Liver Transplantation
Conditions
Keywords
Liver, Transplant
Brief summary
The purpose of this study is to evaluate the sirolimus conversion regimen as compared with the calcineurin inhibitor continuation regimen with regards to renal function in stable liver transplant subjects.
Interventions
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
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than 13 years (age greater than 18 years as required by some local regulations). * Receiving immunosuppressive therapy with calcineurin inhibitors (CI) +/- corticosteroids +/- antimetabolite. * 6 to 144 months after orthotopic liver transplantation. * Cockcroft-Gault GFR values ≥40 mL/min and ≤90mL/min at screening
Exclusion criteria
* History of nonhepatic transplantation * Evidence of systemic infection (sepsis, bacteremia, pneumonia etc). * Known or suspected malignancy \< 5 years before random assignment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Adjusted Mean in Glomerular Filtration Rate (GFR) | Baseline and 12 months | GFR is an index of kidney function. GFR was calculated using Cockcroft-Gault method. A normal GFR is \>90 mL/min, higher values indicate better function. Change=adjusted mean of 12 months minus baseline. Mean adjusted for baseline GFR, with antimetabolite therapy status and hepatitis C status as fixed effects. |
| Patient and Graft Survival | 12 months | Endpoint was a composite assessment of patient and graft survival. Patients categorized as graft survival or graft loss. Graft loss defined as pure graft loss (requiring retransplant) or death (with a functioning graft), if the event occurred in the first 12 months after randomization. Patients with missing graft data were counted as graft losses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Biopsy Confirmed Acute Rejection | 12 months | Overall event rate is determined as yes or no. |
| Mean Serum Creatinine | 12 months | Observed mean values for serum creatinine. |
Countries
Belgium, Canada, Czechia, France, Germany, Italy, Netherlands, Portugal, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Patients were recruited October 2002 to November 2006.
Pre-assignment details
Patients were screened up to 30 days.
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus (SRL) Conversion Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay). | 393 |
| Calcineurin Inhibitors (CNI) Continuation Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively. | 214 |
| Total | 607 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Patients Dosed With Test Article | Adverse Event | 94 | 11 |
| Patients Dosed With Test Article | Lack of Efficacy | 11 | 0 |
| Patients Dosed With Test Article | Lost to Follow-up | 1 | 3 |
| Patients Dosed With Test Article | Nonmedical event | 7 | 3 |
| Patients Dosed With Test Article | Protocol Violation | 11 | 3 |
| Patients Dosed With Test Article | Withdrawal by Subject | 16 | 3 |
| Randomization | Did not receive test article | 4 | 4 |
Baseline characteristics
| Characteristic | Sirolimus (SRL) Conversion | Calcineurin Inhibitors (CNI) Continuation | Total |
|---|---|---|---|
| Age Continuous | 57.0 years | 56.5 years | 57.0 years |
| Mean serum creatinine levels | 122.9 μmol/L STANDARD_DEVIATION 32.3 | 125.2 μmol/L STANDARD_DEVIATION 31.9 | 123.7 μmol/L STANDARD_DEVIATION 32.2 |
| Sex: Female, Male Female | 122 Participants | 64 Participants | 186.0 Participants |
| Sex: Female, Male Male | 271 Participants | 150 Participants | 421.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 386 / 389 | 201 / 210 |
| serious Total, serious adverse events | 193 / — | 79 / — |
Outcome results
Primary
Change From Baseline Adjusted Mean in Glomerular Filtration Rate (GFR)
GFR is an index of kidney function. GFR was calculated using Cockcroft-Gault method. A normal GFR is \>90 mL/min, higher values indicate better function. Change=adjusted mean of 12 months minus baseline. Mean adjusted for baseline GFR, with antimetabolite therapy status and hepatitis C status as fixed effects.
Time frame: Baseline and 12 months
Population: The intent to treat population was analyzed and consisted of all patients randomly assigned to treatment. Patients were stratified by hepatitis C status and whether or not they were receiving antimetabolite therapy at time of randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Conversion | Change From Baseline Adjusted Mean in Glomerular Filtration Rate (GFR) | -4.45 mL/min | Standard Error 1.12 |
| Calcineurin Inhibitors (CNI) Continuation | Change From Baseline Adjusted Mean in Glomerular Filtration Rate (GFR) | -3.07 mL/min | Standard Error 1.36 |
p-value: 0.342Rank ANCOVA
Primary
Patient and Graft Survival
Endpoint was a composite assessment of patient and graft survival. Patients categorized as graft survival or graft loss. Graft loss defined as pure graft loss (requiring retransplant) or death (with a functioning graft), if the event occurred in the first 12 months after randomization. Patients with missing graft data were counted as graft losses.
Time frame: 12 months
Population: Intent to treat analysis population with stratification by antimetabolite therapy and hepatitis C status.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus (SRL) Conversion | Patient and Graft Survival | Graft loss (total) | 26 patients |
| Sirolimus (SRL) Conversion | Patient and Graft Survival | Graft loss: Death | 13 patients |
| Sirolimus (SRL) Conversion | Patient and Graft Survival | Graft loss: Pure (with retransplant) | 0 patients |
| Sirolimus (SRL) Conversion | Patient and Graft Survival | Graft loss: Incomplete data | 13 patients |
| Sirolimus (SRL) Conversion | Patient and Graft Survival | Graft survival | 367 patients |
| Calcineurin Inhibitors (CNI) Continuation | Patient and Graft Survival | Graft loss: Incomplete data | 9 patients |
| Calcineurin Inhibitors (CNI) Continuation | Patient and Graft Survival | Graft survival | 202 patients |
| Calcineurin Inhibitors (CNI) Continuation | Patient and Graft Survival | Graft loss (total) | 12 patients |
| Calcineurin Inhibitors (CNI) Continuation | Patient and Graft Survival | Graft loss: Pure (with retransplant) | 0 patients |
| Calcineurin Inhibitors (CNI) Continuation | Patient and Graft Survival | Graft loss: Death | 3 patients |
95% CI: [-5.2, 2.8]
Secondary
Mean Serum Creatinine
Observed mean values for serum creatinine.
Time frame: 12 months
Population: On-therapy population; consisted of patients who were still receiving study medication at the defined endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Conversion | Mean Serum Creatinine | 119.0 µmol/L | Standard Deviation 38.9 |
| Calcineurin Inhibitors (CNI) Continuation | Mean Serum Creatinine | 122.4 µmol/L | Standard Deviation 31.5 |
p-value: >0.051 way ANOVA, two sided
Secondary
Number of Patients With a Biopsy Confirmed Acute Rejection
Overall event rate is determined as yes or no.
Time frame: 12 months
Population: The analysis population is the intent to treat. Any patient whose clinical rejection data was incomplete was designated as an acute rejection in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus (SRL) Conversion | Number of Patients With a Biopsy Confirmed Acute Rejection | Yes | 46 patients |
| Sirolimus (SRL) Conversion | Number of Patients With a Biopsy Confirmed Acute Rejection | No | 347 patients |
| Calcineurin Inhibitors (CNI) Continuation | Number of Patients With a Biopsy Confirmed Acute Rejection | Yes | 13 patients |
| Calcineurin Inhibitors (CNI) Continuation | Number of Patients With a Biopsy Confirmed Acute Rejection | No | 201 patients |
Comparison: Comparison between treatment groups of percentages of patients with biopsy-confirmed acute rejection.p-value: 0.017Cochran-Mantel-Haenszel