Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

• ClinicalTrials.gov Identifier: NCT02160145
• Recruitment Status: Completed
• First Posted: June 10, 2014
• Results First Posted: August 8, 2018
• Last Update Posted: August 8, 2018
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information

• First Submitted Date: June 6, 2014
• First Posted Date: June 10, 2014
• Results First Submitted Date: May 1, 2018
• Results First Posted Date: August 8, 2018
• Last Update Posted Date: August 8, 2018
• Study Start Date: May 2014
• Actual Primary Completion Date: April 18, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 13, 2018)

The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up. [ Time Frame: Pretreatment baseline to post-treatment follow-up (up to 61 weeks). ]

The mean annualized change in eGFR was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula from pretreatment baseline to post-treatment follow-up, annualized (divided) by each subject's trial duration. The baseline for the primary endpoint was defined as the average of up to 3 eGFR values observed during the screening and placebo run-in periods.

• Original Primary Outcome Measures (submitted: June 6, 2014): Treatment difference in the change of eGFR from pre-treatment baseline to post-treatment follow-up, normalized (divided) by each subject's treatment duration [ Time Frame: prior to and post 13 1/2 months of treatment ]

Current Secondary Outcome Measures (submitted: July 13, 2018)

Mean Annualized Slope of eGFR Change [ Time Frame: Pretreatment baseline to post-treatment follow-up (up to 61 weeks). ]

To compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period, the annualized rate of eGFR change was derived from each individual subject's eGFR slope using the CKD-EPI formula. The annualized eGFR change slope was derived from all eGFR observations from placebo-run-in, tolvaptan run-in, double-blind treatment and post-treatment follow-up periods using the linear mixed model of analysis. The mean annualized slope of eGFR change is presented.

Original Secondary Outcome Measures (submitted: June 6, 2014)

• Treatment difference in annualized slope of eGFR calculated for individual subjects using an appropriate baseline and available, post-randomization, on-treatment assessments [ Time Frame: prior to and post 13 1/2 months of treatment ]
• Plasma tolvaptan and metabolites, including DM-4103 plasma concentrations [ Time Frame: Day -1 through Month 15 1/2 ]
• Uosm and urine specific gravity [ Time Frame: Day -1 through Month 15 1/2 ]
• Adverse events [ Time Frame: Day -1 through Month 15 1/2 ]
  -Adverse events - incidence summarized by treatment group
• Clinical Laboratory Data Changes [ Time Frame: Day -1 through Month 15 1/2 ]
  Clinical Laboratory Data - summary of changes from baseline and clinically significant tests
• Clinical Laboratory Data - Lab Measures [ Time Frame: Day -1 through Month 15 1/2 ]
  Clinical Laboratory Data - laboratory measurements that monitor hepatic transaminases
• Vital Signs Data [ Time Frame: Day -1 through Month 15 1/2 ]
  Vital Signs Data - summary of changes from baseline and clinically significant findings

Current Other Pre-specified Outcome Measures (submitted: July 13, 2018)

• Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up [ Time Frame: Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up. ]
  The mean change from baseline in urine osmolality for the double-blind treatment period collection timepoints and post-treatment follow-up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.
• Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up [ Time Frame: Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up. ]
  The mean change from baseline in urine specific gravity for the double-blind treatment period collection timepoints and post-treatment follow up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease
• Official Title: A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/Day, Split-dose) in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease
• Brief Summary: The purpose of the study is to determine whether tolvaptan is effective and safe for the treatment of late-stage chronic kidney disease due to autosomal dominant polycystic kidney disease (ADPKD)

Detailed Description

The protocol will extend the understanding of the efficacy and safety of tolvaptan treatment in ADPKD patients with late stage 2 to early stage 4 CKD (chronic kidney disease).

This trial will compare the efficacy of tolvaptan treatment in reducing the annualized change in estimated glomerular filtration rate (eGFR) from pre-treatment baseline to post-treatment follow-up, as compared with placebo, in subjects who tolerate tolvaptan during an initial run-in period. The change in eGFR, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula, will provide kidney function data that are complementary to the data demonstrating the benefits previously observed primarily in ADPKD subjects with earlier stages of disease.

Also, it will compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in this type of subjects. Finally, it will compare the overall and hepatic safety profile of tolvaptan with placebo and to compare incidence of ADPKD complications (outcomes) during the trial

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Chronic Kidney Disease
• Autosomal Dominant Polycystic Kidney Disease

Intervention

• Drug: Tolvaptan (OPC-41061)
  Tolvaptan tablets (15 or 30 mg) will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later.
• Drug: Placebo
  Matching placebo tablets will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later

Study Arms

• Experimental: Tolvaptan
  Tolvaptan (OPC-41061)
  Intervention: Drug: Tolvaptan (OPC-41061)
• Placebo Comparator: Placebo
  Placebo
  Intervention: Drug: Placebo

Publications *

• Bennett H, McEwan P, Hamilton K, O'Reilly K. Modelling the long-term benefits of tolvaptan therapy on renal function decline in autosomal dominant polycystic kidney disease: an exploratory analysis using the ADPKD outcomes model. BMC Nephrol. 2019 Apr 23;20(1):136. doi: 10.1186/s12882-019-1290-5.
• Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O; REPRISE Trial Investigators. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017 Nov 16;377(20):1930-1942. doi: 10.1056/NEJMoa1710030. Epub 2017 Nov 4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 18, 2017): 1370
• Original Estimated Enrollment (submitted: June 6, 2014): 1300
• Actual Study Completion Date: April 18, 2017
• Actual Primary Completion Date: April 18, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male and female subjects with eGFR between 25-65 mL/min/1.73m2 (if aged 18 to55) or eGFR between 25-44 mL/min/1.73m2 (if aged 56 to <66)
• Tolvaptan naïve
• Diagnosis of ADPKD by modified pei-Ravine criteria 1) 3 cysts per kidney by sonography or 5 cysts by CT or MRI with family history of ADPKD or 2) 10 cysts per kidney by any radiologic method and exclusion of other cystic kidney diseases if without family history

Exclusion Criteria:

• Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of Investigational medicinal product (IMP)
• Women who are breast-feeding and/or who have a positive pregnancy test prior to receiving IMP
• Need for chronic diuretic use
• Hepatic impairment or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease
• Advanced diabetes, evidence of additional significant renal disease, renal cancer, single kidney, recent renal surgery or acute kidney injury
• Contraindications to required trial assessments
• Medical history or medical findings inconsistent with safety or compliance with trial assessments

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Canada, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Puerto Rico, Romania, Russian Federation, South Africa, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02160145
• Other Study ID Numbers: 156-13-210
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Study Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Verification Date: July 2018