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

Phase 3

Completed

Conditions: Liver Transplantation

Interventions: Drug: tacrolimus
Drug: everolimus
Drug: Basiliximab
Drug: Mycophenolic Acid
Drug: Corticosteroids

Registration Number: NCT01625377

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 188

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tacrolimus	tacrolimus	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
Tacrolimus	Corticosteroids	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
Everolimus (RAD001)	Corticosteroids	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).
Tacrolimus	Mycophenolic Acid	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
Everolimus (RAD001)	tacrolimus	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).
Everolimus (RAD001)	everolimus	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).
Everolimus (RAD001)	Mycophenolic Acid	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).
Tacrolimus	Basiliximab	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
Everolimus (RAD001)	Basiliximab	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).

Primary Outcome Measures

Name	Time	Method
Change From Baseline (Randomization) in Renal Function	Baseline, Week 24	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula	Baseline, Week 24	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.
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System	At Week 24	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)
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation	Baseline to 24 weeks	Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation.
Number of Patients With Treatment Failures	At week 12 and week 24	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.
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR)	at 12 week and 24 week	Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification	at 12 week and 24 week	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.
Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3	At 24 weeks	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.
Number of Patients With Death or Graft Loss	at week 24	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.
Change From Baseline (Randomization) in Serum Creatinine	Baseline, Week 24	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.
Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio	Baseline, week 24	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.
Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula	Baseline, Week 24	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.
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula	Baseline, Week 24	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.