A Twelve-month, Multicenter, Open-label, Randomized Study of the Safety, Tolerability and Efficacy of Everolimus With Basiliximab, Corticosteroids and Two Different Exposure Levels of Tacrolimus in de Novo Renal Transplant Recipients

Study Overview
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Brief Summary
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This study is designed to evaluate whether tacrolimus dose reduction in de novo renal recipients receiving everolimus can preserve renal function while maintaining efficacy.

Official Title
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A Twelve-month, Multicenter, Open-label, Randomized Study of the Safety, Tolerability and Efficacy of Everolimus With IL-2 Receptor Antagonist, Corticosteroids and Two Different Exposure Levels of Tacrolimus in de Novo Renal Transplant Recipients

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Everolimus (RAD001)
* Drug: Tacrolimus
* Drug: Basiliximab
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female of 18-65 years old Patient who has received a primary kidney transplant from a cadaveric, living unrelated or non-human leucocyte antigen (HLA) identical living related donor Recipient of a kidney with a cold ischemia time (CIT) < 30 hours Recipient of a kidney from a donor 10-65 years old Patient able to receive the first dose of tacrolimus within 24 hours from graft reperfusion Female capable of becoming pregnant must have a negative pregnancy test and is required to practice a medically approved method of birth control for the duration of the study and for a period of three months following discontinuation of investigational drug Patient willing and capable of giving written informed consent for study participation and able to participate in the study for 12 months Exclusion criteria Patient who has previously received an organ transplant Recipient of multiple organ transplants Recipient of a kidney transplant from a non heart-beating donor Recipient of donor specific transfusions Recipient of A-B-O incompatible transplant or T-cell cross-match positive transplant Patient with current Panel Reactive Antibodies (PRA) level ≥ 50% Recipient of a kidney from a donor who tests positive for hepatitis B surface antigen or hepatitis C antibodies Patient who is human immunodeficiency virus (HIV) positive Patient who has a positive hepatitis C serology or who is hepatitis B surface antigen positive with evidence of liver injury as indicated by aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels ≥2.5 times upper limit of normal (UNL). Viral serology results obtained within 6 months prior to the administration of the first dose of Certican™ are acceptable Patient with severe hypercholesterolemia (350 mg/dL, 9.1 mmoL/dL) or hypertriglyceridemia ( 500 mg/dL, 5.6 mmoL/L) Patient with white blood cell (WBC) count 3,000/mm3 or with platelet count 75,000/mm3 Patient with any severe allergy requiring acute (within 4 weeks of baseline) or chronic treatment, or with hypersensitivity to drugs similar to Certican (e.g., macrolides) Patient who has been treated with an immunosuppressive drug or an investigational drug within 4 weeks prior to the administration of the first dose of Certican Patient with uncontrolled infection Patient with any surgical or medical condition, other than the current transplant, which in the opinion of the investigator, precludes enrollment in this trial Patient with a known malignancy or a history of malignancy within last 5 years other than successfully treated localized basal or squamous cell carcinoma of the skin Abnormal physical or laboratory findings of clinical significance within 2 weeks prior to the administration of the first dose of Certican™ which at investigator's discretion would interfere with the objectives of the study Breast feeding women Patient with symptoms of significant somatic or mental illness or with unresolved history of drug or alcohol abuse Patient unable to cooperate or communicate with the investigator

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Very low dose tacrolimus<br>The first dose of everolimus was to be administered not later than 24 hours after transplantation with a starting dose of 1.5 mg bis in diem/twice a day (b.i.d.) thereafter adjusted to maintain the trough blood levels between 3 and 8 ng/ml. Tacrolimus was to be initiated within 24 hours after reperfusion of the graft with a starting dose of 0.1 mg/kg/day thereafter adjusted to maintain the trough blood levels between 4 and 7 ng/ml. Up to months three all patients received the same treatment and after three months patients in this arm received tacrolimus to reach a trough blood level between 1.5 and 3 ng/ml. All patients received two doses of 20 mg basiliximab, administered as an intravenous bolus injection. The first dose was given on the day of transplantation, with the second dose being administered on the fourth day post-transplant. Intravenous (i.v.) prednisone (or equivalent) was given pre- or intra-operatively according to center practice. | Drug: Everolimus (RAD001)<br> <br> Drug: Tacrolimus<br> <br> Drug: Basiliximab<br> <br> Drug: Corticosteroids<br> <br> |
| Active Comparator: Low dose tacrolimus<br>The first dose of everolimus was to be administered not later than 24 hours after transplantation with a starting dose of 1.5 mg bis in diem/twice a day (b.i.d.) thereafter adjusted to maintain the trough blood levels between 3 and 8 ng/ml. Tacrolimus was to be initiated within 24 hours after reperfusion of the graft with a starting dose of 0.1 mg/kg/day thereafter adjusted to maintain the trough blood levels between 4 and 7 ng/ml. Up to months three all patients received the same treatment and after three months patients in this arm received tacrolimus to reach a trough blood level between 4 and 7 ng/ml. All patients received two doses of 20 mg basiliximab, administered as an intravenous bolus injection. The first dose was given on the day of transplantation, with the second dose being administered on the fourth day post-transplant. Intravenous (i.v.) prednisone (or equivalent) was given pre- or intra-operatively according to center practice. | Drug: Everolimus (RAD001)<br> <br> Drug: Tacrolimus<br> <br> Drug: Basiliximab<br> <br> Drug: Corticosteroids<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function Assessed by Calculated Glomerular Filtration Rate (cGFR) | Renal function was assessed by calculated glomerular filtration rate (cGFR) using Modification of Diet in Renal Disease (MDRD)formula. GFR [mL/min/1.73m^2] = 186.3*(C-1.154)*(A-0.203)*G*R, where: C is the serum concentration of creatinine [mg/dL], A is patient age at sample collection date [years], G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1 | 12 months post -transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Incidence of Biopsy-proven Acute Rejection (BPAR) | Biopsy-proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy (performed by the local pathologist). For all clinically suspected rejection episodes a graft core biopsy must have been performed before or within a 24 hour period from the initiation of anti-rejection therapy. | from Month 4 through to Month 12 | 
| Percentage of Participants With Efficacy Failure | Efficacy failure was a composite of BPAR, graft loss, death or lost to follow-up. BPAR was defined as a clinically suspected acute rejection confirmed by biopsy (performed by the local pathologist). For all clinically suspected rejection episodes a graft core biopsy must have been performed before or within a 24 hour period from the initiation of anti-rejection therapy. An allograft was presumed to be lost on the day a patient started dialysis and was unable to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, the day of nephrectomy was the day of graft loss. | Month 12 |