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

Study Overview
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Brief Summary
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The purpose of this study is to assess whether a calcineurin inhibitor (CNI)-free regimen with enteric-coated mycophenolate sodium (EC-MPS) and everolimus is as safe and well-tolerated as the standard regimen containing enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine microemulsion, but results in better renal function.

Official Title
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Multi-center, Open-label, Prospective, Randomized, Parallel Group Study Investigating a CNI-free Regimen With Enteric-Coated Mycophenolate Sodium (EC-MPS) and Everolimus in Comparison to Standard Therapy With Enteric-Coated Mycophenolate Sodium (EC-MPS) and Cyclosporine Microemulsion in de Novo Renal Transplant Patients

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Everolimus
* Drug: Cyclosporine
* Drug: Enteric-coated mycophenolate sodium
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : The following inclusion criteria had to be present at BL 1 (Screening visit prior to transplantation): Males or females, aged 18 - 65 years Recipients of de novo cadaveric, living unrelated or living related kidney transplants Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at BL 1, 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 Patients who are willing and able to participate in the study and from whom written informed consent has been obtained Of all patients included into the study at BL 1 (prior to transplantation), those who continued into the randomized study period had to meet the following condition at BL 2, prior to randomization: Patients had to be on an immunosuppressive regimen with EC-MPS (target dose; 1440 mg/day, if tolerated; minimal dose: 720 mg/day), cyclosporine and corticosteroids Patients with an actual serum creatinine =< 3.0 mg/dl Exclusion Criteria: The following exclusion criteria must not be present at BL 1 (Screening visit prior to transplantation): More than one previous renal transplantation Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney Graft loss due to immunological reasons in the first year after transplantation (in case of secondary transplantation) Patients who are recipients of A-B-O incompatible transplants Patients with a historical or current peak PRA of > 25% Patients with already existing antibodies against the HLA-type of the receiving transplant Females of childbearing potential who are planning to become pregnant, who are pregnant and/or lactating, who are unwilling to use effective means of contraception Of all patients included into the study at BL 1 (prior to transplantation), those who met one or more of the following criteria at BL 2, prior to randomization, should not continue into the randomized study period: Graft loss or death Changes to the immunosuppressive regimen prior to randomization due to immunologic reasons Patients who suffered from severe rejection (>= BANFF II acute rejection), recurrent acute rejection, or steroid resistant acute rejection Proteinuria > 1g/day Other protocol-defined exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus + Mycophenolate sodium<br>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. | Drug: Everolimus<br>* Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL.<br>* Other names: certican;Drug: Enteric-coated mycophenolate sodium<br>* Enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day.<br>* Other names: Myfortic;Drug: Corticosteroids<br>* 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.<br>|
| Active Comparator: Cyclosporine + Mycophenolate sodium<br>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. | Drug: Cyclosporine<br>* Tablets orally twice a day to maintain protocol specific target blood levels<br>* Other names: Sandimmun Optoral;Drug: Enteric-coated mycophenolate sodium<br>* Enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day.<br>* Other names: Myfortic;Drug: Corticosteroids<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function (Nankivell Formula) at Month 12 Post Transplantation. | 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. | at Month 12 post transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | 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. | Up to Month 12 | 
| Number of Participants With Occurrence of Treatment Failures | 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). | up to or at Month 12 | 
| Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | 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. | Month 4.5 and Month 12 | 
| Number of Participants Who Experienced an Adverse Event or Serious Adverse Event | 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. | Aes from end of core study period (month 12) to end of follow-up period (month 60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplantation, everolimus, immunosuppressants, CNI-free