12 Month Athena Study: Everolimus vs. Standard Regimen in de Novo Kidney Transplant Patients

Study Overview
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Brief Summary
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This study was designed to evaluate the renal function comparing Certican based immunosuppressive regimens with two different CNIs (Tacrolimus or Cyclosporin A) versus a standard treatment with Mycophenolic Acid and Tacrolimus in de novo renal transplant recipients.

Official Title
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12 Month, Multi-center, Open-label, Prospective, Randomized, Parallel Group Study Investigating a Standard Regimen in de Novo Kidney Transplant Patients Versus a Certican® Based Regimen Either in Combination With Cyclosporin A or Tacrolimus

Conditions
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Kidney Transplantation, Renal Transplantation

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient who had received a primary or secondary kidney transplant Patients who were willing and from whom written informed consent was obtained kidney allograft with a cold ischemia time (CIT) < 30 hours negative pregnancy test prior to study enrollment Exclusion Criteria: --Multi-organ recipients former Graft loss due to immunological reasons Patients who received a kidney from a non-heart beating donor A-B-0 incompatible transplants a current Panel Reactive Antibody (PRA) level of > 20% existing antibodies against the HLA-type of the receiving transplant a known hypersensitivity/contraindication to any of the immunosuppressants Use of other investigational drugs Patients with thrombocytopenia (platelets < 100,000/mm³), with an absolute neutrophil count of < 2,000/mm³ or leucopenia (leucocytes < 3,000/mm³), or hemoglobin < 8 g/dL significant mental illness history of malignancy during the last five years HIV positive uncontrolled hypercholesterolemia or hypertriglyceridemia drug or alcohol abuse pregnant or breast feeding women

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TAC+MPA<br> | Drug: Tacrolimus<br>* Capsules: 0.5 mg, 1 mg or 5 mg. Dosing schedule: transplant to month 2: 4-8ng/ml, month 3 to month 12 3-5 ng/ml according to standard blood levels<br>Drug: Enteric Coated Mycophenolate Sodium (EC-MPS)<br>* Tablets: 180 mg or 360 mg. Dosing: duration of study 360 mg bid and no less than 360 mg daily dose<br>Drug: Mycophenolate mofetil (MMF)<br>* Capsules: 250 or 500 mg. Dosing: duration of study 500 mg bid and no less than 500 mg total daily dose<br>Drug: Corticosteroids<br>* A minimum dose of 5 mg prednisolon or equivalent<br>Drug: Simulect<br>* Lyophilisate in vials with ampoules of sterile water for injection (5 mL), one vial containing 20 mg lyophilisate given intravenously on the day of transplantation and on day four post-transplantation.<br>* Other names: Basiliximab;|
| Experimental: TAC+Certican<br> | Drug: Everolimus<br> <br> * Other names: Certican;Drug: Tacrolimus<br>* Capsules: 0.5 mg, 1 mg or 5 mg. Dosing schedule: transplant to month 2: 4-8ng/ml, month 3 to month 12 3-5 ng/ml according to standard blood levels<br>Drug: Corticosteroids<br>* A minimum dose of 5 mg prednisolon or equivalent<br>Drug: Simulect<br>* Lyophilisate in vials with ampoules of sterile water for injection (5 mL), one vial containing 20 mg lyophilisate given intravenously on the day of transplantation and on day four post-transplantation.<br>* Other names: Basiliximab;|
| Experimental: CycA+Certican<br> | Drug: Everolimus<br> <br> * Other names: Certican;Drug: Cyclosporin A<br>* Capsules: 10 mg, 25 mg, 50 mg or 100 mg. Transplantation to month 2: 75 - 125 ng/ml, month 3 to month 12: 50 - 100 ng/ml<br>Drug: Corticosteroids<br>* A minimum dose of 5 mg prednisolon or equivalent<br>Drug: Simulect<br>* Lyophilisate in vials with ampoules of sterile water for injection (5 mL), one vial containing 20 mg lyophilisate given intravenously on the day of transplantation and on day four post-transplantation.<br>* Other names: Basiliximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomular Filtration Rate (GFR) mL/Min Via Nankivell Method at Month 12 - Standard Regimen vs Certican Regimens | To demonstrate non-inferiority in renal function assessed by glomerular filtration rate (Nankivell formula) in at least one of the Certican® treatment regimens compared to the standard regimen group at month 12 post-transplantation in renal transplant patients. 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. The eGFR is expressed in mL/min per 1.73m². If a patient was on dialysis at the time of urea or creatinine assessment, the eGFR was set to 0. Analysis set = per protocol set | One year post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Composite Treatment Failure Endpoints - Difference Between Groups at Month 12 | Combined endpoint included: biopsy proven acute rejection (BPAR) defined as a rejection which was acute and proven by biopsy, graft loss (GL) defined as: allograft was presumed to be lost on the day the patient starts dialysis and not able to be removed from dialysis or death. Patients who prematurely discontinued the study: if the patient did not suffer from an event before discontinuation and reason was not related to efficacy, the patient was assessed as having had no event, otherwise the patient was assessed as having had an event. Full analysis set (FAS) | Month 12 post transplant | 
| Glomular Filtration Rate (GFR) Via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Method at Month 12 Post Transplant | Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method = GFR=141 x min(Scr/κ, 1)α x max(Scr/κ, 1)1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is 0.329 for females and 0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model | Month 12 post transplant | 
| Glomular Filtration Rate (GFR) mL/Min Via Cockcroft- Gault Method at Month 12 Post Transplant | Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl)For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model | Month 12 post transplant | 
| Glomular Filtration Rate (GFR) Via Modification of Diet in Renal Disease (MDRD) Method at Month 12 Post Transplant | Modification of Diet in Renal Disease (MDRD) = For men: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x (urea nitrogen -0,17) x (albumin0,318) For women: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x (urea nitrogen -0,17) x albumin0,318) x 0.762 with urea nitrogen = urea / 2.144. last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model | Month 12 post transplant | 
| Percentage of Participants With Treatment Failure Endpoints at Month 12 | Treatment failure endpoints: biopsy proven acute rejection (BPAR) defined as a rejection which was acute and proven by biopsy, graft loss (GL) defined as: allograft was presumed to be lost on the day the patient starts dialysis and not able to be removed from dialysis or death. Patients who prematurely discontinued the study: if the patient did not suffer from an event before discontinuation and reason was not related to efficacy, the patient was assessed as having had no event, otherwise the patient was assessed as having had an event. Full analysis set (FAS) | Month 12 post transplant | 
| Percent of Participants With Delayed Graft Function and Slow Graft Function | Delayed graft function (DGF) was defined as the need for dialysis within the first 7 days post-transplantation, excluding the first post-transplantation day. Slow graft function (SGF) was defined as a serum creatinine >3.0 mg/dL at Day 5 post-transplantation. Full analysis set | Post transplant to month 12 | 
| Percent of Participants With Delayed Graft Function by Day | Delayed graft function (DGF) was defined as the need for dialysis within the first 7 days post-transplantation, excluding the first post-transplantation day. | Post transplant up to day 7 | 
| Percent of Participants With Viral Infections | Viral infections for BKV Virus Humane Polyomavirus 1 and Cytomegalovirus | Post transplant to month 12 | 
| Percent of Participants With Wound Healing Complications During Study | Information collected to report wound healing process which included percentage of participants with complications, fluid collections detected and occurrence of lymphoceles | Post transplant until individual reporting | 
| Duration of Wound Healing | A wound will be considered healed if all the suture material and staples are removed and the wound is intact. Number of participants is based on all patients of the respective treatment group in the safety set, excluding patients with no answer (unknown). | Post transplant until individual reporting | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transplant, Renal transplant, Rejection,allograf, Rejection, Xenograft rejection, Host vs graft disease, Kidney Transplant