Efficacy, Safety and Tolerability of Everolimus in Preventing End-stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter, Randomized, Placebo-controlled, Double-blind Study on the Efficacy, Safety and Tolerability of Everolimus in Preventing End-stage Renal Disease (ESRD) in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Conditions
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Autosomal Dominant Polycystic Kidney Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Clinical diagnosis of autosomal dominant polycystic kidney disease ADPKD Chronic kidney disease (CKD) stage II / III 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 ADPKD patients with normal renal function ADPKD patients with CKD stage IV Patients with a history of subarachnoid bleeding Patients with a history of severe infections Patients with life-threatening urinary tract or cyst infection in the past Patients who have received any investigational drug within four weeks prior to baseline Patients who have been treated with any non-protocol immunosuppressive drug or treatment within one month prior to baseline Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br>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.]). | Drug: Everolimus<br>* experimental<br>* Other names: certican;|
| Placebo Comparator: Placebo<br>Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses. | Drug: Placebo<br>* placebo comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Months 24, 36, 48 and 60 | 
| 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. | Months 24, 36, 48 and 60 | 
| 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 | Baseline, Months 12 and 24 | 
| 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. | Months 3, 6, 9, 12, 18 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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end-stage renal disease, ESRD, autosomal dominant polycystic kidney disease, ADPKD, everolimus