Autosomal Dominant Polycystic Kidney Disease, Chronic Kidney Disease
Conditions
Keywords
Chronic Kidney Disease, 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
Interventions
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.
DRUGPlacebo
Matching placebo tablets will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Annualized Slope of eGFR Change | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | 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 | 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. |
Countries
Argentina, Australia, Belgium, Canada, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, Norway, Poland, Puerto Rico, Romania, Russia, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
First subject first visit: 21 May 2014; Last subject last visit: 18 April 2017. Subjects were recruited from 213 sites in 21 countries. Of 2292 subjects screened, 1519 entered the 6-week run-in period; 23 were placebo run-in failures and 126 were tolvaptan titration/run-in failures.
Pre-assignment details
Subjects with Stage 2 - 4 chronic kidney disease (CKD) due to Autosomal Dominant Polycystic Kidney Disease (ADPKD) were stratified by baseline estimated glomerular filtration rate (eGFR) (≤ 45 or \> 45 milliliters/minute/ 1.73 square metres \[mL/min/1.73 m\^2\]), by age (≤ 55 or \> 55 years), and total kidney volume (≤ 2000 mL, \> 2000 mL, or unknown).
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.
Follow-up Period: A 3-week final follow-up for efficacy analysis. | 683 |
| Placebo Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.
Follow-up Period: A 3-week final follow-up for efficacy analysis. | 687 |
| Total Title | 1,370 |
| Total | 2,740 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Prerandomization Single-blind Period | Placebo run-in failure | 23 | 0 | 0 |
| Prerandomization Single-blind Period | Tolvaptan titration/run-in failure | 126 | 0 | 0 |
| Randomized Double-blind Period | Lost to Follow-up | 0 | 1 | 3 |
| Randomized Double-blind Period | Physician Decision | 0 | 7 | 5 |
| Randomized Double-blind Period | Subject decision | 0 | 21 | 20 |
Baseline characteristics
| Characteristic | Placebo | Total Title | Tolvaptan |
|---|---|---|---|
| Age, Continuous | 47.2 years STANDARD_DEVIATION 8.2 | 47.3 years STANDARD_DEVIATION 8.2 | 47.3 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 79 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 647 Participants | 1279 Participants | 632 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 12 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 41 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 48 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 19 Participants | 7 Participants |
| Race (NIH/OMB) White | 632 Participants | 1258 Participants | 626 Participants |
| Sex: Female, Male Female | 354 Participants | 690 Participants | 336 Participants |
| Sex: Female, Male Male | 333 Participants | 680 Participants | 347 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1,491 | 0 / 681 | 1 / 685 |
| other Total, other adverse events | 1,051 / 1,491 | 581 / 681 | 564 / 685 |
| serious Total, serious adverse events | 43 / 1,491 | 85 / 681 | 60 / 685 |
Outcome results
Primary
The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up.
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.
Time frame: Pretreatment baseline to post-treatment follow-up (up to 61 weeks).
Population: The primary endpoint efficacy population consisted of all subjects who were in the randomized sample, took at least 1 dose of investigational medicinal product (IMP) after randomization, and had a baseline and at least 1 valid post-treatment evaluation in eGFR (i.e at least 1 week off-treatment).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up. | -2.339 mL/min/1.73 m^2/year | Standard Error 0.24 |
| Placebo | The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up. | -3.610 mL/min/1.73 m^2/year | Standard Error 0.24 |
Comparison: Tolvaptan versus placebo. Treatment difference in the change of eGFR assessed the efficacy of tolvaptan treatment as compared with placebo in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period.p-value: <0.000195% CI: [0.859, 1.684]ANCOVA
Secondary
Mean Annualized Slope of eGFR Change
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.
Time frame: Pretreatment baseline to post-treatment follow-up (up to 61 weeks).
Population: The key secondary endpoint efficacy population consisted of all randomized subjects who took at least 1 dose of IMP after randomization, and have a baseline (average of up to 3 eGFR values observed during screening and placebo run-in periods) and at least 1 post-randomization evaluation in eGFR during the double-blind treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Mean Annualized Slope of eGFR Change | -3.160 mL/min/1.73m^2/year | Standard Error 0.14 |
| Placebo | Mean Annualized Slope of eGFR Change | -4.170 mL/min/1.73m^2/year | Standard Error 0.142 |
Comparison: Difference in treatment effect was derived from a linear mixed model with effects of treatment, time, treatment ime interaction, acute haemodynamic effect, pretreatment baseline, and randomization stratification factors. An unstructured variance matrix was assumed for the random intercept and time.p-value: <0.000195% CI: [0.618, 1.403]Mixed Models Analysis
Other Pre-specified
Mean Change From Baseline in Urine Osmolality During 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.
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.
Population: The primary safety population consisted of all subjects who were randomized and took at least 1 dose of IMP after randomization. Only subjects with data available for analysis at the timepoints of testing are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month 6 | 22.9 milliosmole per kilogram (mOSm/kg) | Standard Deviation 84.3 |
| Tolvaptan | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month12 | 36.9 milliosmole per kilogram (mOSm/kg) | Standard Deviation 96 |
| Tolvaptan | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month 9 | 30.4 milliosmole per kilogram (mOSm/kg) | Standard Deviation 92.1 |
| Tolvaptan | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Follow-up | 162.4 milliosmole per kilogram (mOSm/kg) | Standard Deviation 114 |
| Tolvaptan | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month 3 | 10.2 milliosmole per kilogram (mOSm/kg) | Standard Deviation 80.3 |
| Placebo | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Follow-up | 179.5 milliosmole per kilogram (mOSm/kg) | Standard Deviation 128.9 |
| Placebo | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month 3 | 177.7 milliosmole per kilogram (mOSm/kg) | Standard Deviation 124.5 |
| Placebo | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month 6 | 179.1 milliosmole per kilogram (mOSm/kg) | Standard Deviation 126.2 |
| Placebo | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month 9 | 179.9 milliosmole per kilogram (mOSm/kg) | Standard Deviation 125.1 |
| Placebo | Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up | Month12 | 180.3 milliosmole per kilogram (mOSm/kg) | Standard Deviation 121.1 |
Other Pre-specified
Mean Change From Baseline in Urine Specific Gravity During 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.
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.
Population: The primary safety population consisted of all subjects who were randomized and took at least 1 dose of IMP after randomization. Only subjects with data available for analysis at the timepoints of testing are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 6 | 0.0003 unitless | Standard Deviation 0.0024 |
| Tolvaptan | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 12 | 0.0006 unitless | Standard Deviation 0.0027 |
| Tolvaptan | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 9 | 0.004 unitless | Standard Deviation 0.0025 |
| Tolvaptan | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Follow-up | 0.0037 unitless | Standard Deviation 0.0031 |
| Tolvaptan | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 3 | 0.0001 unitless | Standard Deviation 0.0022 |
| Placebo | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Follow-up | 0.0040 unitless | Standard Deviation 0.0034 |
| Placebo | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 3 | 0.0041 unitless | Standard Deviation 0.0033 |
| Placebo | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 6 | 0.0042 unitless | Standard Deviation 0.0033 |
| Placebo | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 9 | 0.0040 unitless | Standard Deviation 0.0032 |
| Placebo | Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up | Month 12 | 0.0040 unitless | Standard Deviation 0.0033 |