Kidney Transplantation
Conditions
Brief summary
This study will evaluate whether conversion from cyclosporine, a calcineurin inhibitor (CI) to sirolimus (SRL) results in improved long-term renal function without a negative impact on safety or immunosuppressive efficacy, and to further examine the potential of SRL to reduce the severity and/or progression of chronic allograft nephropathy (CAN).
Detailed description
This open-label, randomized, parallel-group, comparative, outpatient study will be conducted in multiple centers in Taiwan. The study will randomize approximately 120 patients. 80 patients will be randomized to the SRL therapy group (conversion from CI- to SRL-based immunosuppression: group A) and 40 patients to the CI therapy group (continued CI therapy: group B). Dosage and Administration SRL Therapy: At the time of randomization on day 1, each patient will have been receiving: * triple therapy with a CI (tacrolimus or CsA) that began at the time of transplantation or within 2 weeks thereafter AND * corticosteroids corresponding to a dosage range of 2.5 to 15 mg/day for prednisone or prednisolone (2 to 12 mg/day for methylprednisolone) or the alternate day equivalent for at least 12 weeks before randomization, PLUS * either MMF (minimum dose 500 mg/day)/MPS (minimum dose 360 mg/day) or AZA (minimum dose 50 mg/day) for at least 12 weeks before randomization. SRL will be added to the immunosuppressive regimen for Group A. Group B will continue on this CI immunosuppressive regimen.
Interventions
DRUGSirolimus+MMF or MPS or AZA+Steroid
Corticosteroids will be administered according to local practice, within a daily maintenance dosage range of 2.5 to15 mg for prednisone or prednisolone (2 to 12 mg/day for methylprednisolone) or the alternate day equivalent.
DRUGCalcineurin Inhibitors (either cyclosporine or tacrolimus)+MMF or MPS or AZA+Steroid
The maintenance dose of: 1. MMF will not exceed 1500 mg/day or PMS will not exceed 1080 mg/day 2. AZA will not exceed 75 mg/day Thereafter, at the discretion of the investigator, MMF/MPS or AZA may be: 1. continued for the entire 104-week period of randomized therapy 2. subsequently discontinued 3. restarted after discontinuation
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
* Subjects must be at least 18 years of age. * Subjects who are 6 to 60 months after renal transplantation. * Subjects who have a stable graft function.
Exclusion criteria
* Subjects with active major infection, including HIV, decreased platelets, elevated lipids, or multiple organ transplants.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glomerular Filtration Rate (GFR) Change From Baseline | 104 weeks | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is \> 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR \<15 is consistent with kidney failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient and Graft Survival | Week 24 | Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for \>8 weeks), retransplant or death during the first 12 months after randomization. |
| Change From Baseline in Diastolic Blood Pressure at Week 24 | Baseline and Week 24 | Value at Week 24 minus value at baseline. |
| Change From Baseline in Diastolic Blood Pressure at Week 52 | Baseline and Week 52 | Value at Week 52 minus value at baseline. |
| Change From Baseline in Diastolic Blood Pressure at Week 104 | Baseline and Week 104 | Value at Week 104 minus value at baseline. |
| Change From Baseline in Systolic Blood Pressure at Week 24 | Baseline and Week 24 | Value at Week 24 minus value at baseline. |
| Change From Baseline in Systolic Blood Pressure at Week 52 | Baseline and Week 52 | Value at Week 52 minus value at baseline. |
| Change in Glomerular Filtration Rate (GFR) | Baseline and Week 24 | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is \> 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR \<15 is consistent with kidney failure. |
| Change From Baseline in the Severity and Progression of Biopsy-Confirmed Chronic Allograft Nephropathy (CAN) at Week 104 | Baseline and Week 104 | — |
| Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 52 | Weeks 52 | — |
| Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 104 | Week 104 | — |
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 24 | Week 24 | — |
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 52 | Week 52 | — |
| Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 104 | Week 104 | — |
| Change From Baseline in Systolic Blood Pressure at Week 104 | Baseline and Week 104 | Value at Week 104 minus value at baseline. |
Countries
Taiwan
Participant flow
Recruitment details
Patients were recruited in Taiwan from April 2007 to May 2008.
Pre-assignment details
After consent and eligibility criteria patients needed to be receiving: triple therapy with a Calcineurin Inhibitor (CI) (tacrolimus or cyclosporine) that began at the time of transplantation or ≤2 weeks thereafter and corticosteroids plus either mycophenolate mofetil (MMF)/mycophenolate sodium (MPS) or azathioprine (AZA) for at least 12 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus (SRL) SRL added to the immunosuppressive regimen at a daily maintenance dose of 2 mg, following a loading dose of 6 mg. The dose of SRL adjusted as necessary to maintain a whole blood trough concentration range of 10 to 15 ng/mL. CI dose was reduced by 50% and discontinued within 2 weeks if SRL at the target trough level. Once SRL trough level was at target range, MMF dose reduced to a maximum of 1500 mg/day or MPS dose reduced to a maximum of 1080 mg/day and AZA dose reduced to a maximum of 75 mg/day. Corticosteroids were administered according to local practice, within a daily maintenance dosage range (2.5 to 15 mg for prednisone or prednisolone; 2 to 12 mg/day for methylprednisolone) or the alternate day equivalent. | 21 |
| Calcineurin Inhibitor (CI) Patients will continue to receive a CI (tacrolimus or CsA). At the discretion of the investigator, patients will be permitted to: (a) change from MMF/MPS to AZA or vice versa, and from CsA to tacrolimus or vice versa; (b) continue MMF/MPS or AZA for the entire 104-week period of randomized therapy; or (c) discontinue MMF/MPS or AZA and subsequently restart either one after discontinuation. Whole blood CsA or tacrolimus trough concentrations will be monitored at designated intervals and the CI dose adjusted to maintain the following trough concentration ranges: CsA 50-250 ng/mL and Tacrolimus 4-10 ng/mL. | 10 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 0 |
| Overall Study | Premature termination | 13 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Sirolimus (SRL) | Calcineurin Inhibitor (CI) | Total |
|---|---|---|---|
| Age Continuous | 46.8 years STANDARD_DEVIATION 7.9 | 42.2 years STANDARD_DEVIATION 13.9 | 43.3 years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 11 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 21 | 18 / 10 |
| serious Total, serious adverse events | 6 / 21 | 2 / 10 |
Outcome results
Primary
Change in Glomerular Filtration Rate (GFR) Change From Baseline
GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is \> 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR \<15 is consistent with kidney failure.
Time frame: 104 weeks
Population: No patients completed 104 weeks and therefore no data were available for efficacy analysis.
Secondary
Change From Baseline in Diastolic Blood Pressure at Week 104
Value at Week 104 minus value at baseline.
Time frame: Baseline and Week 104
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change From Baseline in Diastolic Blood Pressure at Week 24
Value at Week 24 minus value at baseline.
Time frame: Baseline and Week 24
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change From Baseline in Diastolic Blood Pressure at Week 52
Value at Week 52 minus value at baseline.
Time frame: Baseline and Week 52
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change From Baseline in Systolic Blood Pressure at Week 104
Value at Week 104 minus value at baseline.
Time frame: Baseline and Week 104
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change From Baseline in Systolic Blood Pressure at Week 24
Value at Week 24 minus value at baseline.
Time frame: Baseline and Week 24
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change From Baseline in Systolic Blood Pressure at Week 52
Value at Week 52 minus value at baseline.
Time frame: Baseline and Week 52
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change From Baseline in the Severity and Progression of Biopsy-Confirmed Chronic Allograft Nephropathy (CAN) at Week 104
Time frame: Baseline and Week 104
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change in Glomerular Filtration Rate (GFR)
GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is \> 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR \<15 is consistent with kidney failure.
Time frame: Baseline and Week 104
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change in Glomerular Filtration Rate (GFR)
GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is \> 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR \<15 is consistent with kidney failure.
Time frame: Baseline and Week 52
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Change in Glomerular Filtration Rate (GFR)
GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using Nankivell formula. A normal GFR is \> 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR \<15 is consistent with kidney failure.
Time frame: Baseline and Week 24
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 104
Time frame: Week 104
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 24
Time frame: Week 24
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Incidence and Severity of Biopsy-Confirmed Acute Rejection at Week 52
Time frame: Week 52
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 104
Time frame: Week 104
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Occurence of Acute Rejection or Premature Withdrawal From Study Medication for Any Reason by Week 52
Time frame: Weeks 52
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Patient and Graft Survival
Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for \>8 weeks), retransplant or death during the first 12 months after randomization.
Time frame: Week 104
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Patient and Graft Survival
Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for \>8 weeks), retransplant or death during the first 12 months after randomization.
Time frame: Week 24
Population: Insufficient or no data available for efficacy analyses because study was terminated early.
Secondary
Patient and Graft Survival
Patient survival defined as participants living with or without a functioning graft. Graft survival defined as those participants who did not experience graft loss. Graft loss defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for \>8 weeks), retransplant or death during the first 12 months after randomization.
Time frame: Week 52
Population: Insufficient or no data available for efficacy analyses because study was terminated early.