Efficacy and Safety of Everolimus+EC-MPS After Early CNI Elimination vs EC-MPS +Tacrolimus in Renal Transplant Recipients

Study Overview
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Brief Summary
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The primary objective of this trial is to show non-inferiority of a CNI-free regimen with respect to the renal function at Month 9 post Tx assessed by glomerular filtration rate - Nankivell method - as compared to the standard CNI-based regimen in de novo renal transplant patients.

Official Title
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Efficacy and Safety of Certican® (Everolimus) in Combination With Myfortic® (EC-MPS, Enteric-coated Mycophenolate Sodium) After Early CNI Elimination Versus Myfortic® in Combination With Prograf® in Renal Transplant Recipients

Conditions
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Chronic Renal Failure

Intervention / Treatment
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* Drug: Everolimus
* Drug: Tacrolimus (FK506)
* Drug: Basiliximab
* Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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 screening, 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. 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 Donor age: < 5 years or > 65 years Graft loss due to immunological reasons in the first year after transplantation (in case of secondary transplantation) Patients who had received an investigational drug within 4 weeks of the baseline period Patients who are recipients of A-B-O incompatible transplants or T cell cross-match positive transplants Patients with already existing antibodies against the HLA-type of the receiving transplant Patients with any known hypersensitivity to Simulect®, Certican®, mycophenolic acid, Prograf®, other drugs similar to Certican® (e.g., macrolides), or other components of the formulations. Patients who have received an investigational immunosuppressive drug within four weeks prior to study entry (Baseline visit 1) Patients with thrombocytopenia (platelets < 75,000/mm³), or an absolute neutrophil count of < 1,500/mm³ or leucopenia (leucocytes < 2,500/mm³), or hemoglobin < 6 g/dL Patients with preexisting lung disease (alveolitis, fibrosis) Patients with symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, who are unlikely to comply with the study requirements, or who are unable to give informed consent Patients with a history of malignancy during the last five years, except squamous or basal cell carcinoma of the skin Patients who are HIV positive or Hepatitis B surface antigen positive or Hepatitis C virus positive. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C are excluded. Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin > 3 times UNL) Females of childbearing potential who are planning to become pregnant, who are pregnant or lactating, and/or who are unwilling to use effective means of contraception (see also section 8.2) 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 Patients receiving drugs known to interact with Tacrolimus and/or everolimus according to the list provided in Appendix 3 to this protocol. Other protocol-defined inclusion/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<br>At BL1, all study patients received induction therapy with basiliximab (Simulect®; 2x20mg on day 0 - 2 hours prior to transplantation, and on day 4 after transplantation) and commenced an immunosuppressive regimen consisting of MPA (Myfortic®; target dose: 1440 mg/day, which was also the maximum daily dose) + tacrolimus (Prograf®; based on C0-h levels; Table 9-2) and with corticosteroids. AT BL2 [Month 3 (+1 week) after transplantation], eligible patients were randomized, using living and cadaveric donation as stratum. Patients were switched to the CNI-free regimen. Everolimus was added to the patients immunosuppressive regimen and tacrolimus was removed successively. | Drug: Everolimus<br>* One tablet containing 0.25, 0.5mg or 0.75 mg. Initially 2 mg/day. Afterwards based on blood level (target 6-10 ng/mL)<br>* Other names: Certican;Drug: Basiliximab<br>* One vial containing 20 mg lyophilisate. 2 x 20 mg [day 0 (2 hrs prior to Tx) and day 4 post Tx] to be applied as 10 sec. bolus injection, i.v.<br>* Other names: Simulect;Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)<br>* One tablet containing 180 mg or 360 mg. 1440 mg/day (2x720 mg). If tolerated, dose reduction due to side effectis were possible (min. dose at BL@: 720 mg/day)<br>* Other names: Myfortic;Drug: Corticosteroids<br>* Used according to Israeli standards. A minimum dose of 5mg [prednisone, or equivalent, was used throughout the study period.<br>|
| Active Comparator: Reference Therapy<br>At BL1, all study patients received induction therapy with basiliximab (Simulect®; 2x20mg on day 0 - 2 hours prior to transplantation, and on day 4 after transplantation) and commenced an immunosuppressive regimen consisting of MPA (Myfortic®; target dose: 1440 mg/day, which was also the maximum daily dose) + tacrolimus (Prograf®; based on C0-h levels; Table 9-2) and with corticosteroids. AT BL2 [Month 3 (+1 week) after transplantation], eligible patients were randomized, using living and cadaveric donation as stratum. Patients continued on the prior immunosuppressive regimen consisting of MPA + tacrolimus with corticosteroids. | Drug: Tacrolimus (FK506)<br>* Capsules 0.5 mg, 1 mg. Dosing according to blood level.<br>* Other names: Prograf;Drug: Basiliximab<br>* One vial containing 20 mg lyophilisate. 2 x 20 mg [day 0 (2 hrs prior to Tx) and day 4 post Tx] to be applied as 10 sec. bolus injection, i.v.<br>* Other names: Simulect;Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)<br>* One tablet containing 180 mg or 360 mg. 1440 mg/day (2x720 mg). If tolerated, dose reduction due to side effectis were possible (min. dose at BL@: 720 mg/day)<br>* Other names: Myfortic;Drug: Corticosteroids<br>* Used according to Israeli standards. A minimum dose of 5mg [prednisone, or equivalent, was used throughout the study period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function Assessed as Glomerula Filtration Rate (GFR) - Nankivell Method - 9 Months After Renal Transplantation (LOCF) | The glomerular filtration rate (GFR) is the best clinical estimate of renal function in health and disease, and correlates well with the clinical severity of renal function disturbances. The GFR, calculated according to the Nankivell formula, was used as the primary outcome measure in this study. This equation has been validated in renal transplant patients against the true GFR measured by a radionuclide method and has been confirmed as a very accurate method to calculate the GFR in this specific population (Gaspari et al., 2004)GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C Scr = serum creatinine concentration expressed in mmol/L. BW = body weight in kg, Surea = serum urea in mmol/L and Height is expressed in meters.The Last Observation Carried Forward (LOCF) imputation technique was used for this analysis. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of GFR by the Cockcroft-Gault Method (LOCF) | the GFR was also calculated using the Cockcroft-Gault method (Cockcroft and Gault 1976) and the Modification of Diet in Renal Disease (MDRD) method (Levey et al., 1999, Rodrigo et al., 2003; Pierrat et al., 2003).Cockcroft-Gault formula For men: GFR= (140-Age)X Body Weight[kg]/72X Serum Creatinine[mg/dl] For women: GFR= 0,85x(140-Age) x Body Weight[kg]/72x Serum Creatinine [mg/dl] The Last Observation Carried Forward (LOCF) imputation technique was used for this analysis. | 9 months | 
| Participants Who Had Occurrence of Biopsy Proven Acute Rejection, Graft Loss or Death. | Biopsy-proven acute rejection was defined as a biopsy gradeed IA, IB, IIA, IIB, or III. The allograft was presumed to be lost if the patient started 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. | 9 months | 
| Participants Who Had Occurrence of Treatment Failure. | Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection, graft loss, death, loss to follow up, discontinuation due to lack of efficacy or toxicity or conversion to another regimen. | 9 months | 
| Change in Renal Function (Creatinine Slope) | X(slope)=(1/value of creatinine). | 3 months, 5 months, 7 months, 9 months |