Short-term Renal Hemodynamic Effects of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Phase 2

Completed

Conditions: Autosomal Dominant Polycystic Kidney Disease

Interventions: Drug: Tolvaptan

Registration Number: NCT01336972

Lead Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 29

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A - eGFR > 60 ml/min/1.73m^2	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.
Group B - eGFR 30 to 60 ml/min/1.73m^2	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.
Group C - eGFR < 30 ml/min/1.73m^2	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.

Primary Outcome Measures

Name	Time	Method
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 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 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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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).
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.