Liver Transplantation
Conditions
Brief summary
This two-arm study will assess the efficacy and safety of a long-term calcineurin inhibitor-free maintenance regimen with CellCept and sirolimus in recipients of an orthotropic liver transplant. Patients will be randomized to receive either CellCept 1-1.5 g twice daily (BID) + tacrolimus + cyclosporine, or CellCept 1-1.5 g BID + sirolimus. The anticipated time on study treatment is 1 to 2 years, and the target sample size is 100 to 500 individuals.
Interventions
1-1.5 g orally or intravenously twice daily
DRUGTacrolimus
As prescribed, for 12 months
DRUGCyclosporine
As prescribed, for 12 months
DRUGSirolimus
2-4 mg orally once daily for 9-11 months
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Adult patients 18-74 years of age * Single primary liver transplant from a deceased donor * CellCept plus tacrolimus or cyclosporine from time of transplantation (within 72 hours) * Patients with hepatitis C-positive status may be entered if they have had an intraoperative (back table) biopsy of the transplanted liver or will have a biopsy at the time of randomization. This is not required for patients negative for hepatitis C.
Exclusion criteria
* Liver allograft from a living donor or a split liver * Multiple organ transplant * Dialysis therapy for \>14 days from transplantation to randomization * History of malignancy in the last 5 years (except hepatoma or non-melanoma skin cancer) * Previous sirolimus therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glomerular Filtration Rate (GFR) at 12 Months Posttransplant | 12 months posttransplant | Mean percent change from baseline in estimated glomerular filtration rate (GFR) calculated by modification of diet in renal disease (MDRD)-6 variable equation at 12 months posttransplantation. MDRD-6 variables: serum creatinine, albumin and urea nitrogen, gender, age and ethnicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glomerular Filtration Rate (GFR) at 6 Months Posttransplant | 6 months posttransplant | Mean percent change from baseline in estimated GFR calculated by modification of diet in renal disease (MDRD)-6 variable equation at 6 and 24 months posttransplantation. MDRD-6 variables: serum creatinine, albumin and urea nitrogen, gender, age and ethnicity. |
| Change From Baseline in Glomerular Filtration Rate (GFR) at 24 Months Posttransplant | 24 months posttransplant | Mean percent change from baseline in estimated GFR calculated by modification of diet in renal disease (MDRD)-6 variable equation at 6 and 24 months posttransplantation. MDRD-6 variables: serum creatinine, albumin and urea nitrogen, gender, age and ethnicity. |
| Change From Baseline in Creatinine Clearance | 6, 12, and 24 months posttransplantation | Mean percent change from baseline in calculated creatinine clearance (CL) at 6, 12, and 24 months posttransplantation |
Countries
Canada, United States
Participant flow
Recruitment details
Patients were recruited from 43 study centers in the US and Canada over a period of 3 years (24-Aug-05 to 03-Jul-08)
Pre-assignment details
Eligible for the study were adult patients (18 to 74 years) who had received a single primary orthotopic liver transplant and were receiving or were scheduled to receive treatment with CellCept® + calcineurin inhibitor (CNI)
Participants by arm
| Arm | Count |
|---|---|
| CellCept + CNI (Tacrolimus or Cyclosporine) CellCept 1-1.5 g orally or intravenously twice daily, plus a calcineurin inhibitor (CNI) tacrolimus or cyclosporine for 12 months | 145 |
| CellCept + Sirolimus CellCept 1-1.5 g orally or intravenously twice daily, plus sirolimus 2-4 mg orally once daily for 9-11 months | 148 |
| Total | 293 |
Baseline characteristics
| Characteristic | CellCept + CNI (Tacrolimus or Cyclosporine) | CellCept + Sirolimus | Total |
|---|---|---|---|
| Age Continuous | 53.4 years STANDARD_DEVIATION 7.88 | 53.2 years STANDARD_DEVIATION 8.83 | 53.3 years STANDARD_DEVIATION 8.36 |
| Height | 173.6 cm STANDARD_DEVIATION 10.04 | 173.0 cm STANDARD_DEVIATION 10.26 | 173.3 cm STANDARD_DEVIATION 10.14 |
| Race/Ethnicity, Customized American Indian | 3 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized Asian or Pacific Islander | 3 participants | 11 participants | 14 participants |
| Race/Ethnicity, Customized Black | 11 participants | 8 participants | 19 participants |
| Race/Ethnicity, Customized Other | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 126 participants | 125 participants | 251 participants |
| Sex: Female, Male Female | 35 Participants | 38 Participants | 73 Participants |
| Sex: Female, Male Male | 110 Participants | 110 Participants | 220 Participants |
| Weight | 79 kg STANDARD_DEVIATION 16.32 | 77.9 kg STANDARD_DEVIATION 17.56 | 78.4 kg STANDARD_DEVIATION 16.94 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 134 / 146 | 141 / 148 |
| serious Total, serious adverse events | 65 / 146 | 67 / 148 |
Outcome results
Primary
Change From Baseline in Glomerular Filtration Rate (GFR) at 12 Months Posttransplant
Mean percent change from baseline in estimated glomerular filtration rate (GFR) calculated by modification of diet in renal disease (MDRD)-6 variable equation at 12 months posttransplantation. MDRD-6 variables: serum creatinine, albumin and urea nitrogen, gender, age and ethnicity.
Time frame: 12 months posttransplant
Population: intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept + CNI (Tacrolimus or Cyclosporine) | Change From Baseline in Glomerular Filtration Rate (GFR) at 12 Months Posttransplant | 1.2 Percent change in GFR (mL/min) | Standard Deviation 39.86 |
| CellCept + Sirolimus | Change From Baseline in Glomerular Filtration Rate (GFR) at 12 Months Posttransplant | 19.7 Percent change in GFR (mL/min) | Standard Deviation 40.64 |
p-value: 0.001295% CI: [14.8, 35]ANCOVA
Secondary
Change From Baseline in Creatinine Clearance
Mean percent change from baseline in calculated creatinine clearance (CL) at 6, 12, and 24 months posttransplantation
Time frame: 6, 12, and 24 months posttransplantation
Population: intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CellCept + CNI (Tacrolimus or Cyclosporine) | Change From Baseline in Creatinine Clearance | 6 months | -1.3 Percent change in creatinine CL (mL/min) | Standard Deviation 23.71 |
| CellCept + CNI (Tacrolimus or Cyclosporine) | Change From Baseline in Creatinine Clearance | 12 months | -3.0 Percent change in creatinine CL (mL/min) | Standard Deviation 35.86 |
| CellCept + CNI (Tacrolimus or Cyclosporine) | Change From Baseline in Creatinine Clearance | 24 months | -12.8 Percent change in creatinine CL (mL/min) | Standard Deviation 41.64 |
| CellCept + Sirolimus | Change From Baseline in Creatinine Clearance | 6 months | 18.5 Percent change in creatinine CL (mL/min) | Standard Deviation 39.93 |
| CellCept + Sirolimus | Change From Baseline in Creatinine Clearance | 12 months | 14.0 Percent change in creatinine CL (mL/min) | Standard Deviation 35.16 |
| CellCept + Sirolimus | Change From Baseline in Creatinine Clearance | 24 months | 7.9 Percent change in creatinine CL (mL/min) | Standard Deviation 44.36 |
Comparison: Statistical analysis for calculated creatinine clearance at 6 months posttransplantp-value: <0.000195% CI: [12.5, 29.6]ANCOVA
Comparison: Statistical analysis for calculated creatinine clearance at 12 months posttransplantp-value: <0.000195% CI: [9.9, 26.6]ANCOVA
Comparison: Statistical analysis for calculated creatinine clearance at 24 months posttransplantp-value: 0.000695% CI: [10.2, 37]ANCOVA
Secondary
Change From Baseline in Glomerular Filtration Rate (GFR) at 24 Months Posttransplant
Mean percent change from baseline in estimated GFR calculated by modification of diet in renal disease (MDRD)-6 variable equation at 6 and 24 months posttransplantation. MDRD-6 variables: serum creatinine, albumin and urea nitrogen, gender, age and ethnicity.
Time frame: 24 months posttransplant
Population: intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept + CNI (Tacrolimus or Cyclosporine) | Change From Baseline in Glomerular Filtration Rate (GFR) at 24 Months Posttransplant | -8.6 Mean percent change in GFR (mL/min) | Standard Deviation 43.37 |
| CellCept + Sirolimus | Change From Baseline in Glomerular Filtration Rate (GFR) at 24 Months Posttransplant | 13.5 Mean percent change in GFR (mL/min) | Standard Deviation 49.17 |
p-value: 0.005395% CI: [13.7, 43.7]ANCOVA
Secondary
Change From Baseline in Glomerular Filtration Rate (GFR) at 6 Months Posttransplant
Mean percent change from baseline in estimated GFR calculated by modification of diet in renal disease (MDRD)-6 variable equation at 6 and 24 months posttransplantation. MDRD-6 variables: serum creatinine, albumin and urea nitrogen, gender, age and ethnicity.
Time frame: 6 months posttransplant
Population: intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept + CNI (Tacrolimus or Cyclosporine) | Change From Baseline in Glomerular Filtration Rate (GFR) at 6 Months Posttransplant | 1.1 Percent change in GFR (mL/min) | Standard Deviation 24.39 |
| CellCept + Sirolimus | Change From Baseline in Glomerular Filtration Rate (GFR) at 6 Months Posttransplant | 25.5 Percent change in GFR (mL/min) | Standard Deviation 45.82 |
p-value: <0.000195% CI: [15.7, 35.6]ANCOVA