Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Efficacy and Safety of Everolimus With Enteric-Coated Mycophenolate Sodium (EC-MPS) in a Cyclosporine Microemulsion-free Regimen Compared to Standard Therapy in de Novo Renal Transplant Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT00154310
First received: September 8, 2005
Last updated: October 21, 2013
Last verified: October 2013
Results First Received: January 11, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Renal Transplantation
Interventions: Drug: Everolimus
Drug: Cyclosporine
Drug: Enteric-coated mycophenolate sodium
Drug: Corticosteroids

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was an open-label, randomized, parallel-group, multi-center study with two treatment groups, cyclosporine continuation and cyclosporine withdrawal starting from Month 4.5 post-transplant. Study started in June 2005 and ended in September 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Participant Flow:   Overall Study
    Everolimus + Mycophenolate Sodium     Cyclosporine + Mycophenolate Sodium  
STARTED     155 [1]   145  
COMPLETED     118     117  
NOT COMPLETED     37     28  
Adverse Event                 19                 9  
Lack of Efficacy                 5                 4  
Protocol Violation                 4                 2  
Withdrawal by Subject                 9                 3  
Lost to Follow-up                 0                 8  
Administrative problems                 0                 1  
Death                 0                 1  
[1] "Started" indicates enrolled participants. Randomized participants for two arms are 154 and 146.



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.
Total Total of all reporting groups

Baseline Measures
    Everolimus + Mycophenolate Sodium     Cyclosporine + Mycophenolate Sodium     Total  
Number of Participants  
[units: participants]
  155     145     300  
Age  
[units: Years]
Mean ± Standard Deviation
  46.9  ± 11.67     46.7  ± 11.85     46.8  ± 11.73  
Gender  
[units: participants]
     
Female     53     59     112  
Male     102     86     188  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Renal Function (Nankivell Formula) at Month 12 Post Transplantation.   [ Time Frame: at Month 12 post transplantation ]

Measure Type Primary
Measure Title Renal Function (Nankivell Formula) at Month 12 Post Transplantation.
Measure Description Renal function at the end of the trial assessed as mean absolute values of the glomerular filtration rate (GFR) calculated by Nankivell formula 12 months after renal transplantation. The Nankivell formula: GFR = 6.7 / Scr + BW / 4 – Surea / 2-100 / (height)^2 + C ; where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. Estimated GFR is expressed in mL/min per 1.73m^2.
Time Frame at Month 12 post transplantation  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat Population (randomized patients); Last Observation Carried Forward (LOCF). One patient in

Reporting Groups
  Description
Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values
    Everolimus + Mycophenolate Sodium     Cyclosporine + Mycophenolate Sodium  
Number of Participants Analyzed  
[units: participants]
  154     145  
Renal Function (Nankivell Formula) at Month 12 Post Transplantation.  
[units: mL/minĀ /1.73m^2]
Mean ± Standard Deviation
  71.84  ± 18.53     61.24  ± 16.65  

No statistical analysis provided for Renal Function (Nankivell Formula) at Month 12 Post Transplantation.



2.  Secondary:   Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death   [ Time Frame: Up to Month 12 ]

Measure Type Secondary
Measure Title Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death
Measure Description The number of participants with occurrence of biopsy proven acute rejection (BPAR), graft loss, or death up to Month 12 during the randomized treatment period. BPAR was defined as a biopsy graded IA, IB, IIA, IIB or III according to Banff 97 classification. A graft core biopsy was performed prior to 24 hours following initiation of graft rejection therapy. The allograft is presumed to be lost on the day the patient starts dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was the day of graft loss.
Time Frame Up to Month 12  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat Population (Randomized Patients)

Reporting Groups
  Description
Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values
    Everolimus + Mycophenolate Sodium     Cyclosporine + Mycophenolate Sodium  
Number of Participants Analyzed  
[units: participants]
  154     146  
Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death  
[units: Participants]
   
BPAR: Yes     15     5  
BPAR: No     139     141  
Graft Loss: Yes     0     0  
Graft Loss: No     154     146  
Death: Yes     0     1  
Death: No     154     145  

No statistical analysis provided for Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death



3.  Secondary:   Number of Participants With Occurrence of Treatment Failures   [ Time Frame: up to or at Month 12 ]

Measure Type Secondary
Measure Title Number of Participants With Occurrence of Treatment Failures
Measure Description Treatment failures defined as a composite endpoint of biopsy proven acute rejection, graft loss, death, loss to follow up and discontinuations due to lack of efficacy or toxicity, or conversion to another regimen (at least one condition must be present).
Time Frame up to or at Month 12  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intention to treat (ITT) population (Randomized Patients).

Reporting Groups
  Description
Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values
    Everolimus + Mycophenolate Sodium     Cyclosporine + Mycophenolate Sodium  
Number of Participants Analyzed  
[units: participants]
  154     146  
Number of Participants With Occurrence of Treatment Failures  
[units: Participants]
   
Treatment failure: Yes     29     23  
Treatment failure: No     125     123  

No statistical analysis provided for Number of Participants With Occurrence of Treatment Failures



4.  Secondary:   Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12   [ Time Frame: Month 4.5 and Month 12 ]

Measure Type Secondary
Measure Title Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12
Measure Description An updated 1991 Framingham coronary prediction algorithm was used to estimate the total risk of developing coronary heart diseases (CHD) over the course of 10 years. Risk was calculated separately for male and females. To calculate risk, points were assigned for each of the following risk factors: age, levels of LDL cholesterol, HDL cholesterol, blood pressure, cigarette smoking, and diabetes mellitus. The sum of the individual risk factor points gives a total point score, which ranges from -5 to 18 for men and -16 to 24 for women. Higher points indicate a higher risk for CHD.
Time Frame Month 4.5 and Month 12  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population for whom data was available at Month 4.5 and end of treatment.

Reporting Groups
  Description
Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values
    Everolimus + Mycophenolate Sodium     Cyclosporine + Mycophenolate Sodium  
Number of Participants Analyzed  
[units: participants]
  155     145  
Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12  
[units: Points]
Mean ± Standard Deviation
   
Male (n= 55, 37)     0.5  ± 1.87     0.1  ± 1.86  
Female (n= 22, 35)     0.0  ± 2.01     0.8  ± 2.70  
Total Population (n= 77, 72)     0.4  ± 1.91     0.4  ± 2.32  

No statistical analysis provided for Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12



5.  Secondary:   Number of Participants Who Experienced an Adverse Event or Serious Adverse Event   [ Time Frame: Aes from end of core study period (month 12) to end of follow-up period (month 60) ]

Measure Type Secondary
Measure Title Number of Participants Who Experienced an Adverse Event or Serious Adverse Event
Measure Description Additional information about the number of participants who experienced Adverse Events (greater than 5%) or Serious Adverse Events can be found in the Adverse Event section.
Time Frame Aes from end of core study period (month 12) to end of follow-up period (month 60)  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population consisted of all participants in whom transplantation was performed and who were treated with at least one dose of any immunosuppressive medication.

Reporting Groups
  Description
Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values
    Everolimus + Mycophenolate Sodium     Cyclosporine + Mycophenolate Sodium  
Number of Participants Analyzed  
[units: participants]
  155     145  
Number of Participants Who Experienced an Adverse Event or Serious Adverse Event  
[units: Participants]
   
Adverse Events     155     145  
Serious Adverse Events     95     86  

No statistical analysis provided for Number of Participants Who Experienced an Adverse Event or Serious Adverse Event




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information