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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00414440
First received: December 20, 2006
Last updated: October 2, 2014
Last verified: October 2014

December 20, 2006
October 2, 2014
December 2006
October 2013   (final data collection date for primary outcome measure)
Primary efficacy analysis of total kidney volume (mITT set, multiple imputation) [ Time Frame: Baseline, Month 24 ] [ Designated as safety issue: No ]
Everolimus (RAD001) compared to placebo with respect to the change from baseline in total kidney volume at Month 12 and then at Month 24.
Mean total kidney volume assessed by magnetic resonance imaging at 3 timepoints from the first day to the last day on study medication
Complete list of historical versions of study NCT00414440 on ClinicalTrials.gov Archive Site
  • Changes in mean cyst and parenchyma volumes assessed by magnetic resonance imaging between the first and last day on study medication for extension period [ Time Frame: Months 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
    Changes from baseline at Month 24 in total cyst and parenchyma volumes measured by MRI, changes from baseline at Months 24, 36, 48 and 60 in renal function (as assessed by eGFR, serum creatinine, and urine protein/creatinine ratio), annual change rate in calculated GFR by MDRD formula (cGFR) over two years, changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP), occurrence of end-stage renal disease (ESRD) and overall survival.
  • Changes in renal function were assessed by urinalysis from first day to last day on study medication. [ Time Frame: Months 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
    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.
  • Incidence of newly developing end-stage renal disease (ESRD) assessed by number of patients who require renal replacement therapy during the conduct of the trial [ Time Frame: Months 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
    Incidence of newly developing end-stage renal disease (ESRD) assessed by number of patients who require renal replacement therapy during the conduct of the trial
  • Safety and tolerability of the study drug assessed by monitoring and recording of adverse events, serious adverse events, and all infections [ Time Frame: Months 24, 36, 48 and 60 ] [ Designated as safety issue: Yes ]
    Incidence and severity of AEs, SAEs, infections, neutropenia, leukopenia, thrombopenia, increased lipids, AE of special interest (assumed mTOR inhibitor class-related adverse events and ADPKD-associated complications); incidence of anemia and frequency of abnormal vital signs and laboratory parameters.
  • Changes in blood pressure between the first and last day on study medication assessed by blood pressure measurements at 10 timepoints [ Time Frame: Months 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
    Changes in blood pressure between the first and last day on study medication assessed by blood pressure measurements at 10 timepoints
  • Extension study: Course of calculated GFR (mL/min/1.73 m2) from Month 24 to Month 60 (ITT set, observed cases) [ Time Frame: Months 24, 36, 48 and 60 ] [ Designated as safety issue: No ]
    The course of cGFR was summarized descriptively by visit for the ITT set and the ITT subset compri¬sing completers of the core study. Changes from baseline were calculated for each study visit and summarized descriptively. Changes from baseline were compared between the two treatment groups with an ANCOVA with factor treatment and covariate baseline. The annual change rate in calculated GFR by MDRD formula (cGFR) over five years was calculated. The annual change rate was calculated as the slope obtained via mixed effect linear model with a linear regression to cGFRs with time (in year) for each treatment group. Subgroups analyses were performed on patients with different cGFR values at baseline (≤50, >50, ≤60, >60, ≤70, >70 mL/min/1.73 m²). All analyses of safety variables were based on the safety set. The safety variables in the follow-up period were analyzed descriptively and summarized by treatment group.
  • changes in mean cyst and parenchyma volumes assessed by magnetic resonance imaging between the first and last day on study medication.
  • changes in renal function assessed by urinalysis at 8 timepoints from the first day to last day on study medication.
  • incidence of newly developing end-stage renal disease (ESRD) assessed by number of patients who require renal replacement therapy during the conduct of the trial
  • safety and tolerability of the study drug assessed by monitoring and recording of aderse events, serious adverse events, and all infections
  • changes in blood pressure between the first and last day on study medication assessed by blood pressure measurements at 10 timepoints
Not Provided
Not Provided
 
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.

Not Provided
Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Autosomal Dominant Polycystic Kidney Disease
  • Drug: Placebo
    placebo comparator
  • Drug: Everolimus
    experimental
    Other Name: certican
  • 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.]).
    Intervention: Drug: Everolimus
  • Placebo Comparator: Placebo
    Placebo tablets equivalent to the dosage of everolimus 5 mg/day, divided in 2 equal doses.
    Intervention: Drug: Placebo
Walz G, Budde K, Mannaa M, Nürnberger J, Wanner C, Sommerer C, Kunzendorf U, Banas B, Hörl WH, Obermüller N, Arns W, Pavenstädt H, Gaedeke J, Büchert 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
431
October 2013
October 2013   (final data collection date for primary outcome measure)

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

Both
18 Years to 50 Years
No
Contact information is only displayed when the study is recruiting subjects
Germany,   Austria,   France
 
NCT00414440
CRAD001ADE12, 2006-001485-16
Not Provided
Novartis ( Novartis Pharmaceuticals )
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP