Autosomal Dominant Polycystic Kidney Disease
Conditions
Brief summary
The purpose of the trial was to determine the short-term effects of tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD) at various levels of renal function.
Detailed description
Renal function was assessed during screening with the estimated glomerular filtration rate (eGFR), which was calculated with the 4-variable modification of diet in renal disease (MDRD) equation using a minimum of 2 creatinine measurements. The eGFR values were used to categorize participants into 1 of 3 mutually exclusive strata (\> 60 \[Group A\], 30 to 60 \[Group B\], and \< 30 \[Group C\] mL/min/1.73 m\^2). Each of the 3 groups received the same tolvaptan treatment. During the 3-week treatment period, participants were up-titrated on a weekly basis from 45/15 mg to 60/30 mg to 90/30 mg (AM and PM \[8 hours later\] split-dose) to the maximally tolerated dose. The 3-week treatment period was followed by a 3-week post-treatment period during which no study medication was administered. The effects of the highest tolerated split-dose of tolvaptan on renal hemodynamics and pharmacokinetic and pharmacodynamic parameters were assessed throughout the 6 weeks of the study. The reversibility of changes during the post-treatment period after withdrawal of the drug was determined and the acute transitory effects on kidney volume were also explored.
Interventions
DRUGTolvaptan
Tolvaptan was supplied as 15 and 30 mg tablets.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of autosomal dominant polycystic kidney disease (ADPKD) by Ravine criteria.
Exclusion criteria
* Renal replacement therapy. * Use of therapies for the purpose of affecting polycystic kidney disease (PKD) cysts. * Evidence of significant renal disease, eg, active glomerular nephritides, renal cancer, single kidney. * Significant risk-factors for renal impairment, eg, chronic use of diuretics, advanced diabetes, use of nephrotoxic drugs. * History of significant coagulation defects or hemorrhagic diathesis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | After 3 weeks of treatment and 3 weeks post treatment | Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours). The mGFR was corrected for voiding errors. |
| Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | After 3 weeks of treatment and 3 weeks post treatment | Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours). |
| Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | After 3 weeks of treatment and 3 weeks post treatment | Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From 0 to 5 Hours (AUC0-5) After 3 Weeks of Tolvaptan Treatment. | Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour | Blood sampling for determination of tolvaptan concentrations took place at the Baseline, Final Treatment, and the Post Treatment or Early Termination visits. At the Final Treatment visit (Day 21 \[+/- 1 day)\]), blood samples were collected prior to the start of infusion of study treatment and at 1, 2, 3, 4, and 5 hours postdose. At the Baseline (Day 0), and Post Treatment visit (3 weeks \[+/-3 days\] after last dose), a blood sample was collected prior to the start of infusion of study treatment. |
| Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | After 3 weeks of treatment and 3 weeks post treatment | TKV was measured using magnetic resonance imaging. |
| Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment | After 3 weeks of treatment and 3 weeks post treatment | Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours). |
| Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | 2 hours | The volume of urine from each 2-hour urine collection in the renal function tests at Baseline, Final Treatment, and Post Treatment was recorded. Individual voids in a collection interval were pooled before determination of total volume. |
| Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | 24 hours | A 24-hour split urine sample (approximate times: 0700 to 1700 hours, 1700 hours to bedtime, and bedtime to 0700 hours) was collected beginning the day before the Baseline, Final Treatment, and Post Treatment visits and ending at admission to the renal function ward. Individual voids in a collection interval were pooled and the total volume determined. |
| Time to Peak Plasma Concentration (Cmax) After 3 Weeks of Tolvaptan Treatment. | Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour | Blood sampling for determination of tolvaptan concentrations took place at the Baseline, Final Treatment, and the Post Treatment or Early Termination visits. At the Final Treatment visit (Day 21 \[+/- 1 day)\]), blood samples were collected prior to the start of infusion of study treatment and at 1, 2, 3, 4, and 5 hours postdose. At the Baseline (Day 0), and Post Treatment visit (3 weeks \[+/-3 days\] after last dose), a blood sample was collected prior to the start of infusion of study treatment. |
| Time to Peak Plasma Concentration (Tmax) After 3 Weeks of Tolvaptan Treatment. | Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour | Blood sampling for determination of tolvaptan concentrations took place at the Baseline, Final Treatment, and the Post Treatment or Early Termination visits. At the Final Treatment visit (Day 21 \[+/- 1 day)\]), blood samples were collected prior to the start of infusion of study treatment and at 1, 2, 3, 4, and 5 hours postdose. At the Baseline (Day 0), and Post Treatment visit (3 weeks \[+/-3 days\] after last dose), a blood sample was collected prior to the start of infusion of study treatment. |
Countries
Netherlands
Participant flow
Recruitment details
The trial was conducted in 29 participants at one center in The Netherlands. Participants were stratified based on their estimated glomerular filtration rate (eGFR): \>60, 30-60 and \<30 millilitres (mL)/minute (min)/1.73 meter squared (m2). eGFR was assessed using the 4-variable modification of diet in renal disease (MDRD).
Pre-assignment details
The trial consisted of a 2- to 42-day screening period, a 3-week treatment period, and a 3-week post treatment period.
Participants by arm
| Arm | Count |
|---|---|
| eGFR > 60 mL/Min/1.73m2 Daily split-dose of tolvaptan titrated weekly to the maximally tolerated dose. Starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability. | 10 |
| eGFR 30-60 mL/Min/1.73m2 Daily split-dose of tolvaptan titrated weekly to the maximally tolerated dose. Starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability. | 10 |
| eGFR <30 mL/Min/1.73m2 Daily split-dose of tolvaptan titrated weekly to the maximally tolerated dose. Starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability. | 9 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 | Total |
|---|---|---|---|---|
| Age, Continuous | 38.7 Years STANDARD_DEVIATION 7.1 | 47.8 Years STANDARD_DEVIATION 12.9 | 52.1 Years STANDARD_DEVIATION 6.7 | 46.0 Years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 2 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 10 / 10 | 9 / 9 |
| serious Total, serious adverse events | 1 / 10 | 0 / 10 | 1 / 9 |
Outcome results
Primary
Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours).
Time frame: After 3 weeks of treatment and 3 weeks post treatment
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -16.9 mL/min | Standard Deviation 36.4 |
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | 4.3 mL/min | Standard Deviation 30.2 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -11.1 mL/min | Standard Deviation 18.4 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -8.4 mL/min | Standard Deviation 17.7 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -1.7 mL/min | Standard Deviation 5.1 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -1.3 mL/min | Standard Deviation 10.3 |
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Primary
Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours).
Time frame: After 3 weeks of treatment and 3 weeks post treatment
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -0.005 Ratios | Standard Deviation 0.017 |
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -0.003 Ratios | Standard Deviation 0.018 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -0.013 Ratios | Standard Deviation 0.016 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | 0.005 Ratios | Standard Deviation 0.015 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -0.010 Ratios | Standard Deviation 0.014 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -0.016 Ratios | Standard Deviation 0.023 |
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative findingp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: <0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Primary
Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours). The mGFR was corrected for voiding errors.
Time frame: After 3 weeks of treatment and 3 weeks post treatment
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | 0.1 mL/min | Standard Deviation 4.9 |
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -8.0 mL/min | Standard Deviation 9.1 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -6.2 mL/min | Standard Deviation 6.2 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -1.5 mL/min | Standard Deviation 4 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -0.7 mL/min | Standard Deviation 1.5 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -1.2 mL/min | Standard Deviation 3 |
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: <0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: <0.05paited t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05paired t-test
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: <0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: A change of 10% was chosen as representing a clinically significant change in mGFR or ERPF. For this purpose, the alpha level was set at 0.05 and the beta level (power) at 95% instead of 80%, to decrease the chance of a false-negative finding.p-value: >0.05Wilcoxon (Mann-Whitney)
Secondary
Area Under the Concentration-time Curve From 0 to 5 Hours (AUC0-5) After 3 Weeks of Tolvaptan Treatment.
Blood sampling for determination of tolvaptan concentrations took place at the Baseline, Final Treatment, and the Post Treatment or Early Termination visits. At the Final Treatment visit (Day 21 \[+/- 1 day)\]), blood samples were collected prior to the start of infusion of study treatment and at 1, 2, 3, 4, and 5 hours postdose. At the Baseline (Day 0), and Post Treatment visit (3 weeks \[+/-3 days\] after last dose), a blood sample was collected prior to the start of infusion of study treatment.
Time frame: Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Area Under the Concentration-time Curve From 0 to 5 Hours (AUC0-5) After 3 Weeks of Tolvaptan Treatment. | 2850 ng.h/mL | Standard Deviation 774 |
| eGFR 30-60 mL/Min/1.73m2 | Area Under the Concentration-time Curve From 0 to 5 Hours (AUC0-5) After 3 Weeks of Tolvaptan Treatment. | 2140 ng.h/mL | Standard Deviation 863 |
| eGFR <30 mL/Min/1.73m2 | Area Under the Concentration-time Curve From 0 to 5 Hours (AUC0-5) After 3 Weeks of Tolvaptan Treatment. | 3100 ng.h/mL | Standard Deviation 1060 |
Secondary
Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment.
A 24-hour split urine sample (approximate times: 0700 to 1700 hours, 1700 hours to bedtime, and bedtime to 0700 hours) was collected beginning the day before the Baseline, Final Treatment, and Post Treatment visits and ending at admission to the renal function ward. Individual voids in a collection interval were pooled and the total volume determined.
Time frame: 24 hours
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | 4551.1 mL | Standard Deviation 1792.7 |
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -312.2 mL | Standard Deviation 468.2 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | 3274.4 mL | Standard Deviation 1293.3 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -287.2 mL | Standard Deviation 744.7 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | 2215.0 mL | Standard Deviation 1142 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | 143.1 mL | Standard Deviation 390.4 |
Comparison: Test to compare Final Treatment versus Baseline for all treatment groupsp-value: <0.05Paired t-test
Comparison: Test to compare treatment groups at Final Treatmentp-value: <0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Final Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Final Treatmentp-value: <0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare PostTreatment versus Baseline for all treatment groupsp-value: >0.05Paired t-test
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Post Treatmentp-value: <0.05Wilcoxon (Mann-Whitney)
Secondary
Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment.
The volume of urine from each 2-hour urine collection in the renal function tests at Baseline, Final Treatment, and Post Treatment was recorded. Individual voids in a collection interval were pooled before determination of total volume.
Time frame: 2 hours
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | 888.9 mL | Standard Deviation 730.3 |
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -187.8 mL | Standard Deviation 218.2 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | 625.6 mL | Standard Deviation 478.5 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -10.0 mL | Standard Deviation 335.1 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | 356.7 mL | Standard Deviation 283.2 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | 27.5 mL | Standard Deviation 155 |
Comparison: Test to compare Final Treatment versus Baseline for all treatment groupsp-value: <0.05paired te-test
Comparison: Test to compare treatment groups at Final Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Final Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Final Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare Post Treatment versus Baselinep-value: <0.05paired t-test
Comparison: Test to compare Post Treatment versus Baselinep-value: >0.05paired t-test
Comparison: Test to compare Post Treatment versus Baselinep-value: >0.05Paired t-test
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Secondary
Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment
Renal function measurements were performed using the constant infusion method with 125I-iothalamate and 131I-hippuran. A priming solution containing 20 mL infusion solution (0.04 MBq of 125I-iothalamate and 0.03 MBq of 131I-hippuran) was given at 08:00 hours, followed by a constant infusion of 6 to 12 mL/h, with the lowest infusion rates in subjects with impaired renal function, based on previously known serum creatinine concentrations. Plasma concentrations of both tracers were allowed to stabilize during a 1.5-hour equilibration, which was followed by two 2-hour periods (09:30 to 11:30 hours and 11:30 to 13:30 hours) for simultaneous clearances of 125I-iothalamate and 131I-hippuran. Blood was drawn at 1, 2, 3, 4, and 5 hours post consumption of water/tolvaptan (08:30 hours).
Time frame: After 3 weeks of treatment and 3 weeks post treatment
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment | Final treatment change from Baseline | 4.334 mL/min | Standard Deviation 3.268 |
| eGFR > 60 mL/Min/1.73m2 | Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment | Post treatment change from Baseline | -0.675 mL/min | Standard Deviation 1.475 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment | Final treatment change from Baseline | 2.822 mL/min | Standard Deviation 1.715 |
| eGFR 30-60 mL/Min/1.73m2 | Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment | Post treatment change from Baseline | -0.195 mL/min | Standard Deviation 1.124 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment | Final treatment change from Baseline | 1.701 mL/min | Standard Deviation 1.225 |
| eGFR <30 mL/Min/1.73m2 | Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment | Post treatment change from Baseline | 0.382 mL/min | Standard Deviation 0.543 |
Comparison: Test to compare Final Treatment versus Baseline for all treatment groupsp-value: <0.05paired t-test
Comparison: Test to compare Post Treatment versus Baselinep-value: >0.05paired t-test
Comparison: Test to compare Post Treatment versus Baselinep-value: >0.05paired t-test
Comparison: Test to compare Post Treatment versus Baselinep-value: <0.05paired t-test
p-value: >0.05Wilcoxon (Mann-Whitney)
p-value: >0.05paired t-test
p-value: >0.05Wilcoxon (Mann-Whitney)
p-value: >0.05Wilcoxon (Mann-Whitney)
p-value: >0.05Wilcoxon (Mann-Whitney)
p-value: <0.05Wilcoxon (Mann-Whitney)
Secondary
Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
TKV was measured using magnetic resonance imaging.
Time frame: After 3 weeks of treatment and 3 weeks post treatment
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -4.5 Percent | Standard Deviation 3.7 |
| eGFR > 60 mL/Min/1.73m2 | Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -1.5 Percent | Standard Deviation 2.3 |
| eGFR 30-60 mL/Min/1.73m2 | Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -4.6 Percent | Standard Deviation 2.7 |
| eGFR 30-60 mL/Min/1.73m2 | Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -2.4 Percent | Standard Deviation 3.8 |
| eGFR <30 mL/Min/1.73m2 | Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Final treatment change from Baseline | -1.9 Percent | Standard Deviation 1.9 |
| eGFR <30 mL/Min/1.73m2 | Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment. | Post treatment change from Baseline | -0.7 Percent | Standard Deviation 2.5 |
Comparison: Comparison of all treatment groups versus Baseline at Final Treatmentp-value: <0.05paired t-test
Comparison: Comparison of all treatment groups versus Baseline at Post Treatmentp-value: <0.05paired t-test
Comparison: Test to compare treatment groups at Final Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Final Treatmentp-value: <0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Final Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Comparison: Test to compare treatment groups at Post Treatmentp-value: >0.05Wilcoxon (Mann-Whitney)
Secondary
Time to Peak Plasma Concentration (Cmax) After 3 Weeks of Tolvaptan Treatment.
Blood sampling for determination of tolvaptan concentrations took place at the Baseline, Final Treatment, and the Post Treatment or Early Termination visits. At the Final Treatment visit (Day 21 \[+/- 1 day)\]), blood samples were collected prior to the start of infusion of study treatment and at 1, 2, 3, 4, and 5 hours postdose. At the Baseline (Day 0), and Post Treatment visit (3 weeks \[+/-3 days\] after last dose), a blood sample was collected prior to the start of infusion of study treatment.
Time frame: Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Time to Peak Plasma Concentration (Cmax) After 3 Weeks of Tolvaptan Treatment. | 828 ng/mL | Standard Deviation 297 |
| eGFR 30-60 mL/Min/1.73m2 | Time to Peak Plasma Concentration (Cmax) After 3 Weeks of Tolvaptan Treatment. | 591 ng/mL | Standard Deviation 235 |
| eGFR <30 mL/Min/1.73m2 | Time to Peak Plasma Concentration (Cmax) After 3 Weeks of Tolvaptan Treatment. | 840 ng/mL | Standard Deviation 355 |
Secondary
Time to Peak Plasma Concentration (Tmax) After 3 Weeks of Tolvaptan Treatment.
Blood sampling for determination of tolvaptan concentrations took place at the Baseline, Final Treatment, and the Post Treatment or Early Termination visits. At the Final Treatment visit (Day 21 \[+/- 1 day)\]), blood samples were collected prior to the start of infusion of study treatment and at 1, 2, 3, 4, and 5 hours postdose. At the Baseline (Day 0), and Post Treatment visit (3 weeks \[+/-3 days\] after last dose), a blood sample was collected prior to the start of infusion of study treatment.
Time frame: Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour
Population: All participants who took any trial medication and had a postbaseline renal function test.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | Time to Peak Plasma Concentration (Tmax) After 3 Weeks of Tolvaptan Treatment. | 2.0 hours |
| eGFR 30-60 mL/Min/1.73m2 | Time to Peak Plasma Concentration (Tmax) After 3 Weeks of Tolvaptan Treatment. | 2.0 hours |
| eGFR <30 mL/Min/1.73m2 | Time to Peak Plasma Concentration (Tmax) After 3 Weeks of Tolvaptan Treatment. | 2.0 hours |