Graft vs Host Disease, Kidney Transplantation
Conditions
Keywords
Kidney, Transplant
Brief summary
The purpose of this study is to compare the kidney function in patients who have received a transplanted kidney and were treated with the combination of sirolimus, daclizumab, mycophenolate and corticosteroids versus transplanted patients treated with cyclosporine, mycophenolate and corticosteroids.
Interventions
DRUGsirolimus
15 mg loading dose, followed by 5 mg/day to achieve target trough levels of 10-15 ng/mL at months 1-6, then 8-12 ng/mL at months 7-12
DRUGcyclosporine
Initial dose of 10 mg/kg/day, then twice daily to achieve target trough levels of 300-400 ng/mL at weeks 0-4; 200-300 ng/mL at months 1-2; 150-250 ng/mL at months 2-3; 100-200 ng/mL at months 3-6; 75-150 ng/mL months 6-12
DRUGmycophenolate mofetil
1 g twice daily; may be reduced to 750 mg BID for adverse events, or to 500 mg BID for persisting adverse events
DRUGcorticosteroids
As per center practice. By day 8 prednisolone tapered to 20 mg/day; by day 30 to 15 mg/day; by day 60 to 10 mg/day; after 4 to 6 months to 5-7.5 mg/day
DRUGdaclizumab
IV: 1 mg/kg to a maximum of 100 mg/dose. 5 doses at 2, 4, 6, and 8 weeks after transplantation
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
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
* Kidney transplantation * Donor must be at least 60 years old.
Exclusion criteria
* Current systemic infection * Unstable angina or treatment for serious arrhythmia. * Cancer within the previous 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Creatinine Clearance Rate | 12 months | Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance rate was calculated using the Nankivell formula. Normal values for healthy, young males are in the range of 100-135 ml/min and for females 90-125 ml/min. A low creatinine clearance indicates poor kidney function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Acute Rejection | 3 and 12 months | The diagnosis of acute rejection was made via kidney biopsy (Banff criteria). The Banff criteria are standardized diagnostic categories based on histological assessments (e.g., cell types and distributions). Biopsy was performed before initiation of anti-rejection therapy, or at least within 24 hours of the start of therapy. |
| Patient and Graft Survival | 12 months | Graft survival is measured by graft loss which is defined as removal of the transplant. |
| Mean Creatinine Clearance Rate - 3 Months | 3 months | Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance rate was calculated using the Nankivell formula. Normal values for healthy, young males are in the range of 100-135 ml/min and for females 90-125 ml/min. A low creatinine clearance indicates poor kidney function. |
Countries
Norway, Sweden
Participant flow
Recruitment details
Patients were recruited in Sweden from November 2004 to September 2007.
Pre-assignment details
Prior to enrollment in study, patients were screened for eligibility. If eligibility criteria were met, patients were enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus Sirolimus: initiated within 24 hours before or after transplantation; Loading dose of 15mg followed by 5mg/day (morning) until doses are adjusted to achieve steady state whole-blood trough levels of 10-15ng/ml during months 1-6, followed by 8-12ng/ml during months 7-12 Daclizumab: administered intravenously over 15 minutes at a dose of 1mg/kg to a maximum of 100mg per dose. First dose administered within24 hours before transplantation, with subsequent doses at weeks 2, 4, 6 and 8 weeks after transplantation, for a total of five doses.
Mycophenolate mofetil: 1000mg twice daily. Dose can be reduced to 750mg twice daily in the case of adverse events and reduced further to 500mg if adverse events persist.
Corticosteroids: given according to transplant center standard of care pre- and postoperatively. By day 8 prednisolone should be tapered to 20mg/day, by day 30 to 15mg/day, by day 60 to 10mg/day, and after 4-6 months to 5-7.5mg/day. | 31 |
| Cyclosporine (CsA) Cyclosporine: first dose of 10mg/kg/day administered orally or via a NG-tube, no later than 24 hours after transplant. (First dose may be initiated prior to transplantation.) Subsequent doses given in equally divided doses (where possible) of twice daily at approximately 12-hour intervals. The subsequent doses should be adjusted to achieve target therapeutic ranges in whole blood.
Mycophenolate mofetil: 1000mg twice daily. Dose can be reduced to 750mg twice daily in the case of adverse events and reduced further to 500mg if adverse events persist.
Corticosteroids: given according to transplant center standard of care pre- and postoperatively. By day 8 prednisolone should be tapered to 20mg/day, by day 30 to 15mg/day, by day 60 to 10mg/day, and after 4-6 months to 5-7.5mg/day. | 30 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 9 |
| Overall Study | Lack of Efficacy | 3 | 1 |
| Overall Study | Procedural complications | 9 | 3 |
| Overall Study | Protocol deviation | 0 | 1 |
Baseline characteristics
| Characteristic | Sirolimus | Cyclosporine (CsA) | Total |
|---|---|---|---|
| Age Continuous | 61.00 years STANDARD_DEVIATION 10 | 59.60 years STANDARD_DEVIATION 10.1 | 60.31 years STANDARD_DEVIATION 10.04 |
| Sex: Female, Male Female | 9 Participants | 13 Participants | 22 Participants |
| Sex: Female, Male Male | 22 Participants | 17 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / — | 30 / — |
| serious Total, serious adverse events | 26 / — | 24 / — |
Outcome results
Primary
Mean Creatinine Clearance Rate
Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance rate was calculated using the Nankivell formula. Normal values for healthy, young males are in the range of 100-135 ml/min and for females 90-125 ml/min. A low creatinine clearance indicates poor kidney function.
Time frame: 12 months
Population: All patients who completed 12 months of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Mean Creatinine Clearance Rate | 56.800 ml/min | Standard Deviation 21.522 |
| Cyclosporine (CsA) | Mean Creatinine Clearance Rate | 53.449 ml/min | Standard Deviation 15.497 |
p-value: 0.6081ANOVA
Secondary
Mean Creatinine Clearance Rate - 3 Months
Creatinine clearance is a measure of kidney function. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Creatinine clearance can be measured directly or estimated using established formulas. For this study, the creatinine clearance rate was calculated using the Nankivell formula. Normal values for healthy, young males are in the range of 100-135 ml/min and for females 90-125 ml/min. A low creatinine clearance indicates poor kidney function.
Time frame: 3 months
Population: All patients who completed 3 months of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Mean Creatinine Clearance Rate - 3 Months | 55.200 ml/min | Standard Deviation 22.403 |
| Cyclosporine (CsA) | Mean Creatinine Clearance Rate - 3 Months | 51.878 ml/min | Standard Deviation 15.974 |
p-value: 0.4662ANOVA
Secondary
Number of Patients With Acute Rejection
The diagnosis of acute rejection was made via kidney biopsy (Banff criteria). The Banff criteria are standardized diagnostic categories based on histological assessments (e.g., cell types and distributions). Biopsy was performed before initiation of anti-rejection therapy, or at least within 24 hours of the start of therapy.
Time frame: 3 and 12 months
Population: All patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Number of Patients With Acute Rejection | 3 months | 3 patients |
| Sirolimus | Number of Patients With Acute Rejection | 12 months | 5 patients |
| Cyclosporine (CsA) | Number of Patients With Acute Rejection | 3 months | 9 patients |
| Cyclosporine (CsA) | Number of Patients With Acute Rejection | 12 months | 10 patients |
Secondary
Patient and Graft Survival
Graft survival is measured by graft loss which is defined as removal of the transplant.
Time frame: 12 months
Population: All patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Patient and Graft Survival | Patient survival | 31 patients |
| Sirolimus | Patient and Graft Survival | Graft loss | 0 patients |
| Cyclosporine (CsA) | Patient and Graft Survival | Patient survival | 29 patients |
| Cyclosporine (CsA) | Patient and Graft Survival | Graft loss | 3 patients |