Once-a-day Regimen With Everolimus, Low Dose Cyclosporine and Steroids in Comparison With Steroid Withdrawal or Twice a Day Regimen With Everolimus, Low Dose Cyclosporine and Steroids.

Study Overview
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Brief Summary
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This study will compare the following immunosuppressive regimens in recipients of kidney transplantation: A) everolimus, cyclosporine and steroids given once-a-day; B) everolimus and cyclosporine given twice a day with steroid withdrawal; C) everolimus, cyclosporine given twice a day and continuous steroids. The purpose of this study is to evaluate regimens A and B in comparison with the control group (group C) for efficacy, using as main endpoint the treatment failure rate, a composite endpoint including death, graft loss, BPAR and lost to follow-up between randomization and Month 12.

Official Title
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Once-a-day Regimen or Steroid Withdrawal in de Novo Kidney Transplant Recipients Treated With Everolimus, Cyclosporine and Steroids: a 12-month, Prospective, Randomized, Multicenter, Open-label Study. The EVIDENCE Study (EVerolImus Once-a-Day rEgimen With Neoral Versus Corticosteroid Elimination).

Conditions
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de Novo Kidney Transplant Recipients, Renal Transplantation

Intervention / Treatment
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* Drug: everolimus
* Drug: cyclosporine
* Drug: Prednison (continuous steroids)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: recipients of 1st or 2nd single kidney transplant donor age >14 years females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at Baseline (Visit 2), and are required to practice an approved method of birth control for the duration of the study and for a period of 2 months following discontinuation of study medication patientswho are willing and able to participate in the study and from whom written informed consent has been obtained Exclusion criteria: Exclusion criteria at screening (pre-transplantation, Visit 1): recipients of kidney-pancreas transplant, double kidney or any other transplant recipients of a 2nd kidney transplant who lost the 1st for immunological reasons focal segmental glomerulosclerosis (FSGS), primary oxaluria or other diseases (as cause of end stage renal failure - ESRF) at high risk of rapid recurrence or requiring continuous corticosteroid treatment recipients of A-B-O incompatible transplants historical or current peak PRA of >25% (current = 3 months) patients with already existing antibodies against the donor thrombocytopenia (platelets <75,000/mm³), absolute neutrophil count of <1,500/mm³, leucopenia (leucocytes <2,500/mm³), or hemoglobin <6 g/dL symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, or to comply with the study requirements, or to give informed consent history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases patients who are HIV positive or Hepatitis B surface antigen positive (HbsAg); HCV positive patients receiving interferon and/or ribavirin evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin >3 times UNL) evidence of drug or alcohol abuse body mass index (BMI) >35 patients who need to be treated with drugs known to strongly interact with CsA and/or everolimus (as detailed in Appendix 2 of the protocol) should be excluded, if according the investigator this interferes with the objectives of the study women of child-bearing potential, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5 mIU/mL) use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer history of hypersensitivity to any of the study drugs or to drugs of similar chemical classes patients with severe active infections or any other medical condition(s) that in the view of the investigator prohibits participation in the study (specify as required) Additional exclusion criteria post-transplantation (Visit 2): • graft not perfused or with thrombosis of the main vessels, according to angioscintigraphy or echocolordoppler within 48 hours after the end of surgical procedure To avoid any possible influence of the confounding factors on the results of this study additional exclusion criteria at randomization were (Visit 5, Month 3): unsatisfactory renal function (CrCl according Cockcroft and Gault<40 mL/min) proteinuria ≥0.8 g/24 hrs steroid-resistant, humoral, moderate/severe (BANFF grade ≥II) biopsy proven acute rejections multiple (2 or more) biopsy proven or treated acute rejections or acute rejections leading to relevant loss of renal function acute rejection or impairment of renal function (increase of serum creatinine>30%) in the month preceding randomization severe/uncontrollable adverse events with suspected relationship to everolimus (e.g. anemia, oral aphtosis, arthralgia) for the control of which the investigator has planned the withdrawal of everolimus severe infections requiring hospitalization in the two weeks preceding randomization poor compliance to prescribed treatments Other protocol-defined inclusion/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 |
| --- | --- |
| Experimental: Group A -Once-a-day regimen<br>Everolimus: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12. Cyclosporine: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL. Prednisone: In patients randomized to Group A before Amendment 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning. | Drug: everolimus<br>* Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.<br>* Other names: Certican®);Drug: cyclosporine<br>* Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.<br>* Other names: CsA, Sandimmun® Neoral®;Drug: Prednison (continuous steroids)<br>* continuous steroids<br>|
| Experimental: Group B - Steroid Withdrawal group<br>Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine:after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12. Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks. | Drug: everolimus<br>* Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.<br>* Other names: Certican®);Drug: cyclosporine<br>* Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.<br>* Other names: CsA, Sandimmun® Neoral®;Drug: Prednison (continuous steroids)<br>* continuous steroids<br>|
| Active Comparator: Group C - Standard twice-a-day group<br>Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12. Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning. | Drug: everolimus<br>* Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.<br>* Other names: Certican®);Drug: cyclosporine<br>* Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.<br>* Other names: CsA, Sandimmun® Neoral®;Drug: Prednison (continuous steroids)<br>* continuous steroids<br>|
| Experimental: Not Randomized Population (NRP)<br>NRP defined in whom a renal transplantation was performed, received at least one dose of study drug (everolimus) but who did not qualify for randomization at Visit 5, Day 90. This group was addressed as not randomized patients (NRP) and described with respect to baseline characteristics, treatment and outcome variables. | Drug: everolimus<br>* Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.<br>* Other names: Certican®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Failure Rate | Occurrence or not of treatment failure in each patient. Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection (a biopsy graded IA, IB, IIA, IIB or III according to Banff '97 grading with 2007 update), graft loss, death or lost to follow-up occurring after randomization (V5) and within M12 (V9). | Between randomization (Month 3) and Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12 | eGFR by Nankivell, in terms of descriptive statistics and change vs randomization visit - to compare the changes in the estimated GFR (Nankivell) between randomization and Month 12 in the steroid withdrawal group (Group B) to the change observed in the standard twice-a-day group (Group C), for non-inferiority | Month 3 to Month 12 | 
| Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12 | Occurrence of BPAR (after randomization) between arm B (steroid withdrawal group) and arm c (standard twice-a-day group). BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III according to Banff 1997 grading with 2007 update. | Month 3 to Month 12 | 
| Number of Participants With Graft and Patient Survival After Randomization | Graft Survival, calculated from the date of transplantation to the date of irreversible graft failure signified by return to long-term retransplantation or the date of the last follow-up during the period when the transplant was still functioning or to the date of death. Patient survival, calculated from the date of transplantation to the date of death or the date of the last follow-up. | Month 3 to Month 12 | 
| Change in Estimated Creatine Clearance | At each visit, estimated creatinine clearance was measured in the local laboratory to analyze the evolution of the renal function. The following indirect measures of renal function were computed: estimated creatinine clearance according to Cockcroft and Gault formula and MDRD formula. | M3, M12 | 
| Change in Serum Creatinine | Serum creatinine (a blood measurement) is an important indicator of renal health because it is an easily-measured by-product of muscle metabolism. Measuring serum creatinine is a simple test and it is the most commonly used indicator of renal function. | M3, M12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppression, renal transplantation, once-a-day regimen, steroid withdrawal, drug minimization, immunosuppression for prevention of acute rejections