A Study Investigating the Renal Tolerability, Efficacy, and Safety of a CNI-free Versus a Standard Regimen in de Novo Heart Transplant (HTx) Recipients

Study Overview
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Brief Summary
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This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.

Detailed Description
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This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.

Official Title
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A Multi-center, Randomized, Open-label, Parallel Group Study Investigating the Renal Tolerability, Efficacy and Safety of a CNI-free Regimen (Everolimus and MPA) Versus a CNI-regimen With Everolimus in Heart Transplant Recipients

Conditions
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Heart Transplantation

Intervention / Treatment
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* Drug: Everolimus (EVR)
* Drug: cyclosporine A (CyA)
* Drug: tacrolimus (TAC)
* Drug: Enteric coated mycophenolate sodium (EC-MPS)
* Drug: mycophenolate mofetil (MMF)
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Heart transplantation, 3 months prior to enrollment Patients have to receive an immunosuppressive regimen with Sandimmun® Optoral, Certican® and corticosteroids Sufficient graft function Sufficient renal function Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at baseline, 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 Exclusion criteria: Multi-organ recipients, re-transplantation, or previous transplant with any other organ. Patients who are recipients of A-B-O incompatible transplants Cold ischemia time >6 hours Historical or current peak PRA of > 25% at time of transplantation Already existing antibodies against the HLA-type of the receiving transplant Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: CNI-regimen<br>CNI-regimen: cyclosporine A (CyA) or tacrolimus (TAC) with everolimus (EVR) with corticosteroids | Drug: Everolimus (EVR)<br>* Everolimus 0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL)<br>* Other names: Certican, RAD001;Drug: cyclosporine A (CyA)<br>* 10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels for CNI-regimen group. For CNI-free-regimen dispense on month 6 to 9 only<br>* Other names: Sandimmun Optoral;Drug: tacrolimus (TAC)<br>* 0.5 mg, 1 mg, or 5 mg capsule given according to blood levels for CNI-regimen. For CNI-free-regimen give on month 6 to 9 only<br>* Other names: Prograf;Drug: Corticosteroids<br>* according to local standard: 0.05-0.3 mg/kg of prednisolone or equivalent<br>|
| Experimental: CNI-free-regimen<br>CNI-free regimen: everolimus (EVR) with MPA (either MMF or enteric coated mycophenolate sodium (EC-MPS)) and corticosteroids | Drug: Everolimus (EVR)<br>* Everolimus 0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL)<br>* Other names: Certican, RAD001;Drug: cyclosporine A (CyA)<br>* 10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels for CNI-regimen group. For CNI-free-regimen dispense on month 6 to 9 only<br>* Other names: Sandimmun Optoral;Drug: tacrolimus (TAC)<br>* 0.5 mg, 1 mg, or 5 mg capsule given according to blood levels for CNI-regimen. For CNI-free-regimen give on month 6 to 9 only<br>* Other names: Prograf;Drug: Enteric coated mycophenolate sodium (EC-MPS)<br>* 180 mg or 360 mg tablet dosed 1440-2280 mg per day<br>* Other names: Myfortic;Drug: mycophenolate mofetil (MMF)<br>* 250 mg or 500 mg tablets with a dose of 1500-3000 mg per day<br>* Other names: CellCept;Drug: Corticosteroids<br>* according to local standard: 0.05-0.3 mg/kg of prednisolone or equivalent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 | Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 cGFR (in mL/min/1.73 m2) = 186.3*(C-1.154)*(A-0.203)*G*R where C = the serum concentration of creatinine (mg/dL), A = age (years), G = 0.742 when gender is female, otherwise G = 1, R = 1.21 when race is black, otherwise R = 1. | Month 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18 | Treatment failure was defined as composite endpoint of biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute rejection episodes associated with hemodynamic compromise, graft loss / re-transplant, death, loss to follow up (at least one condition must be present). If participant had an occurrence in each period it was counted for each period. | Month 6 to Month 9; Month 9 to Month 18 | 
| Occurrence of Major Cardiac Events (MACE) From Month 6 to 18 | Major cardiac events (MACE) was defined as one of the following: any death, myocardial infarction, coronary artery bypass grafting | Month 6 to Month 18 | 
| Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18 | Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 12 and 18. For men: GFR=(140-Age) x Body weight (kg) / 72 x Serum Creatinine (mg/dl) For women: GFR=0.85 (140 -Age) x Body weight(kg)/ 72 x Serum Creatinine (mg/dl) | Month 12 and 18 | 
| Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Serum Creatinine is an indicator of renal function measured in the blood | Month 6, 8, 9, 10 12 and 18 | 
| Reciprocal Creatinine Slope Between Month 6 and Month 18 | Reciprocal Creatinine Slope is an indication of renal function over time with a higher slope value indicating an improvement in renal function. | Between Month 6 and Month 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Transplantation, Cardiac Transplantation, CNI-sparing, renal function, CNI, Cyclosporine A, Everolimus, mycophenolic acid