Comparison of CNI-based Regimen Versus CNI-free Regimen in Kidney Transplant Recipients.

Study Overview
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Brief Summary
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Calcineurin inhibitors (CNI), a potent immunosuppressive drug used in kidney transplant recipients to prevent graft rejection, may cause renal impairment. The aim of this study is to assess whether a CNI-free regimen with enteric-coated mycophenolate sodium and everolimus is as safe and well tolerated as a standard regimen consisting of enteric-coated mycophenolate sodium and cyclosporine microemulsion without a compromise in therapeutic efficacy while resulting in an improved 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 and Everolimus in Comparison to Standard Therapy With Enteric-coated Mycophenolate Sodium and Ciclosporin Microemulsion in Stable Renal Transplant Patients

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Everolimus
* Drug: Cyclosporin A (CsA)
* Drug: Tacrolimus
* Drug: Enteric Coated - Mycophenolate Sodium (EC-MPS)
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, aged > 18 years, Maintenance renal transplant recipients at least 6 months post-transplantation, Patients with a serum creatinine < 2,5 mg/dL stable for at least three month (according to the investigator), Females capable of becoming pregnant had to have a negative serum pregnancy test within seven days prior to or at baseline, and were required to practice an approved method of birth control for the duration of the study and for a period of six weeks following discontinuation of study medication, even where there had been a history of infertility, Patients receiving Myfortic® (Myfortic dose . 720 mg/d) and Sandimmun® Optoral with or without corticosteroids as part of their immunosuppressive regimen for at least 1 month before baseline; Exclusion Criteria: More than one previous renal transplantation, Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney, Patient with proteinuria > 1000 mg/day at baseline, Hypersensitivity to Certican®, Sandimmun® Optoral, Prograf®, mycophenolic acid, or other components of the formulation, Patients who had received an investigational drug within four weeks prior to baseline, Severe rejection (≥ Banff II acute rejection), recurrent acute rejection, or steroid resistant rejection within six months of enrollment, Thrombocytopenia (platelets < 100,000/mm³), with an absolute neutrophil count of < 1,500/mm³ or leukopenia (leukocytes < 4,000/mm³), or hemoglobin < 8 g/dL, Abnormal physical or laboratory findings of clinical significance within two weeks of study inclusion which at the investigator's discretion would interfere with the objectives of the study, Symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, or patients who were unlikely to comply with the study requirements, or who were unable to give informed consent, History of malignancy during the last five years, except squamous or basal cell carcinoma of the skin, Patients who were HIV positive, or hepatitis C, or hepatitis B surface antigen positiveEvidence of severe liver disease (including abnormal liver enzyme profile, i.e. aspartate transaminase (AST), alanine aminotransferase (ALT) or total bilirubin > 3 times upper limit of normal (ULN), Females of childbearing potential who were planning to become pregnant, who were pregnant or lactating and/or who were unwilling to use effective means of contraception, Presence of a clinically significant infection requiring continued therapy, severe diarrhea, active peptic ulcer disease or uncontrolled diabetes mellitus that in the opinion of the investigator would interfere with the appropriate conduct of the study, Evidence of drug or alcohol abuse Other protocol-defined exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Calcineurin Inhibitor (CNI) group<br>Participants received Cyclosporine A (CsA) plus Enteric Coated Mycophenolate Sodium (EC-MPS) plus corticosteroids, or Tacrolimus A (CsA) plus Enteric Coated Mycophenolate Sodium (EC-MPS) plus corticosteroids. | Drug: Cyclosporin A (CsA)<br>* The dose was based on the participants' blood level of C0h (80-150 ng/ml).<br>* Other names: Sandimmun Optoral;Drug: Tacrolimus<br>* The dose was based on the participants' blood level of C0h (5-10 ng/ml).<br>* Other names: Prograf;Drug: Enteric Coated - Mycophenolate Sodium (EC-MPS)<br>* The dose was ≥ 720 mg/day.<br>* Other names: Myfortic;Drug: Corticosteroids<br>* Corticosteroids were given according to local standard and/or the Investigators' discretion.<br>|
| Experimental: Certican group<br>Participants were switched in a step-wise fashion from the CNI based regimen to Everolimus (RAD001). | Drug: Everolimus<br>* Participants, switching from the CsA based treatment, initially received everolimus 1.5 mg/day and then from day 7, 3 mg/day, and then from day 14, the dose was based on the participants' blood level (6-10 ng/ml). Participants, switching from the tacrolimus based treatment, initially received 3 mg/day and then from day 14, the dose was based on the participants' blood level (6-10 ng/ml).<br>* Other names: RAD001, Certican;Drug: Enteric Coated - Mycophenolate Sodium (EC-MPS)<br>* The dose was ≥ 720 mg/day.<br>* Other names: Myfortic;Drug: Corticosteroids<br>* Corticosteroids were given according to local standard and/or the Investigators' discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function | The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biopsy Proven Acute Rejection, Graft Loss, and Death | The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment. | 12 months | 
| Occurrence of Treatment Failures | The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment. | 12 months | 
| Evolution of Renal Function | The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment. | Baseline, 12 months | 
| Number of Participants Who Experienced Adverse Events and Death | Participants were monitored for adverse events, serious adverse events and deaths thorughout the prospective and follow-up phases of the study. | 12 months | 
| Changes in Cardiovascular Risk | The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment. | Baseline, 12 months | 
| Changes in Proteinuria | The analysis for this outcome measure was not perfomed because the analyses could not be powered for efficacy due to low recruitment. | Baseline, 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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enteric-coated mycophenolate sodium, everolimus, CNI-free regimen