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

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)

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.

Study Overview

• Status: Completed
• Conditions: Autosomal Dominant Polycystic Kidney Disease
• Intervention / Treatment: Drug: Placebo; Drug: Everolimus

• Study Type: Interventional
• Enrollment (Actual): 431
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, INNSBRUCK
    • Novartis Investigative Site
  • Linz, Austria, A-4010
    • Novartis Investigative Site
  • Wien, Austria, 1090
    • Novartis Investigative Site
• France
  • Brest, France, 29200
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Nantes Cedex, France, 44035
    • Novartis Investigative Site
  • Paris cedex 15, France, 75015
    • Novartis Investigative Site
  • Toulouse Cedex 4, France, 31054
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10117
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt am Main, Germany, 60596
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Homburg, Germany, 66421
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Koeln, Germany, 51109
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Lübeck, Germany, 23538
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Regensburg, Germany, 93053
    • Novartis Investigative Site
  • Würzburg, Germany, 97080
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C, Kunzendorf U, Banas B, Horl WH, Obermuller N, Arns W, Pavenstadt H, Gaedeke J, Buchert M, May C, Gschaidmeier H, Kramer S, Eckardt KU. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2010 Aug 26;363(9):830-40. doi: 10.1056/NEJMoa1003491. Epub 2010 Jun 26. Erratum In: N Engl J Med. 2010 Nov 11;363(20):1977. N Engl J Med. 2010 Sep 16;363(12):1190.

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: December 20, 2006
• First Submitted That Met QC Criteria: December 20, 2006
• First Posted (Estimate): December 21, 2006

Study Record Updates

• Last Update Posted (Estimate): January 14, 2015
• Last Update Submitted That Met QC Criteria: January 13, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: end-stage renal disease, ESRD, autosomal dominant polycystic kidney disease, ADPKD, everolimus
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Renal Insufficiency; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Renal Insufficiency, Chronic; Musculoskeletal Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Kidney Failure, Chronic; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Arthrogryposis; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CRAD001ADE12; 2006-001485-16