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

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

Sponsors

Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Source 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.

Overall Status Completed
Start Date October 2010
Completion Date November 2011
Primary Completion Date November 2011
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
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
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
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
Secondary Outcome
Measure Time Frame
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
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
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
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
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
Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. 24 hours
Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment. 2 hours
Enrollment 29
Condition
Intervention

Intervention type: Drug

Intervention name: Tolvaptan

Description: Tolvaptan was supplied as 15 and 30 mg tablets.

Other name: OPC-41061

Eligibility

Criteria:

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.

Gender: All

Minimum age: 18 Years

Maximum age: 70 Years

Healthy volunteers: No

Overall Official
Location
facility University Medical Center Groningen
Location Countries

Netherlands

Verification Date

February 2019

Responsible Party

Responsible party type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Arm group label: Group A - eGFR > 60 ml/min/1.73m^2

Arm group type: Experimental

Description: 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.

Arm group label: Group B - eGFR 30 to 60 ml/min/1.73m^2

Arm group type: Experimental

Description: 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.

Arm group label: Group C - eGFR < 30 ml/min/1.73m^2

Arm group type: Experimental

Description: 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.

Study Design Info

Allocation: Non-Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov