Liver Transplantation
Conditions
Brief summary
This 2 arm study will compare the efficacy and safety of switching to CellCept combined with different regimens of reduced calcineurin inhibitors (CNI) in patients with liver transplants. Patients currently receiving CNI treatment will be randomized into one of 2 groups to receive either 1) CellCept 2.0g/day po bid + 50% reduction of CNI from baseline or 2) CellCept 2.0g/day po bid + \>=75% reduction of CNI from baseline. The anticipated time on study treatment is 1 year, and the target sample size is \<100 individuals.
Interventions
DRUGMycophenolate mofetil
1.5 to 2.0 g daily PO BID
DRUGCNI (50%)
50% reduction from BL
DRUGCNI (≥75%)
≥75% reduction from BL
Sponsors
Hoffmann-La Roche
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
* adult patients, \>=18 years of age; * single organ recipients of liver allograft; * CNI-based immunosuppressive regimen prior to study entry and regimen adjustment; * \>=6 months post-transplant, with renal dysfunction (serum creatinine 140-300micromol/L at entry); * negative pregnancy test for women of childbearing potential; contraception must be taken before beginning study drug therapy and until 6 weeks after last dose of study medication.
Exclusion criteria
* treatment with CellCept or any other product which delivers mycophenolic acid within the 3 months prior to the recent switch to CellCept relevant for enrollment; * known contraindications to CNI, corticosteroids or CellCept.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Decrease in Glomerular Filtration Rate (GFR) of Greater Than 20% | Week 52 | The percentage of participants with a greater than 20% decrease of GFR during the 1-year period following regimen adjustment. Cockcroft and Gault formula was used for calculated creatinine clearance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) at Week 52 | Week 52 | BPAR was graded according to Banff criteria. |
| Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Baseline and Weeks 16, 28, and 40 | Creatinine clearance calculated using the Cockcroft and Gault formula: For adult males, creatinine clearance in mL/min equaled (=) \[(140 minus (-) age in years) multiplied by (\*) (weight in kilograms (kg)\] divided by \[72 \* serum creatinine in milligrams per deciliter (mg/dL)\]. For adult females, creatinine clearance in mL/min = 0.85 \* \[(140 - age in years) \* (weight in kg)\] divided by (72 \* serum creatinine in mg/dL). |
| Percentage of Participants With Graft Loss or Death at Week 52 | Week 52 | Graft loss was defined for this protocol as re-transplantion or death. |
| Percentage Change in Creatinine Clearance From Baseline | Weeks 16, 28, 40, and 52 | Creatinine clearance was calculated using the Cockcroft and Gault formula. |
| Percentage of Participants Experiencing Acute Rejection, Graft Loss, Death, or a Decrease From BL in Creatinine Clearance of ≥20% at Week 52 | Week 52 | The percentage of participants who experienced at least 1 of the following: a ≥20% decrease from BL in creatinine clearance, acute rejection, graft loss, or death 1 year after randomization. |
| Change From Baseline in Corrected Creatinine Clearance (mL/Min) at Week 52 | Week 52 | Corrected creatinine clearance was calculated using the Cockcroft and Gault formula: For adult males, creatinine clearance in mL/min = \[(140 - age in years) \* (weight in kg\] divided by \[72 \* serum creatinine in mg/dL\]. For adult females, creatinine clearance in mL/min = 0.85 \* \[(140 - age in years) \* (weight in kg)\] divided by (72 \* serum creatinine in mg/dL). |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MMF, 50% CNI Participants received MMF capsules, 1.5 to 2.0 g, PO, BID up to Week 52. Participants also received a CNI (at discretion of investigator) at a reduced dosage of up to 50% through Week 52. The dosage of CNI was reduced to 25% of the dose at entry within the first week, and to 50% of the dose at entry within the first 2 weeks. This 50% reduced CNI dose was to be continued through Week 52. Corticosteroids were administered per documented center practice throughout the study with a goal of reducing steroid dose to 0 by 13 weeks post-transplant. | 37 |
| MMF, 75% CNI Participants received MMF capsules, 1.5 to 2.0 g, PO, BID up to Week 52. Participants also received a CNI (at discretion of investigator) at a reduced dosage of up to at least 75% through Week 52. The dosage of CNI was reduced to 50% of the dose at entry within the first 2 weeks, and to at least 75% of the dose at entry within the following 2 weeks. This 75% reduced CNI dose was to be continued through Week 52. Corticosteroids were administered per documented center practice throughout the study with a goal of reducing steroid dose to 0 by 13 weeks post-transplant. | 34 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | MMF, 50% CNI | MMF, 75% CNI | Total |
|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 8.7 | 52.4 years STANDARD_DEVIATION 11.1 | 52.6 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 33 Participants | 30 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 43 | 15 / 40 |
| serious Total, serious adverse events | 1 / 43 | 3 / 40 |
Outcome results
Primary
Percentage of Participants With Decrease in Glomerular Filtration Rate (GFR) of Greater Than 20%
The percentage of participants with a greater than 20% decrease of GFR during the 1-year period following regimen adjustment. Cockcroft and Gault formula was used for calculated creatinine clearance.
Time frame: Week 52
Population: PP population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, 50% CNI | Percentage of Participants With Decrease in Glomerular Filtration Rate (GFR) of Greater Than 20% | 5.4 percentage of participants |
| MMF, 75% CNI | Percentage of Participants With Decrease in Glomerular Filtration Rate (GFR) of Greater Than 20% | 0.0 percentage of participants |
p-value: 0.494ANOVA
Secondary
Change From Baseline in Corrected Creatinine Clearance (mL/Min) at Week 52
Corrected creatinine clearance was calculated using the Cockcroft and Gault formula: For adult males, creatinine clearance in mL/min = \[(140 - age in years) \* (weight in kg\] divided by \[72 \* serum creatinine in mg/dL\]. For adult females, creatinine clearance in mL/min = 0.85 \* \[(140 - age in years) \* (weight in kg)\] divided by (72 \* serum creatinine in mg/dL).
Time frame: Week 52
Population: PP population; number (n) = number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MMF, 50% CNI | Change From Baseline in Corrected Creatinine Clearance (mL/Min) at Week 52 | 6.551 mL/min |
| MMF, 75% CNI | Change From Baseline in Corrected Creatinine Clearance (mL/Min) at Week 52 | 6.442 mL/min |
95% CI: [-5.342, 5.561]
Secondary
Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min])
Creatinine clearance calculated using the Cockcroft and Gault formula: For adult males, creatinine clearance in mL/min equaled (=) \[(140 minus (-) age in years) multiplied by (\*) (weight in kilograms (kg)\] divided by \[72 \* serum creatinine in milligrams per deciliter (mg/dL)\]. For adult females, creatinine clearance in mL/min = 0.85 \* \[(140 - age in years) \* (weight in kg)\] divided by (72 \* serum creatinine in mg/dL).
Time frame: Baseline and Weeks 16, 28, and 40
Population: PP population; number (n) = number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF, 50% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Change at Week 16 (n=37,33) | 4.884 mL/min | Standard Deviation 6.016 |
| MMF, 50% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Baseline (n=36,31) | 1.385 mL/min | Standard Deviation 3.433 |
| MMF, 50% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Change at Week 40 (n=35,27) | 6.131 mL/min | Standard Deviation 9.148 |
| MMF, 50% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Change at Week 28 (n=34,33) | 5.333 mL/min | Standard Deviation 9.365 |
| MMF, 75% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Change at Week 40 (n=35,27) | 4.125 mL/min | Standard Deviation 10.802 |
| MMF, 75% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Baseline (n=36,31) | 2.250 mL/min | Standard Deviation 4.469 |
| MMF, 75% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Change at Week 28 (n=34,33) | 4.560 mL/min | Standard Deviation 8.325 |
| MMF, 75% CNI | Changes From Baseline in Creatinine Clearance (Milliliters Per Minute [mL/Min]) | Change at Week 16 (n=37,33) | 5.629 mL/min | Standard Deviation 8.825 |
Comparison: Between group comparison at Baselinep-value: 0.374ANOVA
Comparison: Change from Baseline at Week 16p-value: 0.685ANCOVA
Comparison: Change from Baseline at Week 28p-value: 0.722ANCOVA
Comparison: Change from Baseline at Week 40p-value: 0.432ANCOVA
Secondary
Percentage Change in Creatinine Clearance From Baseline
Creatinine clearance was calculated using the Cockcroft and Gault formula.
Time frame: Weeks 16, 28, 40, and 52
Population: PP population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF, 50% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 52 (n=37,34) | 10.17 percentage change from baseline | Standard Deviation 20.63 |
| MMF, 50% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 16 (n=37,33) | 10.38 percentage change from baseline | Standard Deviation 13.97 |
| MMF, 50% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 28 (n=34,33) | 11.45 percentage change from baseline | Standard Deviation 19.87 |
| MMF, 50% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 40 (n=35,27) | 12.37 percentage change from baseline | Standard Deviation 19.14 |
| MMF, 75% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 40 (n=35,27) | 7.03 percentage change from baseline | Standard Deviation 17.86 |
| MMF, 75% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 52 (n=37,34) | 11.51 percentage change from baseline | Standard Deviation 16.2 |
| MMF, 75% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 28 (n=34,33) | 7.51 percentage change from baseline | Standard Deviation 12.53 |
| MMF, 75% CNI | Percentage Change in Creatinine Clearance From Baseline | Week 16 (n=37,33) | 8.72 percentage change from baseline | Standard Deviation 13.45 |
Comparison: Change from Baseline at Week 16p-value: 0.616ANCOVA
Comparison: Change from Baseline at Week 28p-value: 0.334ANCOVA
Comparison: Change from Baseline at Week 40p-value: 0.267ANCOVA
Comparison: Change from Baseline at Week 52p-value: 0.764ANCOVA
Secondary
Percentage of Participants Experiencing Acute Rejection, Graft Loss, Death, or a Decrease From BL in Creatinine Clearance of ≥20% at Week 52
The percentage of participants who experienced at least 1 of the following: a ≥20% decrease from BL in creatinine clearance, acute rejection, graft loss, or death 1 year after randomization.
Time frame: Week 52
Population: PP population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, 50% CNI | Percentage of Participants Experiencing Acute Rejection, Graft Loss, Death, or a Decrease From BL in Creatinine Clearance of ≥20% at Week 52 | 8.1 percentage of participants |
| MMF, 75% CNI | Percentage of Participants Experiencing Acute Rejection, Graft Loss, Death, or a Decrease From BL in Creatinine Clearance of ≥20% at Week 52 | 8.8 percentage of participants |
p-value: 1ANCOVA
Secondary
Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) at Week 52
BPAR was graded according to Banff criteria.
Time frame: Week 52
Population: PP population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, 50% CNI | Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) at Week 52 | 0.0 percentage of participants |
| MMF, 75% CNI | Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) at Week 52 | 5.9 percentage of participants |
Secondary
Percentage of Participants With Graft Loss or Death at Week 52
Graft loss was defined for this protocol as re-transplantion or death.
Time frame: Week 52
Population: PP population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF, 50% CNI | Percentage of Participants With Graft Loss or Death at Week 52 | Graft loss | 0.0 percentage of participants |
| MMF, 50% CNI | Percentage of Participants With Graft Loss or Death at Week 52 | Death | 0.0 percentage of participants |
| MMF, 75% CNI | Percentage of Participants With Graft Loss or Death at Week 52 | Graft loss | 0.0 percentage of participants |
| MMF, 75% CNI | Percentage of Participants With Graft Loss or Death at Week 52 | Death | 0.0 percentage of participants |