Kidney Transplantation
Conditions
Brief summary
This 2 arm study will compare the efficacy and safety of CellCept, combined with low or standard dose tacrolimus plus corticosteroids, in patients with kidney transplants. Patients will be randomized into one of 2 groups to receive either 1)CellCept 2.0g/day po bid + tacrolimus 10-12ng/mL followed by a maintenance dose of 8-10ng/mL + corticosteroids or 2)CellCept 2.0g/day po bid + tacrolimus 8-10ng/mL in the first 2 months,3-7ng/mL in month 3 followed by a maintenance dose of 3-5ng/mL + corticosteroids. The anticipated time on study treatment is 1 year, and the target sample size is 100-500 individuals.
Interventions
DRUGtacrolimus, low dose
Initial dose of 0.1-0.15 mg/kg PO BID to reach a target trough dose of 8 to 10 ng/mL from Day 0 through Month 3; 0.05-0.08 mg/kg PO BID to reach a target trough dose of 2-5 ng/mL in Month 3 and continued through Month 12.
DRUGcorticosteroids
According to center's practice
DRUGmycophenolate mofetil
0.75-1 g PO BID from Day 0 through Month 12
DRUGtacrolimus, standard dose
Initial dose of 0.1-0.15 mg/kg PO BID to reach a target trough dose of 8-10 ng/mL from Day 0 through Month 3; the dose was adjusted to reach a target trough level of 7-10 ng/mL in Month 3 and continued through Month 12.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 75 Years
Healthy volunteers
No
Inclusion criteria
* adult patients, \<=75 years of age; * single organ recipients of renal allograft; * negative pregnancy test for women of childbearing potential; reliable contraception must be used before starting drug therapy, until 6 weeks after the last dose of study medication.
Exclusion criteria
* severe gastrointestinal disease which may influence the absorption of oral drug therapy; * severe infection, HIV or active hepatitis; * active gastric ulcers; * malignancy other than cured skin cancer; * severe anemia, leucopenia or thrombocytopenia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chronic Allograft Damage Index (CADI) Score at Month 12 After Transplantation | Month 12 | CADI scoring was defined for 6 histological categories: interstitial inflammatory cell infiltration (0 equals (=) no or mild inflammation, 1=approximately (\ )25 percent (%) cell infiltration, 2=26-50% cell infiltration, and 3=greater than (\>)50% cell infiltration); interstitial fibrosis (0=none, 1=\ 25% interstitial affected, 2=26-50% interstitial affected, and 3=\>50% interstitial affected); tubular atrophy (0=none, 1=\ 15% proximal tubular atrophy \[PTA\], 2=16-30% PTA, and 3=\>30% PTA); mesangial matrix proliferation (MMP; 0=none, 1=25% non-glomerulosclerosis \[NGS\] combined with moderate MMP, 2=25-50% NGS combined with MMP, and 3=\>50% NGS combined with MMP); glomerular sclerosis (0=none, 1=\ 15% glomerulus affected, 2=16-50% glomerulus affected, and 3=\>50% glomerulus affected); endothelial proliferation (EP; 0=none, 1=EP to less than (\<)25% remaining artery/small artery membrane \[RA/SAM\], 2=EP to 26-50% \[RA/SAM\], and 3=\>50% \[RA/SAM\]). CADI score was the sum of the 6 histological findings. |
| Glomerular Filtration Rate (GFR) at Month 12 After Transplantation | Month 12 | GFR was determined using the Cockcroft-Gault formula to calculate the creatinine clearance, at Month 12 after renal transplantation. For males, creatinine clearance \[milliliters per minute (mL/min)\] = \[(140 minus age) multiplied by (\*) (body weight in kg) divided by \[72 \* serum creatinine mg per deciliter (mg/dL)\]. For females, creatinine clearance (mL/min) = 0.85 \* \[(140 minus age) \* (body weight in kg)\] divided by \[72 \* serum creatinine (mg/dL)\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Acute Rejection Post-Transplant | BL, Weeks 2, 4, 13, 26, 39, and 52 | The median time, in days, between randomization and acute rejection. |
| Percentage of Participants With Treatment Failure at 12 Months Post-Transplant | Month 12 | Treatment failure was defined by the occurrence of any of the following: use of additional maintenance immunosuppressive medication not specified in the assigned treatment group; discontinuation of any of the assigned immunosuppressants for more than 14 consecutive days or 30 cumulative days; graft loss or return to chronic dialysis; or death. |
| Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Months 6 and 12 | — |
| Serum Creatinine (Micromoles Per Liter [µmol/L]) | BL, Weeks 2, 4, 13, 26, 39, and 52 | The mean serum creatinine values in µmol/L at Baseline (BL), Weeks 2, 4, 13, 26, 39, and 52. |
| Glomerular Filtration Rate (GFR) (mL/Min) | BL, Weeks 2, 4, 13, 26, 39, and 52 | The mean GFR values in mL/min at BL, Weeks 2, 4, 13, 26, 39, and 52. |
| Participant and Graft Survival | Months 6 and 12 | The percentage of participants surviving with grafts intact at 6 and 12 months after renal transplant. |
| Time to First Acute Rejection Post-Transplant - Number of Participants With an Event | BL, Weeks 2, 4, 13, 26, 39, and 52 | — |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MMF, Standard Dose Tacrolimus Participants received MMF capsules, 0.75-1 g PO, BID from Day 0 through Month 12 (maximum dose administered was 1.5 g BID, at discretion of investigator). Participants also received tacrolimus PO, BID, dosed to reach a target trough level of 10-12 ng/mL from Day 0 through Month 3; the dose was adjusted to reach a target trough level of 8-10 ng/mL in Month 3 and continued through Month 12. Participants also received intraoperative and maintenance corticosteroids per center practice. | 104 |
| MMF, Low Dose Tacrolimus Participants received MMF capsules, 0.75-1 g PO, BID from Day 0 through Month 12 (maximum dose administered was 1.5 g BID, at discretion of investigator. Participants also received tacrolimus PO, BID, dosed to reach a target trough level of 8-10 ng/mL from Day 0 through Month 2; the dose was adjusted reach a target trough level of 3-7 ng/mL in Month 3 and adjusted to achieve a target trough level of 3-5 ng/mL thereafter, through Month 12. Participants also received intraoperative and maintenance corticosteroids per center practice. | 106 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 10 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Reason not specified | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | MMF, Standard Dose Tacrolimus | MMF, Low Dose Tacrolimus | Total |
|---|---|---|---|
| Age, Continuous | 37.9 years STANDARD_DEVIATION 11.05 | 39.6 years STANDARD_DEVIATION 10.16 | 38.8 years STANDARD_DEVIATION 10.62 |
| Sex: Female, Male Female | 29 Participants | 34 Participants | 63 Participants |
| Sex: Female, Male Male | 75 Participants | 72 Participants | 147 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 104 | 37 / 106 |
| serious Total, serious adverse events | 1 / 104 | 5 / 106 |
Outcome results
Primary
Chronic Allograft Damage Index (CADI) Score at Month 12 After Transplantation
CADI scoring was defined for 6 histological categories: interstitial inflammatory cell infiltration (0 equals (=) no or mild inflammation, 1=approximately (\ )25 percent (%) cell infiltration, 2=26-50% cell infiltration, and 3=greater than (\>)50% cell infiltration); interstitial fibrosis (0=none, 1=\ 25% interstitial affected, 2=26-50% interstitial affected, and 3=\>50% interstitial affected); tubular atrophy (0=none, 1=\ 15% proximal tubular atrophy \[PTA\], 2=16-30% PTA, and 3=\>30% PTA); mesangial matrix proliferation (MMP; 0=none, 1=25% non-glomerulosclerosis \[NGS\] combined with moderate MMP, 2=25-50% NGS combined with MMP, and 3=\>50% NGS combined with MMP); glomerular sclerosis (0=none, 1=\ 15% glomerulus affected, 2=16-50% glomerulus affected, and 3=\>50% glomerulus affected); endothelial proliferation (EP; 0=none, 1=EP to less than (\<)25% remaining artery/small artery membrane \[RA/SAM\], 2=EP to 26-50% \[RA/SAM\], and 3=\>50% \[RA/SAM\]). CADI score was the sum of the 6 histological findings.
Time frame: Month 12
Population: ITT population; only participants with biopsy confirmed CADI assessment 12 months post-transplantation were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF, Standard Dose Tacrolimus | Chronic Allograft Damage Index (CADI) Score at Month 12 After Transplantation | 1.82 score on a scale | Standard Deviation 1.974 |
| MMF, Low Dose Tacrolimus | Chronic Allograft Damage Index (CADI) Score at Month 12 After Transplantation | 2.13 score on a scale | Standard Deviation 2 |
p-value: 0.081395% CI: [-0.08, 1.4]ANCOVA
Primary
Glomerular Filtration Rate (GFR) at Month 12 After Transplantation
GFR was determined using the Cockcroft-Gault formula to calculate the creatinine clearance, at Month 12 after renal transplantation. For males, creatinine clearance \[milliliters per minute (mL/min)\] = \[(140 minus age) multiplied by (\*) (body weight in kg) divided by \[72 \* serum creatinine mg per deciliter (mg/dL)\]. For females, creatinine clearance (mL/min) = 0.85 \* \[(140 minus age) \* (body weight in kg)\] divided by \[72 \* serum creatinine (mg/dL)\].
Time frame: Month 12
Population: ITT population; only participants with assessable parameters for the calculation of GFR were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) at Month 12 After Transplantation | 77.08 mL/min | Standard Deviation 18.25 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) at Month 12 After Transplantation | 80.12 mL/min | Standard Deviation 18.362 |
p-value: 0.794995% CI: [-13.77, 10.58]ANCOVA
Secondary
Glomerular Filtration Rate (GFR) (mL/Min)
The mean GFR values in mL/min at BL, Weeks 2, 4, 13, 26, 39, and 52.
Time frame: BL, Weeks 2, 4, 13, 26, 39, and 52
Population: ITT population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 4 (n=99,98) | 71.77 mL/min | Standard Deviation 23.578 |
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 26 (n=84,83) | 75.92 mL/min | Standard Deviation 21.046 |
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 2 (n=101,102) | 67.95 mL/min | Standard Deviation 30.14 |
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 39 (n=83,77) | 77.34 mL/min | Standard Deviation 19.046 |
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 13 (n=88,91) | 78.13 mL/min | Standard Deviation 18.686 |
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 52 (n=86,82) | 77.08 mL/min | Standard Deviation 18.25 |
| MMF, Standard Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Baseline (n=95,96) | 14.37 mL/min | Standard Deviation 8.08 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 52 (n=86,82) | 80.12 mL/min | Standard Deviation 18.362 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Baseline (n=95,96) | 15.41 mL/min | Standard Deviation 13.759 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 2 (n=101,102) | 71.02 mL/min | Standard Deviation 22.177 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 4 (n=99,98) | 72.87 mL/min | Standard Deviation 19.934 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 13 (n=88,91) | 75.71 mL/min | Standard Deviation 17.906 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 26 (n=84,83) | 76.77 mL/min | Standard Deviation 17.536 |
| MMF, Low Dose Tacrolimus | Glomerular Filtration Rate (GFR) (mL/Min) | Week 39 (n=83,77) | 78.00 mL/min | Standard Deviation 16.036 |
Secondary
Participant and Graft Survival
The percentage of participants surviving with grafts intact at 6 and 12 months after renal transplant.
Time frame: Months 6 and 12
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF, Standard Dose Tacrolimus | Participant and Graft Survival | 6 months post-transplant | 100.0 percentage of participants |
| MMF, Standard Dose Tacrolimus | Participant and Graft Survival | 12 months post-transplant | 100.0 percentage of participants |
| MMF, Low Dose Tacrolimus | Participant and Graft Survival | 6 months post-transplant | 100.0 percentage of participants |
| MMF, Low Dose Tacrolimus | Participant and Graft Survival | 12 months post-transplant | 99.1 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant
Time frame: Months 6 and 12
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF, Standard Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Acute rejection, 6 months post-transplant | 2.6 percentage of participants |
| MMF, Standard Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Acute rejection, 12 months post-transplant | 2.6 percentage of participants |
| MMF, Standard Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Graft loss, 6 months post-transplant | 0.0 percentage of participants |
| MMF, Standard Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Graft loss, 12 months post-transplant | 0.0 percentage of participants |
| MMF, Standard Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Death, 6 months post-transplant | 0.0 percentage of participants |
| MMF, Standard Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Death, 12 months post-transplant | 0.0 percentage of participants |
| MMF, Low Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Death, 6 months post-transplant | 0.0 percentage of participants |
| MMF, Low Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Acute rejection, 6 months post-transplant | 5.2 percentage of participants |
| MMF, Low Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Graft loss, 12 months post-transplant | 0.0 percentage of participants |
| MMF, Low Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Acute rejection, 12 months post-transplant | 5.2 percentage of participants |
| MMF, Low Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Death, 12 months post-transplant | 0.9 percentage of participants |
| MMF, Low Dose Tacrolimus | Percentage of Participants Experiencing Acute Rejection, Graft Loss, or Death at 6 and 12 Months Post-Transplant | Graft loss, 6 months post-transplant | 0.0 percentage of participants |
Comparison: Acute rejection, 6 months post-transplantp-value: 0.6812Fisher Exact
Comparison: Acute rejection, 12 months post-transplantp-value: 0.6812Fisher Exact
Comparison: Death, 12 months post-transplantp-value: 1Fisher Exact
Secondary
Percentage of Participants With Treatment Failure at 12 Months Post-Transplant
Treatment failure was defined by the occurrence of any of the following: use of additional maintenance immunosuppressive medication not specified in the assigned treatment group; discontinuation of any of the assigned immunosuppressants for more than 14 consecutive days or 30 cumulative days; graft loss or return to chronic dialysis; or death.
Time frame: Month 12
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, Standard Dose Tacrolimus | Percentage of Participants With Treatment Failure at 12 Months Post-Transplant | 9.6 percentage of participants |
| MMF, Low Dose Tacrolimus | Percentage of Participants With Treatment Failure at 12 Months Post-Transplant | 6.6 percentage of participants |
p-value: 0.4586Fisher Exact
Secondary
Serum Creatinine (Micromoles Per Liter [µmol/L])
The mean serum creatinine values in µmol/L at Baseline (BL), Weeks 2, 4, 13, 26, 39, and 52.
Time frame: BL, Weeks 2, 4, 13, 26, 39, and 52
Population: ITT population; n (number) = number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF, Standard Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 4 (n=99,98) | 118.47 µmol/L | Standard Deviation 76.134 |
| MMF, Standard Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 26 (n=84,83) | 105.70 µmol/L | Standard Deviation 45.403 |
| MMF, Standard Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 2 (n=101,102) | 154.57 µmol/L | Standard Deviation 151.374 |
| MMF, Standard Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 39 (n=83,77) | 102.22 µmol/L | Standard Deviation 38.035 |
| MMF, Standard Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 13 (n=88,91) | 97.52 µmol/L | Standard Deviation 24.947 |
| MMF, Standard Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 52 (n=86,82) | 103.10 µmol/L | Standard Deviation 48.251 |
| MMF, Standard Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Baseline (n=95,96) | 662.93 µmol/L | Standard Deviation 351.913 |
| MMF, Low Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 52 (n=86,82) | 94.19 µmol/L | Standard Deviation 21.964 |
| MMF, Low Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Baseline (n=95,96) | 639.70 µmol/L | Standard Deviation 287.044 |
| MMF, Low Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 2 (n=101,102) | 115.71 µmol/L | Standard Deviation 52.648 |
| MMF, Low Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 4 (n=99,98) | 107.08 µmol/L | Standard Deviation 32.668 |
| MMF, Low Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 13 (n=88,91) | 100.10 µmol/L | Standard Deviation 25.345 |
| MMF, Low Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 26 (n=84,83) | 97.51 µmol/L | Standard Deviation 21.997 |
| MMF, Low Dose Tacrolimus | Serum Creatinine (Micromoles Per Liter [µmol/L]) | Week 39 (n=83,77) | 95.16 µmol/L | Standard Deviation 20.877 |
Secondary
Time to First Acute Rejection Post-Transplant
The median time, in days, between randomization and acute rejection.
Time frame: BL, Weeks 2, 4, 13, 26, 39, and 52
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMF, Standard Dose Tacrolimus | Time to First Acute Rejection Post-Transplant | 40 days |
| MMF, Low Dose Tacrolimus | Time to First Acute Rejection Post-Transplant | 18 days |
p-value: 1Log Rank
Secondary
Time to First Acute Rejection Post-Transplant - Number of Participants With an Event
Time frame: BL, Weeks 2, 4, 13, 26, 39, and 52
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, Standard Dose Tacrolimus | Time to First Acute Rejection Post-Transplant - Number of Participants With an Event | 2 participants |
| MMF, Low Dose Tacrolimus | Time to First Acute Rejection Post-Transplant - Number of Participants With an Event | 4 participants |