Liver Transplantation
Conditions
Keywords
Liver transplantation, Everolimus, Tacrolimus, Renal function
Brief summary
This trial evaluated the efficacy and safety of Everolimus in combination with tacrolimus versus a standard immunosuppressive regimen concerning kidney function in liver transplant recipients.
Interventions
DRUGEverolimus
tablet containing 0.25mg, 0.5mg, 0.75mg or 1.0mg
DRUGTacrolimus
capsule containing 0.5, 1.0, or 5.0mg
DRUGCorticosteroids
For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids may have been used for the duration of the study according to the investigator's discretion, but may not have been eliminated sooner than 6 months post-transplantation.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Male or female recipients of a full-size liver allograft, aged 18 to 65 years.
Exclusion criteria
Patients with thrombocytopenia (platelets \<50,000/mm³), with an absolute neutrophil count of \<1,000/mm³ or leucopenia (leucocytes \<2000/mm³), with anemia with Hb \< 6g/dl at time of randomization Patients with uncontrolled hypercholesterolemia (\>350mg/dL; \>9mmol/L) or hypertriglyceridemia (\>750 mg/dL; \>8.5 mmol/L) at time of randomization 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 |
|---|---|---|
| Estimated Glomerular Filtration Rate (GFR) | month 12 | The estmated GFR was calculated using MDRD-4 formula (Modification of Diet in Renal Disease Study Group). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | 12 months | Percentage of Participants with Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death at Month 12 |
| Number of Participants With HCV | 12 months | Number of Participants with HCV (hepatitis C virus) assessed as treatment emergent adverse events of special interest |
| Estimated GFR - PP Set | month 12 | This was a sensitivity analysis for the primary outcome measure based on the per-protocol set of patients. |
| Incidence of de Novo HCC Malignancies | 12 months | Incidence of de novo Hepatocellular Carcinoma (HCC) malignancies assessed as treatment emergent adverse events of special interest |
| Incidence and Severity of CMV Viral Infections. | 12 months | Incidence and severity of cytomegalovirus (CMV) viral infections assessed as treatment emergent adverse events of special interest. |
| Incidence of HCV Related Fibrosis | 12 months | Incidence of hepatitis C virus (HCV) related fibrosis assessed as treatment emergent adverse events of special interest |
Countries
Germany
Participant flow
Recruitment details
In total, 642 patients were screened for study eligibility at 15 study centers in Germany. 339 patients were randomized out of which 333 received study treatment and were included in the analyses.
Pre-assignment details
Patients were screened for eligibility prior to liver transplantation (LTx). The study treatment started after a run-in period that ended on the day of randomization, scheduled at Day 7-21 post-LTx. Patients may have been initiated on an optional induction therapy, MMF, TAC at investigators' discretion.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus/Tacrolimus Tacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: \< 5 ng/mL) | 169 |
| Tacrolimus Tacrolimus (C0-h: 6-10 ng/ml) | 164 |
| Total | 333 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 1 | 2 |
| Overall Study | Death | 2 | 4 |
| Overall Study | Graft loss/Retransplantation | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Never Received Study Treatment | 2 | 4 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 7 |
Baseline characteristics
| Characteristic | Tacrolimus | Everolimus/Tacrolimus | Total |
|---|---|---|---|
| Age, Continuous | 53.46 Years STANDARD_DEVIATION 9.64 | 53.68 Years STANDARD_DEVIATION 9.38 | 53.57 Years STANDARD_DEVIATION 9.49 |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Caucasian | 157 Participants | 168 Participants | 325 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Female | 43 Participants | 36 Participants | 79 Participants |
| Sex: Female, Male Male | 121 Participants | 133 Participants | 254 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 169 | 4 / 164 |
| other Total, other adverse events | 164 / 169 | 153 / 164 |
| serious Total, serious adverse events | 111 / 169 | 101 / 164 |
Outcome results
Primary
Estimated Glomerular Filtration Rate (GFR)
The estmated GFR was calculated using MDRD-4 formula (Modification of Diet in Renal Disease Study Group).
Time frame: month 12
Population: FAS (Full Analysis Set - All Randomized AND Treated Patients) with LOCF (last observation carried forward)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus/Tacrolimus | Estimated Glomerular Filtration Rate (GFR) | 73.46 mL/min | Standard Deviation 25.57 |
| Tacrolimus | Estimated Glomerular Filtration Rate (GFR) | 71.95 mL/min | Standard Deviation 27.17 |
p-value: 0.09795% CI: [-0.74, 8.91]ANCOVA
Secondary
Estimated GFR - PP Set
This was a sensitivity analysis for the primary outcome measure based on the per-protocol set of patients.
Time frame: month 12
Population: Per Protocol Set (PP)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus/Tacrolimus | Estimated GFR - PP Set | 74.83 mL/min | Standard Deviation 25.19 |
| Tacrolimus | Estimated GFR - PP Set | 70.65 mL/min | Standard Deviation 24.91 |
p-value: 0.008595% CI: [2.06, 13.92]ANCOVA
Secondary
Incidence and Severity of CMV Viral Infections.
Incidence and severity of cytomegalovirus (CMV) viral infections assessed as treatment emergent adverse events of special interest.
Time frame: 12 months
Population: Safety Set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus/Tacrolimus | Incidence and Severity of CMV Viral Infections. | Asymptomatic | 0 Participants |
| Everolimus/Tacrolimus | Incidence and Severity of CMV Viral Infections. | Moderate | 13 Participants |
| Everolimus/Tacrolimus | Incidence and Severity of CMV Viral Infections. | Mild | 16 Participants |
| Everolimus/Tacrolimus | Incidence and Severity of CMV Viral Infections. | Severe | 4 Participants |
| Everolimus/Tacrolimus | Incidence and Severity of CMV Viral Infections. | No CMV viral infection | 136 Participants |
| Tacrolimus | Incidence and Severity of CMV Viral Infections. | Severe | 1 Participants |
| Tacrolimus | Incidence and Severity of CMV Viral Infections. | Asymptomatic | 5 Participants |
| Tacrolimus | Incidence and Severity of CMV Viral Infections. | Mild | 20 Participants |
| Tacrolimus | Incidence and Severity of CMV Viral Infections. | Moderate | 9 Participants |
| Tacrolimus | Incidence and Severity of CMV Viral Infections. | No CMV viral infection | 129 Participants |
Secondary
Incidence of de Novo HCC Malignancies
Incidence of de novo Hepatocellular Carcinoma (HCC) malignancies assessed as treatment emergent adverse events of special interest
Time frame: 12 months
Population: Safety Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Everolimus/Tacrolimus | Incidence of de Novo HCC Malignancies | 0 Participants |
| Tacrolimus | Incidence of de Novo HCC Malignancies | 2 Participants |
Secondary
Incidence of HCV Related Fibrosis
Incidence of hepatitis C virus (HCV) related fibrosis assessed as treatment emergent adverse events of special interest
Time frame: 12 months
Population: Safety Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Everolimus/Tacrolimus | Incidence of HCV Related Fibrosis | 1 Participants |
| Tacrolimus | Incidence of HCV Related Fibrosis | 0 Participants |
Secondary
Number of Participants With HCV
Number of Participants with HCV (hepatitis C virus) assessed as treatment emergent adverse events of special interest
Time frame: 12 months
Population: Safety Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Everolimus/Tacrolimus | Number of Participants With HCV | 6 Participants |
| Tacrolimus | Number of Participants With HCV | 12 Participants |
Secondary
Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death
Percentage of Participants with Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death at Month 12
Time frame: 12 months
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus/Tacrolimus | Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | 9.5 Percent of Patients |
| Tacrolimus | Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | 7.9 Percent of Patients |
p-value: 0.699Fisher Exact