Kidney Transplantation
Conditions
Brief summary
This 2-arm study recruited kidney transplant patients who were receiving standard care of calcineurin inhibitors (CNIs, tacrolimus or cyclosporine), CellCept (1.0-1.5 g twice daily) and corticosteroids. They were either randomized to continue this regimen, or CNI therapy was discontinued and replaced by sirolimus therapy (in combination with CellCept and corticosteroids). The effect of these 2 regimens on efficacy, safety and kidney function was evaluated. The anticipated time on study treatment was 1-2 years, and the target sample size was 100-500 individuals.
Interventions
1.0-1.5 g oral dose twice daily
DRUGCorticosteroids
As prescribed
As prescribed
DRUGSirolimus
As prescribed
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Adult patients 18-75 years of age * Kidney transplant 30-180 days post-transplantation * Receipt of cyclosporine or tacrolimus, CellCept, and corticosteroids for greater than 14 days prior to study entry * No known contraindications to sirolimus
Exclusion criteria
* Multiple organ transplant recipients or secondary kidney transplant recipients * Corticosteroid-resistant rejection episode within 90 days prior to study entry or corticosteroid-sensitive rejection episode within 30 days prior to study entry * More than 1 biopsy-proven episode of acute rejection prior to study entry * Treated with sirolimus before the study * Organ transplant or expected organ transplant, other than kidney * History of malignancy in the last 5 years (except successfully treated localized non-melanotic skin cancer)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 12 | baseline to 12 months | The primary efficacy endpoint was mean percent change in renal function from baseline to 12 months postrandomization, as measured by Glomerular Filtration Rate utilizing renal clearance of cold iothalamate. percent change= \[(Glomerular Filtration Rate at Month 12-Glomerular Filtration Rate at baseline)/Glomerular Filtration Rate at baseline\]\*100 percent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 24 | Baseline to 24 months | A secondary efficacy endpoint was mean percent change in renal function from baseline to 24 months postrandomization, as measured by Glomerular Filtration Rate utilizing renal clearance of cold iothalamate. percent change= \[(Glomerular Filtration Rate at Month 24-Glomerular Filtration Rate at baseline)/Glomerular Filtration Rate at baseline\]\*100 percent. |
| Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | baseline, 6, 12, and 24 months | Renal allograft function determined by mean percent change from baseline in serum creatinine by treatment group at 6, 12, and 24 months postrandomization. percent change= \[(serum creatinine at Month t-serum creatinine at baseline)/serum creatinine at baseline\]\*100 percent, where t=6, 12, and 24 months postrandomization. |
| Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | baseline 6, 12, and 24 months | Renal allograft function determined by mean percent change from baseline in calculated creatinine clearance (Cockroft and Gault method) by treatment group at 6, 12, and 24 months postrandomization. percent change= \[(calculated creatinine clearance at Month t - calculated creatinine clearance at baseline)/calculated creatinine clearance at baseline\]\*100 percent, where t=6, 12, and 24 months postrandomization |
| Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | baseline, 6, 12, and 24 months | Renal allograft function determined by mean percent change from baseline in calculated Glomerular Filtration Rate (Nankivell equation) by treatment group at 6, 12, and 24 months postrandomization. percent change= \[(calculated Glomerular Filtration Rate at Month t - calculated Glomerular Filtration Rate at baseline)/calculated Glomerular Filtration Rate at baseline\]\*100 percent, where t=6, 12, and 24 months postrandomization. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mycophenolate Mofetil + Sirolimus Mycophenolate mofetil orally twice daily at a dose of 1.0 g to 1.5 g + sirolimus orally at a dose of 2 g to 10 g followed by a maintenance dose of 2 mg once daily | 148 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus Mycophenolate mofetil orally twice daily at a dose of 1.0 g to 1.5 g + cyclosporine or tacrolimus according to the study center protocol | 151 |
| Total | 299 |
Baseline characteristics
| Characteristic | Mycophenolate Mofetil + Sirolimus | Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Total |
|---|---|---|---|
| Age Continuous | 48.7 years STANDARD_DEVIATION 12.9 | 48.7 years STANDARD_DEVIATION 12.7 | 48.7 years STANDARD_DEVIATION 12.8 |
| Sex: Female, Male Female | 55 Participants | 55 Participants | 110 Participants |
| Sex: Female, Male Male | 93 Participants | 96 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 147 / 148 | 148 / 153 |
| serious Total, serious adverse events | 60 / 148 | 64 / 153 |
Outcome results
Primary
Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 12
The primary efficacy endpoint was mean percent change in renal function from baseline to 12 months postrandomization, as measured by Glomerular Filtration Rate utilizing renal clearance of cold iothalamate. percent change= \[(Glomerular Filtration Rate at Month 12-Glomerular Filtration Rate at baseline)/Glomerular Filtration Rate at baseline\]\*100 percent.
Time frame: baseline to 12 months
Population: Intent-to-treat population. Analysis population (AP) at Baseline: Mycophenolate mofetil (MMF) + sirolimus = 148, MMF + cyclosporine or tacrolimus (CNI) = 151; AP at Month 12: MMF+sirolimus = 120, MMF+CNI = 111.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 12 | Baseline | 59.5 percent change | Standard Deviation 23.86 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 12 | Mean Percent Change from Baseline at Month 12 | 24.4 percent change | Standard Deviation 70 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 12 | Baseline | 58.8 percent change | Standard Deviation 26.06 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 12 | Mean Percent Change from Baseline at Month 12 | 5.2 percent change | Standard Deviation 56.33 |
Comparison: The primary analysis tested the null hypothesis that mean percent change from baseline to 12 months for Group 1 (mycophenolate mofetil + sirolimus) was equal to that for Group 2 (mycophenolate mofetil + cyclosporine or tacrolimus) based on the intent-to-treat population.p-value: 0.01295% CI: [4.2, 33.2]ANCOVA
Secondary
Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24
Renal allograft function determined by mean percent change from baseline in calculated creatinine clearance (Cockroft and Gault method) by treatment group at 6, 12, and 24 months postrandomization. percent change= \[(calculated creatinine clearance at Month t - calculated creatinine clearance at baseline)/calculated creatinine clearance at baseline\]\*100 percent, where t=6, 12, and 24 months postrandomization
Time frame: baseline 6, 12, and 24 months
Population: Intent-to-treat population. Analysis population (AP) at Baseline: Mycophenolate mofetil (MMF) + sirolimus = 148, MMF + cyclosporine or tacrolimus (CNI) = 151; AP at Month 6: MMF+sirolimus = 117, MMF+CNI = 129; AP at Month 12: MMF+sirolimus = 124, MMF+CNI = 123; AP at Month 24: MMF+sirolimus = 120, MMF+CNI = 116.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Baseline | 59.7 percent change | Standard Deviation 16.85 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 6 | 7.0 percent change | Standard Deviation 19.54 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 12 | 4.4 percent change | Standard Deviation 24.38 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 24 | 4.7 percent change | Standard Deviation 27.58 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 24 | -4.2 percent change | Standard Deviation 27.66 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Baseline | 60.5 percent change | Standard Deviation 19.97 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 12 | -2.3 percent change | Standard Deviation 25.09 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Creatinine Clearance From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 6 | -1.7 percent change | Standard Deviation 17.22 |
Comparison: 6 monthsp-value: <0.00195% CI: [4.1, 13.3]ANCOVA
Comparison: 12 monthsp-value: 0.02995% CI: [0.7, 13.1]ANCOVA
Comparison: 24 monthsp-value: 0.01595% CI: [1.7, 15.9]ANCOVA
Secondary
Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation)
Renal allograft function determined by mean percent change from baseline in calculated Glomerular Filtration Rate (Nankivell equation) by treatment group at 6, 12, and 24 months postrandomization. percent change= \[(calculated Glomerular Filtration Rate at Month t - calculated Glomerular Filtration Rate at baseline)/calculated Glomerular Filtration Rate at baseline\]\*100 percent, where t=6, 12, and 24 months postrandomization.
Time frame: baseline, 6, 12, and 24 months
Population: Intent-to-treat population. Analysis population (AP) at Baseline: Mycophenolate mofetil (MMF) + sirolimus = 148, MMF + cyclosporine or tacrolimus (CNI) = 151; AP at Month 6: MMF+sirolimus = 117, MMF+CNI = 130; AP at Month 12: MMF+sirolimus = 123, MMF+CNI = 123; AP at Month 24: MMF+sirolimus = 120, MMF+CNI = 116.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Baseline | 71.3 percent change | Standard Deviation 13.82 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Percent Change from Baseline at Month 6 | 8.3 percent change | Standard Deviation 19.57 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Percent Change from Baseline at Month 12 | 5.2 percent change | Standard Deviation 25.33 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Percent Change from Baseline at Month 24 | 6.5 percent change | Standard Deviation 28.43 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Percent Change from Baseline at Month 24 | -1.8 percent change | Standard Deviation 27.31 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Baseline | 72.7 percent change | Standard Deviation 16.2 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Percent Change from Baseline at Month 12 | -0.9 percent change | Standard Deviation 23.42 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Calculated Glomerular Filtration Rate From Baseline to Months 6, 12, and 24 (Nankivell Equation) | Percent Change from Baseline at Month 6 | -0.5 percent change | Standard Deviation 15.98 |
Comparison: 6 monthsp-value: <0.00195% CI: [4.2, 12.9]ANCOVA
Comparison: 12 monthsp-value: 0.05995% CI: [-0.2, 11.9]ANCOVA
Comparison: 24 monthsp-value: 0.03695% CI: [0.5, 14.5]ANCOVA
Secondary
Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 24
A secondary efficacy endpoint was mean percent change in renal function from baseline to 24 months postrandomization, as measured by Glomerular Filtration Rate utilizing renal clearance of cold iothalamate. percent change= \[(Glomerular Filtration Rate at Month 24-Glomerular Filtration Rate at baseline)/Glomerular Filtration Rate at baseline\]\*100 percent.
Time frame: Baseline to 24 months
Population: Intent-to-treat population. Analysis population (AP) at Baseline: Mycophenolate mofetil (MMF) + sirolimus = 148, MMF + cyclosporine or tacrolimus (CNI) = 151; AP at Month 24: MMF+sirolimus = 115, MMF+CNI = 105.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 24 | Baseline | 59.5 percent change | Standard Deviation 23.86 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 24 | Percent Change from Baseline at Month 24 | 8.6 percent change | Standard Deviation 55.32 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 24 | Baseline | 58.8 percent change | Standard Deviation 26.06 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Glomerular Filtration Rate From Baseline to Month 24 | Percent Change from Baseline at Month 24 | 3.4 percent change | Standard Deviation 67.28 |
p-value: 0.54395% CI: [-9.6, 18.2]ANCOVA
Secondary
Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24
Renal allograft function determined by mean percent change from baseline in serum creatinine by treatment group at 6, 12, and 24 months postrandomization. percent change= \[(serum creatinine at Month t-serum creatinine at baseline)/serum creatinine at baseline\]\*100 percent, where t=6, 12, and 24 months postrandomization.
Time frame: baseline, 6, 12, and 24 months
Population: Intent-to-treat population. Analysis population (AP) at Baseline: Mycophenolate mofetil (MMF) + sirolimus = 148, MMF + cyclosporine or tacrolimus (CNI) = 151; AP at Month 6: MMF+sirolimus = 117, MMF+CNI = 130; AP at Month 12: MMF+sirolimus = 124, MMF+CNI = 123; AP at Month 24: MMF+sirolimus = 120, MMF+CNI = 116.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Baseline | 121.1 percent change | Standard Deviation 29.96 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 12 | 6.0 percent change | Standard Deviation 57.81 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 6 | -3.7 percent change | Standard Deviation 18.78 |
| Mycophenolate Mofetil + Sirolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 24 | 6.1 percent change | Standard Deviation 59.84 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 24 | 30.8 percent change | Standard Deviation 114.23 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Baseline | 124.4 percent change | Standard Deviation 37.87 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 6 | 6.6 percent change | Standard Deviation 34.61 |
| Mycophenolate Mofetil + Cyclosporine or Tacrolimus | Mean Percent Change in Serum Creatinine From Baseline to Months 6, 12, and 24 | Percent Change from Baseline at Month 12 | 20.4 percent change | Standard Deviation 92.81 |
Comparison: 6 monthsp-value: 0.00395% CI: [-17.9, -3.7]ANCOVA
Comparison: 12 monthsp-value: 0.10895% CI: [-35.4, 3.5]ANCOVA
Comparison: 24 monthsp-value: 0.03995% CI: [-47.7, -1.2]ANCOVA