Autosomal Dominant Polycystic Kidney Disease
Conditions
Keywords
end-stage renal disease, ESRD, autosomal dominant polycystic kidney disease, ADPKD, everolimus
Brief summary
This study will assess whether everolimus (RAD001) is effective in preventing cyst and kidney expansion as well as worsening of renal function in patients with ADPKD and whether the application of 5 mg/day everolimus as monotherapy is safe and well tolerated.
Interventions
DRUGPlacebo
placebo comparator
DRUGEverolimus
experimental
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Clinical diagnosis of autosomal dominant polycystic kidney disease ADPKD 2. Chronic kidney disease (CKD) stage II / III 3. Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at baseline, and are required to practice an approved method of birth control for the duration of the study and for a period of 6 weeks following discontinuation of study medication, even where there has been a history of infertility
Exclusion criteria
1. ADPKD patients with normal renal function 2. ADPKD patients with CKD stage IV 3. Patients with a history of subarachnoid bleeding 4. Patients with a history of severe infections 5. Patients with life-threatening urinary tract or cyst infection in the past 6. Patients who have received any investigational drug within four weeks prior to baseline 7. Patients who have been treated with any non-protocol immunosuppressive drug or treatment within one month prior to baseline Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy Analysis of Total Kidney Volume (mITT Set, Multiple Imputation) | Baseline, Month 24 | Everolimus (RAD001) compared to placebo with respect to the change from baseline in total kidney volume at Month 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Months 24, 36, 48 and 60 | Course of calculated GFR (mL/min/1.73 m\^2) at Months 24, 36, 48 and 60 |
| Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | Months 24, 36, 48 and 60 | Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported. |
| Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline, Months 12 and 24 | Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP), at baseline and then months 12 and 24 |
| Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Months 3, 6, 9, 12, 18 and 24 | Change in renal function was assessed by the Glomerular Filtration Rate (GFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported. |
Countries
Austria, France, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Everolimus Patients in the everolimus group initially received 5 mg/day everolimus divided in 2 equal doses (i.e. 2.5 mg b.i.d.). Dose adjustments were performed to achieve a blood trough level of 3-8 ng/mL (maximum daily dose: 10 mg/day \[5 mg b.i.d.\]). | 214 |
| Placebo Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses. | 217 |
| Total | 431 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Period | Withdrawal by Subject | 70 | 32 |
| Extension Period | Administrative | 16 | 16 |
| Extension Period | Death | 1 | 2 |
| Extension Period | Did not consent to continue follow up | 61 | 54 |
| Extension Period | Lost to Follow-up | 44 | 52 |
| Extension Period | Not included in follow up period | 18 | 8 |
| Extension Period | Other | 1 | 1 |
| Extension Period | Withdrawal by Subject | 9 | 7 |
Baseline characteristics
| Characteristic | Everolimus | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 44.6 years STANDARD_DEVIATION 10.1 | 44.5 years STANDARD_DEVIATION 10.4 | 44.5 years STANDARD_DEVIATION 10.3 |
| Race/Ethnicity, Customized Asian Oriental | 4 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other, Unknown or Not Reported | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 208 participants | 217 participants | 425 participants |
| Sex: Female, Male Female | 105 Participants | 117 Participants | 222 Participants |
| Sex: Female, Male Male | 109 Participants | 100 Participants | 209 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 205 / 214 | 185 / 217 |
| serious Total, serious adverse events | 80 / 214 | 51 / 217 |
Outcome results
Primary
Primary Efficacy Analysis of Total Kidney Volume (mITT Set, Multiple Imputation)
Everolimus (RAD001) compared to placebo with respect to the change from baseline in total kidney volume at Month 24.
Time frame: Baseline, Month 24
Population: mITT set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Everolimus | Primary Efficacy Analysis of Total Kidney Volume (mITT Set, Multiple Imputation) | 230.1 mL |
| Placebo | Primary Efficacy Analysis of Total Kidney Volume (mITT Set, Multiple Imputation) | 300.8 mL |
Secondary
Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR
Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported.
Time frame: Months 24, 36, 48 and 60
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | >70 mL/min/1.73 m^2 n=11, 18 | -14.8 mL/min/1.73 m^2 | Standard Deviation 22.7 |
| Everolimus | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | ≤70 mL/min/1.73 m^2 n=53, 57 | -16.1 mL/min/1.73 m^2 | Standard Deviation 17.6 |
| Everolimus | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | >60 mL/min/1.73 m^2 n=21.26 | -17.0 mL/min/1.73 m^2 | Standard Deviation 17.3 |
| Everolimus | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | ≤60 mL/min/1.73 m^2 n=43,49 | -15.3 mL/min/1.73 m^2 | Standard Deviation 19 |
| Everolimus | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | >50 mL/min/1.73 m^2 n=36,39 | -19.0 mL/min/1.73 m^2 | Standard Deviation 17.3 |
| Everolimus | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | ≤50 mL/min/1.73 m^2 n=28, 36 | -11.8 mL/min/1.73 m^2 | Standard Deviation 19.2 |
| Placebo | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | >50 mL/min/1.73 m^2 n=36,39 | -19.4 mL/min/1.73 m^2 | Standard Deviation 12.6 |
| Placebo | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | >70 mL/min/1.73 m^2 n=11, 18 | -20.5 mL/min/1.73 m^2 | Standard Deviation 11.1 |
| Placebo | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | ≤60 mL/min/1.73 m^2 n=43,49 | -15.1 mL/min/1.73 m^2 | Standard Deviation 14.7 |
| Placebo | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | ≤70 mL/min/1.73 m^2 n=53, 57 | -15.6 mL/min/1.73 m^2 | Standard Deviation 15.2 |
| Placebo | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | ≤50 mL/min/1.73 m^2 n=28, 36 | -14.0 mL/min/1.73 m^2 | Standard Deviation 15.8 |
| Placebo | Calculated GFR, Change From Baseline at Month 60 by Baseline cGFR | >60 mL/min/1.73 m^2 n=21.26 | -20.0 mL/min/1.73 m^2 | Standard Deviation 13.6 |
Secondary
Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit
Change in renal function was assessed by the Glomerular Filtration Rate (GFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported.
Time frame: Months 3, 6, 9, 12, 18 and 24
Population: ITT set, observed cases
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Week 2 | 1.7 mL/min/1.73m^2 | Standard Deviation 5.9 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 9 | -4.6 mL/min/1.73m^2 | Standard Deviation 8.2 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 3 | -0.5 mL/min/1.73m^2 | Standard Deviation 8.2 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 12 | -5.4 mL/min/1.73m^2 | Standard Deviation 7.5 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Week 4 | 0.6 mL/min/1.73m^2 | Standard Deviation 6.3 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 18 | -7.7 mL/min/1.73m^2 | Standard Deviation 8.5 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 6 | -2.3 mL/min/1.73m^2 | Standard Deviation 7.7 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 24 | -8.9 mL/min/1.73m^2 | Standard Deviation 8.8 |
| Everolimus | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Week 1 | 2.0 mL/min/1.73m^2 | Standard Deviation 5.9 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 24 | -7.7 mL/min/1.73m^2 | Standard Deviation 6.6 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Week 1 | -0.9 mL/min/1.73m^2 | Standard Deviation 6.1 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Week 2 | -0.9 mL/min/1.73m^2 | Standard Deviation 6.5 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Week 4 | -1.2 mL/min/1.73m^2 | Standard Deviation 6.7 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 3 | -2.4 mL/min/1.73m^2 | Standard Deviation 6.7 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 6 | -2.2 mL/min/1.73m^2 | Standard Deviation 6.7 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 9 | -2.4 mL/min/1.73m^2 | Standard Deviation 6 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 12 | -3.2 mL/min/1.73m^2 | Standard Deviation 6.9 |
| Placebo | Calculated GFR (mL/Min/1.73 m^2), Change From Baseline by Visit | Month 18 | -5.5 mL/min/1.73m^2 | Standard Deviation 6.7 |
Secondary
Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP), at baseline and then months 12 and 24
Time frame: Baseline, Months 12 and 24
Population: ITT, observed cases
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline SBP | 136 mmHG | Standard Deviation 16 |
| Everolimus | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 12 SBP | 134 mmHG | Standard Deviation 15 |
| Everolimus | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 24 SBP | 134 mmHG | Standard Deviation 17 |
| Everolimus | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline DBP | 88 mmHG | Standard Deviation 11 |
| Everolimus | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 12 DBP | 86 mmHG | Standard Deviation 10 |
| Everolimus | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 24 DBP | 85 mmHG | Standard Deviation 10 |
| Placebo | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 12 DBP | 86 mmHG | Standard Deviation 10 |
| Placebo | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline SBP | 135 mmHG | Standard Deviation 17 |
| Placebo | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline DBP | 88 mmHG | Standard Deviation 10 |
| Placebo | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 12 SBP | 134 mmHG | Standard Deviation 16 |
| Placebo | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 24 DBP | 85 mmHG | Standard Deviation 10 |
| Placebo | Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Month 24 SBP | 134 mmHG | Standard Deviation 15 |
Secondary
Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60
Course of calculated GFR (mL/min/1.73 m\^2) at Months 24, 36, 48 and 60
Time frame: Months 24, 36, 48 and 60
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 24 | 43.9 mL/min/1.73 m^2 | Standard Deviation 23.9 |
| Everolimus | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 36 | 42.6 mL/min/1.73 m^2 | Standard Deviation 23.5 |
| Everolimus | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 48 | 39.6 mL/min/1.73 m^2 | Standard Deviation 22.2 |
| Everolimus | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 60 | 37.7 mL/min/1.73 m^2 | Standard Deviation 23.8 |
| Placebo | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 60 | 37.6 mL/min/1.73 m^2 | Standard Deviation 21.6 |
| Placebo | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 24 | 48.8 mL/min/1.73 m^2 | Standard Deviation 20.8 |
| Placebo | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 48 | 42.7 mL/min/1.73 m^2 | Standard Deviation 22.5 |
| Placebo | Course of Calculated GFR (mL/Min/1.73 m^2) From Month 24 to Month 60 | Month 36 | 44.9 mL/min/1.73 m^2 | Standard Deviation 22.2 |