Clinical trial NCT01336972: Short-term Renal Hemodynamic Effects of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autosomal Dominant Polycystic Kidney Disease
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2011-04-18
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Mean Change From Baseline in Measured Glomerular Filtration Rate (mGFR) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
timeFrame: After 3 weeks of treatment and 3 weeks post treatment
measure: Mean Change From Baseline in Effective Renal Plasma Flow (ERPF) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
timeFrame: After 3 weeks of treatment and 3 weeks post treatment
measure: Mean Change From Baseline in Filtration Fraction (GFR/ERFP) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
timeFrame: After 3 weeks of treatment and 3 weeks post treatment
Secondary outcomes:
measure: Mean Change From Baseline in Free Water Clearance After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment
timeFrame: After 3 weeks of treatment and 3 weeks post treatment
measure: Time to Peak Plasma Concentration (Cmax) After 3 Weeks of Tolvaptan Treatment.
timeFrame: Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour
measure: Time to Peak Plasma Concentration (Tmax) After 3 Weeks of Tolvaptan Treatment.
timeFrame: Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour
measure: Area Under the Concentration-time Curve From 0 to 5 Hours (AUC0-5) After 3 Weeks of Tolvaptan Treatment.
timeFrame: Day 0: 0 hour, Day 21: (0, 1, 2, 3, 4 and 5 hours postdose), 3 Weeks after last dose: 0 hour
measure: Percentage Change From Baseline in Total Kidney Volume (TKV) After 3 Weeks of Tolvaptan Treatment and at 3 Weeks Post Treatment.
timeFrame: After 3 weeks of treatment and 3 weeks post treatment
measure: Mean Change From Baseline in 24 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment.
timeFrame: 24 hours
measure: Mean Change From Baseline in 2 Hour Urine Volume After 3 Weeks Tolvaptan Treatment and at 3 Weeks Post Treatment.
timeFrame: 2 hours
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
name: Frank Czerwiec, MD, PhD
role: STUDY_DIRECTOR
affiliation: University Medical Center Groningen
name: Ron T Gansevoort, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Boertien WE, Meijer E, de Jong PE, Bakker SJ, Czerwiec FS, Struck J, Oberdhan D, Shoaf SE, Krasa HB, Gansevoort RT. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013 Dec;84(6):1278-86. doi: 10.1038/ki.2013.285. Epub 2013 Jul 31.
citation: Reddy B, Chapman AB. Acute Response to Tolvaptan in ADPKD: A Window to Predict Long-term Efficacy? Am J Kidney Dis. 2015 Jun;65(6):811-3. doi: 10.1053/j.ajkd.2015.03.004. No abstract available.
citation: Boertien WE, Meijer E, de Jong PE, ter Horst GJ, Renken RJ, van der Jagt EJ, Kappert P, Ouyang J, Engels GE, van Oeveren W, Struck J, Czerwiec FS, Oberdhan D, Krasa HB, Gansevoort RT. Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis. 2015 Jun;65(6):833-41. doi: 10.1053/j.ajkd.2014.11.010. Epub 2015 Jan 15.
citation: Kramers BJ, van Gastel MDA, Boertien WE, Meijer E, Gansevoort RT. Determinants of Urine Volume in ADPKD Patients Using the Vasopressin V2 Receptor Antagonist Tolvaptan. Am J Kidney Dis. 2019 Mar;73(3):354-362. doi: 10.1053/j.ajkd.2018.09.016. Epub 2018 Dec 19.