A National Multi-center Randomized, Open Label Study to Evaluate Efficacy and Safety of Everolimus With EC-MPS Compared to Standard Treatment Combination Tacrolimus and EC-MPS in de Novo Liver Transplant Recipients

Study Overview
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Brief Summary
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The aims of the study was to evaluate the safety and efficacy of early introduction one month post-transplantation of everolimus associated to EC-MPS with tacrolimus discontinuation in de novo liver transplant recipients and to evaluate if it leads to a better renal function 6 month post-transplantation compared to standard treatment associating tacrolimus and EC-MPS. The renal function was estimated by glomerular filtration rate.

Official Title
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A National, Multi-center, Randomized, Open Label Study to Evaluate the Efficacy and Safety of Everolimus Combined With Enteric-coated Mycophenolate Sodium Compared to the Standard Treatment Combining Tacrolimus and Enteric-coated Mycophenolate Sodium in de Novo Liver Transplant Recipients

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: tacrolimus
* Drug: everolimus
* Drug: Basiliximab
* Drug: Mycophenolic Acid
* Drug: Corticosteroids


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Man or woman aged 18 years or greater, recipient of a primary liver transplant from a deceased donor with whole or split liver Key Exclusion Criteria: Patient recipient of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant Recipient of a liver from a living donor or cadaveric non heart beating donor ABO incompatible transplant graft Transplantation following autoimmune liver hepatitis, primitive sclerosing cholangitis or primitive biliary cirrhosis Estimated glomerular filtration rate ≤ 30ml/min at selection History of malignancy within the 5 past years, other than non-metastatic basal or squamous cell carcinoma and hepatocellular carcinoma Alpha-foeto-protein > 1000 ng/ml (only in case of hepatocellular carcinoma)

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: Tacrolimus<br>From transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids | Drug: tacrolimus<br>* Arm 1 : tacrolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to 16 weeks post-transplantation at the latest.<br>* Other names: Prograf®;Drug: Basiliximab<br>* Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4<br>* Other names: Simulect®;Drug: Mycophenolic Acid<br>* Dose of 1440 mg/day from transplantation to month 6 post- transplantation<br>* Other names: Myfortic®;Drug: Corticosteroids<br>* Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice<br>|
| Experimental: Everolimus (RAD001)<br>From transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest). | Drug: tacrolimus<br>* Arm 1 : tacrolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to 16 weeks post-transplantation at the latest.<br>* Other names: Prograf®;Drug: everolimus<br>* Arm 1: no everolimus Arm 2: everolimus (C0 6-10 ng/ml) from randomization to month 6 post-transplantation<br>* Other names: Certican® / RAD001;Drug: Basiliximab<br>* Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4<br>* Other names: Simulect®;Drug: Mycophenolic Acid<br>* Dose of 1440 mg/day from transplantation to month 6 post- transplantation<br>* Other names: Myfortic®;Drug: Corticosteroids<br>* Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Randomization) in Renal Function | Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula. GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Treatment Failures | Incidence of treatment failures, assessed with composite criterion including treated biopsy proven acute rejection (tBPAR) with a rejection activity index (RAI) according to Banff classification >3, graft loss or death at 6 months. Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft. | At week 12 and week 24 | 
| Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) | Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy. | at 12 week and 24 week | 
| Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification | Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy. The severity of BPAR was categorized as : Mild (Banff grade I, RAI = 4 and 5) Moderate (Banff grade II, RAI = 6 and 7) Severe (Banff grade III, RAI = 8 and 9) Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. | at 12 week and 24 week | 
| Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 | Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The patients with treated or untreated BPAR having RAI score > 3 were reported in this end point. | At 24 weeks | 
| Number of Patients With Death or Graft Loss | The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft. | at week 24 | 
| Change From Baseline (Randomization) in Serum Creatinine | Change in serum creatinine concentrations from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit. | Baseline, Week 24 | 
| Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio | Change in urine protein/creatinine ratio from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit. | Baseline, week 24 | 
| Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula | Creatinine clearance by the Cockcroft-Gault formula is computed in mL/min/1.73m^2 from the creatinine clearance in mL/min by multiplying it by 1.73 and dividing it by the body surface area Baseline was Day 28 visit. | Baseline, Week 24 | 
| Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula | Change in glomerular filtration rate was calculated using the MDRD abbreviated formula. GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit. | Baseline, Week 24 | 
| Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula | GFR estimated by using the Chronic kidney disease- epidemiology (CKD-EPI) formula: eGFR (mL/min/1.73m^2) = 141 * min(C/K,1)^ α * max(C/K,1)^-1.209 * 0.993^A * 1.1018 (if male) * 1.159 (if black) where C = serum creatinine (in mg/dL) ; A = Age (in years); K = 0.7 for women and 0.9 for men; α = -0.329 for women and -0.411 for men. Baseline was Day 28 visit. | Baseline, Week 24 | 
| Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System | Kidney disease outcomes quality initiative (K/DOQI) classification is based on glomerular filtration rate (GFR), abbreviated MDRD formula (mL/min/1.73m^2) : Stage 1 : GFR >= 90; Stage 2 = GFR was between 60-89; Stage 3 = GFR was between 30-59 ; Stage 4 = GFR was between 15-29; Stage 5 = GFR was < 15 (or dialysis) | At Week 24 | 
| Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation | Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation. | Baseline to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Everolimus,, liver transplantation,, early introduction,, renal function