A Phase 2 interventional study of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease, sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc.. Completed at 1 site in Netherlands. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2019-03-05.
Sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. · Phase 2, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Participants received tolvaptan for the first 3 weeks of the 6 week study. Participants were up-titrated on a weekly basis from tolvaptan 45/15 mg to 60/30 mg to 90/30 mg oral split-dose (AM and PM \[8 hours later\]) to the maximally tolerated dose.
Drug: Tolvaptan
Participants received tolvaptan for the first 3 weeks of the 6 week study. Participants were up-titrated on a weekly basis from tolvaptan 45/15 mg to 60/30 mg to 90/30 mg oral split-dose (AM and PM \[8 hours later\]) to the maximally tolerated dose.
Drug: Tolvaptan
Participants received tolvaptan for the first 3 weeks of the 6 week study. Participants were up-titrated on a weekly basis from tolvaptan 45/15 mg to 60/30 mg to 90/30 mg oral split-dose (AM and PM \[8 hours later\]) to the maximally tolerated dose.
Drug: Tolvaptan
Tolvaptan was supplied as 15 and 30 mg tablets.
Also known as: OPC-41061
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
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
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
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
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
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
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
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
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
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
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).
| Milestone | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 ml/Min/1.73m2 |
|---|---|---|---|
| Started | 10 | 10 | 9 |
| Completed | 9 | 9 | 9 |
| Not completed | 1 | 1 | 0 |
| Withdrew: Adverse event | 1 | 1 | 0 |
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.
| mL/min | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Final treatment change from Baseline | -8.0 ± 9.1 | -6.2 ± 6.2 | -0.7 ± 1.5 |
| Post treatment change from Baseline | 0.1 ± 4.9 | -1.5 ± 4.0 | -1.2 ± 3.0 |
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).
| mL/min | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Final treatment change from Baseline | -16.9 ± 36.4 | -11.1 ± 18.4 | -1.7 ± 5.1 |
| Post treatment change from Baseline | 4.3 ± 30.2 | -8.4 ± 17.7 | -1.3 ± 10.3 |
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).
| Ratios | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Final treatment change from Baseline | -0.005 ± 0.017 | -0.013 ± 0.016 | -0.010 ± 0.014 |
| Post treatment change from Baseline | -0.003 ± 0.018 | 0.005 ± 0.015 | -0.016 ± 0.023 |
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).
| mL/min | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Final treatment change from Baseline | 4.334 ± 3.268 | 2.822 ± 1.715 | 1.701 ± 1.225 |
| Post treatment change from Baseline | -0.675 ± 1.475 | -0.195 ± 1.124 | 0.382 ± 0.543 |
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.
| ng/mL | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Time to Peak Plasma Concentration (Cmax) After 3 Weeks of Tolvaptan Treatment. | 828 ± 297 | 591 ± 235 | 840 ± 355 |
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.
| hours | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Time to Peak Plasma Concentration (Tmax) After 3 Weeks of Tolvaptan Treatment. | 2.0 (1.00 to 3.00) | 2.0 (1.00 to 3.00) | 2.0 (1.00 to 5.00) |
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.
| ng.h/mL | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | 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. | 2850 ± 774 | 2140 ± 863 | 3100 ± 1060 |
TKV was measured using magnetic resonance imaging.
| Percent | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Final treatment change from Baseline | -4.5 ± 3.7 | -4.6 ± 2.7 | -1.9 ± 1.9 |
| Post treatment change from Baseline | -1.5 ± 2.3 | -2.4 ± 3.8 | -0.7 ± 2.5 |
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.
| mL | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Final treatment change from Baseline | 4551.1 ± 1792.7 | 3274.4 ± 1293.3 | 2215.0 ± 1142.0 |
| Post treatment change from Baseline | -312.2 ± 468.2 | -287.2 ± 744.7 | 143.1 ± 390.4 |
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.
| mL | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Final treatment change from Baseline | 888.9 ± 730.3 | 625.6 ± 478.5 | 356.7 ± 283.2 |
| Post treatment change from Baseline | -187.8 ± 218.2 | -10.0 ± 335.1 | 27.5 ± 155.0 |
Collected over Adverse events were collected from the time of signing the informed consent to 7 days after the early termination visit or up to the 21 Day Post-Treatment Visit. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| eGFR > 60 mL/Min/1.73m2 | — | 1/10 (10%) | 10/10 (100%) |
| eGFR 30-60 mL/Min/1.73m2 | — | 0/10 (0%) | 10/10 (100%) |
| eGFR <30 mL/Min/1.73m2 | — | 1/9 (11.1%) | 9/9 (100%) |
| Event | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| Angina pectorisCardiac disorders | 0/10 | 0/10 | 1/9 |
| PolyuriaRenal and urinary disorders | 1/10 | 0/10 | 0/9 |
| Event | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 |
|---|---|---|---|
| ThirstGeneral disorders | 10/10 | 10/10 | 8/9 |
| PolyuriaRenal and urinary disorders | 9/10 | 9/10 | 7/9 |
| NocturiaRenal and urinary disorders | 8/10 | 6/10 | 6/9 |
| Dry mouthGastrointestinal disorders | 6/10 | 5/10 | 5/9 |
| FatigueGeneral disorders | 2/10 | 1/10 | 3/9 |
| Decreased appetiteMetabolism and nutrition disorders | 2/10 | 3/10 | 2/9 |
| Renal painRenal and urinary disorders | 3/10 | 0/10 | 1/9 |
| NauseaGastrointestinal disorders | 1/10 | 1/10 | 2/9 |
| OedemaGeneral disorders | 0/10 | 0/10 | 2/9 |
| HeadacheNervous system disorders | 2/10 | 2/10 | 2/9 |
| Age, Continuous(Years) | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 | Total |
|---|---|---|---|---|
| Mean | 38.7 ± 7.1 | 47.8 ± 12.9 | 52.1 ± 6.7 | 46.0 ± 10.7 |
| Sex: Female, Male(Participants) | eGFR > 60 mL/Min/1.73m2 | eGFR 30-60 mL/Min/1.73m2 | eGFR <30 mL/Min/1.73m2 | Total |
|---|---|---|---|---|
| Female | 6 | 6 | 2 | 14 |
| Male | 4 | 4 | 7 | 15 |
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Otsuka Pharmaceutical Development & Commercialization, Inc.