.
- Background: PubMed 1987308Zerbe RL, Miller JZ, Robertson GL. The reproducibility and heritability of individual differences in osmoregulatory function in normal human subjects. J Lab Clin Med. 1991 Jan;117(1):51-9.
- Background: PubMed 4727463Robertson GL, Mahr EA, Athar S, Sinha T. Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest. 1973 Sep;52(9):2340-52. doi: 10.1172/JCI107423.
- BackgroundRobertson GL. Disorders of Thirst in Man. In: Thirst: Physiological and Psychological Aspects. Ed. D Ramsey Springer Verlag, London. 1991; pp 453-475
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gary L Robertson, MD principal investigator
Northwestern University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tolvaptan and Hypertonic saline infusion in people with Healthy, run by Northwestern University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Plasma Osmolarity With Tolvaptan (time frame: 22 hours). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01973140, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2026.