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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2a, Single-center Study Investigating the Short-term Renal Hemodynamic Effects, Safety and Pharmacokinetics/ Pharmacodynamics of Oral Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease at Various Stages of Renal Function

Conditions
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Autosomal Dominant Polycystic Kidney Disease

Intervention / Treatment
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* Drug: Tolvaptan


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A - eGFR > 60 ml/min/1.73m^2<br>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<br>* Tolvaptan was supplied as 15 and 30 mg tablets.<br>* Other names: OPC-41061;|
| Experimental: Group B - eGFR 30 to 60 ml/min/1.73m^2<br>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<br>* Tolvaptan was supplied as 15 and 30 mg tablets.<br>* Other names: OPC-41061;|
| Experimental: Group C - eGFR < 30 ml/min/1.73m^2<br>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<br>* Tolvaptan was supplied as 15 and 30 mg tablets.<br>* Other names: OPC-41061;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 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). | After 3 weeks of treatment and 3 weeks post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | 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. | 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. | 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. | 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. | 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. | 2 hours |