Liver Transplantation
Conditions
Keywords
Liver transplantation, everolimus, CNI-minimization, CNI-elimination, renal function
Brief summary
The purpose of this study was, starting from the Italian clinical practice in liver transplantation, to optimize the immunosuppressive therapy, considering specific patient characteristics as alcoholic cirrhosis, hepatitis C virus (HCV), hepatocellular carcinoma (HCC), and short/long-term implications. Then efficacy and safety of a calcineurin inhibitor (CNI)-withdrawal regimen was evaluated in comparison with a CNI-minimization regimen.
Interventions
DRUGEverolimus
Commercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration.
DRUGTacrolimus
Commercial product labeled according to local requirements will be provided as 0.5 mg, 1.0 mg and 5.0 mg capsules for oral administration.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
at Baseline: * Male and female liver transplant recipients who are ≥ 18 years of age, treated with a tacrolimus-based immunosuppressive regimen, who have received an induction therapy or i.v. steroids as per local clinical practice. * Recipients of a full-size or technically modified liver allograft will be eligible at 4 weeks (± 7 days) after liver transplantation. * Allograft is functioning at an acceptable level by the time of Baseline as defined by the AST, ALT, total bilirubin levels ≤ 3 times ULN and INR \< 1.5 times ULN. * Abbreviated MDRD-4 eGFR ≥ 30 mL/min/1.73m2. Serum creatinine results obtained within 5 days prior to Baseline are acceptable. Inclusion criteria at Randomization: * Effective tacrolimus minimization, confirmed by stable blood trough levels in the two months prior to randomization, i.e. verification of last two tacrolimus blood trough level ≤ 5 ng/mL in the two months prior to randomization. Investigators should make adjustments in tacrolimus dosing to continue to target trough levels ≤ 5 ng/mL prior to randomization. * Abbreviated MDRD-4 eGFR ≥ 30 mL/min/1.73m2. Serum creatinine results obtained within 5 days prior to Visit 5 are acceptable.
Exclusion criteria
at Baseline: * Patients who are recipients of multiple solid organ transplants, (e.g., multivisceral or combined liver-kidney transplants), or have previously received an organ or tissue transplanted, or who received an AB0 incompatible transplant. * Patients who experienced more than one episode of treated biopsy proven acute rejection (BANFF ≥ 3 or RAI ≥ 7) or one steroid-resistant acute rejection. * Patients who require renal replacement therapy. * Patients with a confirmed spot urine protein/creatinine ratio that indicates ≥1.0 g/24 hrs of proteinuria. * History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR) | At 12 months post-transplant | Renal function was assessed by eGFR using the MDRD-4 formula at 12 months after transplant: eGFR = 186.3 \* (serum creatinine)-1.154 \* age-0.203 \* (0.742 for women) \* (1.21 if African American) where serum creatinine was in mg/dL and age in years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | At 12 and 18 months post-transplant | Participants were assessed for tBPAR, AR, GL or death. For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, a liver biopsy was to be performed preferably within 24 hours, latest within 48 hours whenever clinically possible. A treated biopsy proven acute rejection was considered an episode of acute rejection when demonstrated by local pathology reading with a rejection activity index of at least 3 or greater of acute rejection index and when treated with anti-rejection therapy. The allograft was considered lost on the day the subject was re-transplanted or died due to liver failure. |
| Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant | baseline, 12 months post-transplant | Blood samples were collected to assess serum creatinine. |
Countries
Italy
Participant flow
Recruitment details
68 participants completed run-in but only 50 decided to move forward to randomization.
Pre-assignment details
This study included a run-in period and a randomization period. Run-in started 4 weeks post-transplant and ended at 5 months post randomization. After run-in, eligible participants were randomized in a 1:1 ratio to tacrolimus elimination or tacrolimus minimization.
Participants by arm
| Arm | Count |
|---|---|
| Total Enrolled at run-in Participants, who had a successful liver transplantation and who had initiated a tacrolimus-based regimen and possible induction therapy or intravenous (i.v.) steroids according to local practice, were enrolled into the study 4 weeks (+/- 7 days) after transplantation and started on a everolimus-based regimen with tacrolimus minimization up until 5 months post transplantation. | 78 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Participants in Run-in Period | Administrative problems | 0 | 0 | 1 |
| Participants in Run-in Period | Death | 0 | 0 | 1 |
| Participants in Run-in Period | Lost to Follow-up | 0 | 0 | 5 |
| Participants in Run-in Period | Withdrawal by Subject | 0 | 0 | 3 |
| Participants Randomized | Death | 1 | 0 | 0 |
| Participants Randomized | Lost to Follow-up | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total Enrolled at run-in |
|---|---|
| Age, Continuous | 53.73 Years STANDARD_DEVIATION 9.69 |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 57 / 78 | 20 / 24 | 21 / 26 | 16 / 24 | 15 / 26 |
| serious Total, serious adverse events | 25 / 78 | 4 / 24 | 9 / 26 | 4 / 24 | 9 / 26 |
Outcome results
Primary
Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR)
Renal function was assessed by eGFR using the MDRD-4 formula at 12 months after transplant: eGFR = 186.3 \* (serum creatinine)-1.154 \* age-0.203 \* (0.742 for women) \* (1.21 if African American) where serum creatinine was in mg/dL and age in years.
Time frame: At 12 months post-transplant
Population: The safety population, which included all randomized participants who received at least one dose of study medication post-randomization, was considered for the analysis. eGFR values missing at 12 months post transplantation were imputed using the Last Observation carried Forward (LOCF) approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Tacrolimus Elimination Arm) | Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR) | 85.50 mL/min/1.73m^2 | Standard Error 3.97 |
| Group B (Tacrolimus Minimization Arm) | Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR) | 80.26 mL/min/1.73m^2 | Standard Error 3.87 |
p-value: 0.301395% CI: [-4.86, 15.34]ANOVA
Secondary
Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant
Blood samples were collected to assess serum creatinine.
Time frame: baseline, 12 months post-transplant
Population: The safety population, which included all randomized participants who received at least one dose of study medication post-randomization, was considered for the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Tacrolimus Elimination Arm) | Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant | -0.11 mg/dL | Standard Error 0.04 |
| Group B (Tacrolimus Minimization Arm) | Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant | -0.05 mg/dL | Standard Error 0.03 |
Secondary
Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D)
Participants were assessed for tBPAR, AR, GL or death. For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, a liver biopsy was to be performed preferably within 24 hours, latest within 48 hours whenever clinically possible. A treated biopsy proven acute rejection was considered an episode of acute rejection when demonstrated by local pathology reading with a rejection activity index of at least 3 or greater of acute rejection index and when treated with anti-rejection therapy. The allograft was considered lost on the day the subject was re-transplanted or died due to liver failure.
Time frame: At 12 and 18 months post-transplant
Population: The safety population, which included all randomized participants who received at least one dose of study medication post-randomization, was considered for the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | tBPAR, 12 months | 2 Participants |
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | AR, 12 months | 2 Participants |
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | GL, 12 months | 0 Participants |
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | Death, 12 months | 1 Participants |
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | tBPAR, 18 months | 2 Participants |
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | AR, 18 months | 2 Participants |
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | GL, 18 months | 0 Participants |
| Group A (Tacrolimus Elimination Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | Death, 18 months | 1 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | Death, 18 months | 1 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | tBPAR, 12 months | 1 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | tBPAR, 18 months | 1 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | AR, 12 months | 1 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | GL, 18 months | 0 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | GL, 12 months | 0 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | AR, 18 months | 1 Participants |
| Group B (Tacrolimus Minimization Arm) | Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D) | Death, 12 months | 0 Participants |