Inflammation
Conditions
Brief summary
To compare the safety and efficacy of cyclosporine (CsA) + mycophenolate mofetil (MMF) + corticosteroids © to CsA + Rapamune + Cs with CsA elimination in the Rapamune arm with the introduction of MMF in de novo renal allograft recipients.
Interventions
DRUGCsA+Rapamune+CS
Part 1: Rapamune will be given as a loading dose of 6 mg once followed by maintenance dose of 2 mg to achieve a target trough level of 8-15 ng/ml. Part 2: Rapamune dose will be adjusted to achieve a target trough level of 10-15ng/ml through 6 months
DRUGCsA+MMF+CS
The control arm is the standard local practice (official protocol) in Iran: Cyclosporine + MMF + Corticosteroid. The time period is from pre-study screening / baseline evaluation up to 12 months for patients who are maintained on CsA + MMF + CS.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age 13 years and weight 40 kg * End-stage renal disease, with patients receiving a primary or secondary renal allograft from a living-unrelated donor, or from a living-related donor. * Women who are of childbearing potential must have a negative pregnancy test before enrollment in the study and agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months following discontinuation from the study. * Total white blood cell count 4.0 x 109/L (4,000/mmP3P), platelet count 100 x 10P9P/L(100,000/mmP3P), fasting triglycerides ≤ 4.6 mmol/L (400 mg/dL), fasting cholesterol ≤ 7.8 mmol/L (300 mg/dL). If it is not possible to obtain fasting triglycerides and cholesterol before surgery, historical values (within 1 year) may be used. * Signed and dated informed consent (parent or legal guardian must provide consent for patients \<18 years of age). An assent form will be signed by patients \< 18 years of age enrolled in the study.
Exclusion criteria
* Evidence of active systemic or localized major infection at the time of initial Sirolimus administration. * Cadaveric donors * History of malignancy within 5 years before enrollment into the study (with the exception of adequately treated basal cell or squamous cell carcinoma of the skin) * Use of any investigational drug other than specified in the protocol during the 4 weeks before enrolling in the study. * Use of planned antibody induction therapy at the time of transplantation. * Active gastrointestinal disorder that may interfere with drug absorption. * Known hypersensitivity to Sirolimus, MMF or Cyclosporine or its derivatives. * Multiple organ transplants (2 or more organ transplant e.g. Kidney and Pancreas). * Patient with high risk of rejection (eg. Patients with a PRA \>50%, black patients and patients with 2nd transplant who lost their first graft within the first 6 months). * Evidence of infiltrate, cavitation, or consolidation on chest x-ray obtained during pre-study screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Efficacy Failure | Baseline up to Month 12 | Efficacy failure was defined as first occurrence of either biopsy confirmed acute rejection, graft loss or death within 12 months of post-transplantation. Percentage of participants with efficacy failure was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Creatinine Clearance | Month 3, 6, 12 | Creatinine clearance (CCr) is a measure of kidney function. CCr is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Normal values for healthy, young males are in the range of 100-135 millimeters per minute (mL/min) and for females, 90-125 mL/min. Creatinine clearance decreases with age. A low creatinine clearance rate indicates poor kidney function. |
| Glomerular Filtration Rate (GFR) by Nankivell Method | Month 3, 6, 12 | GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR was calculated using the Nankivell formula. GFR by Nankivell equation= (6.7 per serum creatinine) plus (0.25\*body weight) minus (0.5\*serum urea) minus (100 per height square) plus (35 for male or 25 for female). A normal GFR is greater than (\>)90 mL/min per 1.73 m\^2 \[mL/min/1.73 m\^2\], although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR less than (\<)15 mL/min/1.73 m\^2 indicated kidney failure. |
| Incidence of Biopsy-Confirmed Acute Rejection | Baseline up to Month 6 | Diagnosis of acute rejection was made via kidney biopsy using Banff criteria. Percentage of participants with biopsy-confirmed acute rejection was reported. |
| Histologic Grade of First Acute Rejection | Baseline up to Month 12 | Diagnosis of acute rejection was made via kidney biopsy. Categorization of biopsies with suspected acute rejection was based on histological findings using updated 1997 Banff criteria. Grade 1A: cases with significant interstitial infiltration (\>25% of parenchyma affected) and foci of moderate tubulitis (5-10 cells/tubular cross section), Grade 1B: with severe tubulitis (\>10 cells/tubular cross section), Grade 2A: mild-moderate intimal arteritis, Grade 2B: severe intimal arteritis and Grade 3: transmural arterits and/or fibrinoid necrosis. Data is reported as percentage of participants. |
| Percentage of Participants Who Survived | Month 12 | Survival defined as participants living with or without a functioning graft. |
| Serum Creatinine Level | Month 3, 6, 12 | Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. An increased level of creatinine in the blood indicates decreased kidney function. Normal adult blood levels of creatinine are 0.5 to 1.1 milligram per deciliter (mg/dL) for females and 0.6 to 1.2 mg/dL for males; however, the normal values are age-dependent as elderly patients typically have smaller muscle mass. |
| Incidence of Presumptive or Documented Infection | Baseline up to Month 12 | Presumptive or documented infection during the 12 months after transplantation; was confirmed by culture, biopsy, or serology and reported. Percentage of participants with presumptive or documented infection was reported. |
| Incidence of Histologically Confirmed Lymphoproliferative Disease | Baseline up to Month 12 | Lymphoproliferative disorder represents an abnormal proliferation of B cells in response to either primary or reactivated infection with Epstein-Barr virus. Percentage of participants with histologically confirmed lymphoproliferative disease was reported. |
| Percentage of Participants With Efficacy Failure or Premature Elimination | Month 12 | Efficacy failure was defined as the first occurrence of acute rejection, graft loss, or death. Premature elimination was defined as elimination from the study for any other reason. |
| Incidence of Anemia | Baseline up to Month 12 | Diagnostic criterion for anemia was based on the laboratory results; in men: hemoglobin (Hb) \<14 gram per deciliter (g/dL), hematocrit (Hct) \<42%, or red blood cells (RBCs) \<4.5 million/liter (million/L); for women: Hb \<12 g/dL, Hct \<37%, or RBC \< 4 million/L. Percentage of participants with anaemia was reported. |
| Number of Participants Who Discontinued | Month 12 | Number of participants who discontinued the study treatment due to any reason is reported. |
| Percentage of Participants With Graft Survival | Month 12 | 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. |
Countries
Iran
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CsA+Rapamune+CS Month 0-3: rapamune 6 mg tablet orally once as a loading dose within 48 hours of transplantation, followed by rapamune 2 mg tablet orally once daily as a maintenance dose to achieve a target trough level of 8-15 ng/mL in combination with CsA tablets orally to achieve a trough level of 150-250 ng/mL. Month 4-6: CsA was withdrawn abruptly, MMF tablet orally at a dose of 1-1.5 g/day and rapamune dose adjusted to achieve a target trough level of 10-15 ng/mL. Month 7-12: rapamune dose adjusted to achieve a target trough level of 8-12 ng/mL, MMF tablet orally at a dose of 1-1.5 g/day. Participants also received CS tablets orally as per local practice with a minimum daily dose of 5 mg over 12 months. | 125 |
| CsA+MMF+CS Month 0-5: CsA tablets orally to achieve a trough level of 150-300 ng/mL. Month 6-12: CsA tablets orally to achieve a trough level of 100-200 ng/mL. Participants also received MMF tablet orally at a dose of 2 g/day and CS tablets orally as per local practice with a minimum daily dose of 5 mg over 12 months. | 120 |
| Total | 245 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 5 |
| Overall Study | Graft Loss | 6 | 6 |
| Overall Study | Lost to Follow-up | 6 | 14 |
| Overall Study | Other | 5 | 1 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Study Events | 7 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | CsA+Rapamune+CS | CsA+MMF+CS | Total |
|---|---|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 13.4 | 41.6 years STANDARD_DEVIATION 15.1 | 39.9 years STANDARD_DEVIATION 14.3 |
| Sex: Female, Male Female | 47 Participants | 45 Participants | 92 Participants |
| Sex: Female, Male Male | 78 Participants | 75 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 67 / 125 | 44 / 120 |
| serious Total, serious adverse events | 56 / 125 | 44 / 120 |
Outcome results
Primary
Incidence of Efficacy Failure
Efficacy failure was defined as first occurrence of either biopsy confirmed acute rejection, graft loss or death within 12 months of post-transplantation. Percentage of participants with efficacy failure was reported.
Time frame: Baseline up to Month 12
Population: Per-protocol 1 (PP1) population included all participants who had completed study, also included those who dropped out of study due to occurrence of death, graft loss, or biopsy-confirmed acute rejection and had no major protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Incidence of Efficacy Failure | 11.4 percentage of participants |
| CsA+MMF+CS | Incidence of Efficacy Failure | 13.5 percentage of participants |
Comparison: Chi-square test was used to test superiority of arm CsA+Rapamune+CS versus arm CsA+MMF+CS.p-value: 0.34190% CI: [-5.5, 1.5]Chi-squared
Secondary
Creatinine Clearance
Creatinine clearance (CCr) is a measure of kidney function. CCr is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Normal values for healthy, young males are in the range of 100-135 millimeters per minute (mL/min) and for females, 90-125 mL/min. Creatinine clearance decreases with age. A low creatinine clearance rate indicates poor kidney function.
Time frame: Month 3, 6, 12
Population: PP1 population. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure. 'n' is number of participants evaluable at specific time points for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CsA+Rapamune+CS | Creatinine Clearance | Month 3 (n=102, 94) | 64.0 mL/min | Standard Deviation 19.9 |
| CsA+Rapamune+CS | Creatinine Clearance | Month 6 (n=101, 92) | 72.8 mL/min | Standard Deviation 19.3 |
| CsA+Rapamune+CS | Creatinine Clearance | Month 12 (n=98, 91) | 76.4 mL/min | Standard Deviation 22.7 |
| CsA+MMF+CS | Creatinine Clearance | Month 3 (n=102, 94) | 63.9 mL/min | Standard Deviation 16 |
| CsA+MMF+CS | Creatinine Clearance | Month 6 (n=101, 92) | 71.6 mL/min | Standard Deviation 18.3 |
| CsA+MMF+CS | Creatinine Clearance | Month 12 (n=98, 91) | 74.0 mL/min | Standard Deviation 28.6 |
Comparison: Month 3: One-way ANOVA was used to test the difference.p-value: 0.979ANOVA
Comparison: Month 6: One-way ANOVA was used to test the difference.p-value: 0.66ANOVA
Comparison: Month 12: One-way ANOVA was used to test the difference.p-value: 0.518ANOVA
Secondary
Glomerular Filtration Rate (GFR) by Nankivell Method
GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR was calculated using the Nankivell formula. GFR by Nankivell equation= (6.7 per serum creatinine) plus (0.25\*body weight) minus (0.5\*serum urea) minus (100 per height square) plus (35 for male or 25 for female). A normal GFR is greater than (\>)90 mL/min per 1.73 m\^2 \[mL/min/1.73 m\^2\], although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR less than (\<)15 mL/min/1.73 m\^2 indicated kidney failure.
Time frame: Month 3, 6, 12
Population: PP1 population. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure. 'n' is number of participants evaluable at specific time points for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CsA+Rapamune+CS | Glomerular Filtration Rate (GFR) by Nankivell Method | Month 3 (n=102, 94) | 59.5 mL/min/1.73 m^2 | Standard Deviation 20.4 |
| CsA+Rapamune+CS | Glomerular Filtration Rate (GFR) by Nankivell Method | Month 6 (n=101, 92) | 65.2 mL/min/1.73 m^2 | Standard Deviation 16 |
| CsA+Rapamune+CS | Glomerular Filtration Rate (GFR) by Nankivell Method | Month 12 (n=98, 91) | 67.4 mL/min/1.73 m^2 | Standard Deviation 17.5 |
| CsA+MMF+CS | Glomerular Filtration Rate (GFR) by Nankivell Method | Month 3 (n=102, 94) | 58.8 mL/min/1.73 m^2 | Standard Deviation 15.2 |
| CsA+MMF+CS | Glomerular Filtration Rate (GFR) by Nankivell Method | Month 6 (n=101, 92) | 64.3 mL/min/1.73 m^2 | Standard Deviation 19.5 |
| CsA+MMF+CS | Glomerular Filtration Rate (GFR) by Nankivell Method | Month 12 (n=98, 91) | 67.5 mL/min/1.73 m^2 | Standard Deviation 46.5 |
Comparison: Month 3: One-way ANOVA was used to test the difference.p-value: 0.786ANOVA
Comparison: Month 6: One-way ANOVA was used to test the difference.p-value: 0.738ANOVA
Comparison: Month 12: One-way ANOVA was used to test the difference.p-value: 0.977ANOVA
Secondary
Histologic Grade of First Acute Rejection
Diagnosis of acute rejection was made via kidney biopsy. Categorization of biopsies with suspected acute rejection was based on histological findings using updated 1997 Banff criteria. Grade 1A: cases with significant interstitial infiltration (\>25% of parenchyma affected) and foci of moderate tubulitis (5-10 cells/tubular cross section), Grade 1B: with severe tubulitis (\>10 cells/tubular cross section), Grade 2A: mild-moderate intimal arteritis, Grade 2B: severe intimal arteritis and Grade 3: transmural arterits and/or fibrinoid necrosis. Data is reported as percentage of participants.
Time frame: Baseline up to Month 12
Population: PP2 population included all participants who had completed study, also included those who dropped out of the study due to biopsy confirmed acute rejection at Month 6. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CsA+Rapamune+CS | Histologic Grade of First Acute Rejection | 1A | 100.0 percentage of participants |
| CsA+Rapamune+CS | Histologic Grade of First Acute Rejection | 1B | 0.0 percentage of participants |
| CsA+MMF+CS | Histologic Grade of First Acute Rejection | 1A | 66.7 percentage of participants |
| CsA+MMF+CS | Histologic Grade of First Acute Rejection | 1B | 33.3 percentage of participants |
Secondary
Incidence of Anemia
Diagnostic criterion for anemia was based on the laboratory results; in men: hemoglobin (Hb) \<14 gram per deciliter (g/dL), hematocrit (Hct) \<42%, or red blood cells (RBCs) \<4.5 million/liter (million/L); for women: Hb \<12 g/dL, Hct \<37%, or RBC \< 4 million/L. Percentage of participants with anaemia was reported.
Time frame: Baseline up to Month 12
Population: Analysis population included all participants enrolled in the study. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Incidence of Anemia | 94.3 percentage of participants |
| CsA+MMF+CS | Incidence of Anemia | 98.3 percentage of participants |
Comparison: Fisher's exact test was used to test the difference.p-value: 0.172Fisher Exact
Secondary
Incidence of Biopsy-Confirmed Acute Rejection
Diagnosis of acute rejection was made via kidney biopsy using Banff criteria. Percentage of participants with biopsy-confirmed acute rejection was reported.
Time frame: Baseline up to Month 6
Population: PP2 population included all participants who had completed study, also included those who dropped out of the study due to biopsy confirmed acute rejection at Month 6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Incidence of Biopsy-Confirmed Acute Rejection | 4.0 percentage of participants |
| CsA+MMF+CS | Incidence of Biopsy-Confirmed Acute Rejection | 3.2 percentage of participants |
Comparison: Fisher's exact test was used to test the difference.p-value: 0.999Fisher Exact
Secondary
Incidence of Histologically Confirmed Lymphoproliferative Disease
Lymphoproliferative disorder represents an abnormal proliferation of B cells in response to either primary or reactivated infection with Epstein-Barr virus. Percentage of participants with histologically confirmed lymphoproliferative disease was reported.
Time frame: Baseline up to Month 12
Population: Analysis population included all participants enrolled in the study. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Incidence of Histologically Confirmed Lymphoproliferative Disease | 1.0 percentage of participants |
| CsA+MMF+CS | Incidence of Histologically Confirmed Lymphoproliferative Disease | 0.0 percentage of participants |
Comparison: Fisher's exact test was used to test the difference.p-value: 0.999Fisher Exact
Secondary
Incidence of Presumptive or Documented Infection
Presumptive or documented infection during the 12 months after transplantation; was confirmed by culture, biopsy, or serology and reported. Percentage of participants with presumptive or documented infection was reported.
Time frame: Baseline up to Month 12
Population: Analysis population included all participants enrolled in the study. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Incidence of Presumptive or Documented Infection | 20.3 percentage of participants |
| CsA+MMF+CS | Incidence of Presumptive or Documented Infection | 18.6 percentage of participants |
Comparison: Chi-square test was used to test the difference.p-value: 0.868Chi-squared
Secondary
Number of Participants Who Discontinued
Number of participants who discontinued the study treatment due to any reason is reported.
Time frame: Month 12
Population: Analysis population included all participants enrolled in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Number of Participants Who Discontinued | 29 participants |
| CsA+MMF+CS | Number of Participants Who Discontinued | 29 participants |
Comparison: Chi-square test was used to test the difference.p-value: 0.978Chi-squared
Secondary
Percentage of Participants Who Survived
Survival defined as participants living with or without a functioning graft.
Time frame: Month 12
Population: PP3 population included all participants who had completed study, also included those who dropped out of the study due to the occurrence of death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Percentage of Participants Who Survived | 98.0 percentage of participants |
| CsA+MMF+CS | Percentage of Participants Who Survived | 94.8 percentage of participants |
Comparison: Fisher's exact test was used to test the difference.p-value: 0.276Fisher Exact
Secondary
Percentage of Participants With Efficacy Failure or Premature Elimination
Efficacy failure was defined as the first occurrence of acute rejection, graft loss, or death. Premature elimination was defined as elimination from the study for any other reason.
Time frame: Month 12
Population: Analysis population included all participants enrolled in the study. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Percentage of Participants With Efficacy Failure or Premature Elimination | 22.0 percentage of participants |
| CsA+MMF+CS | Percentage of Participants With Efficacy Failure or Premature Elimination | 22.9 percentage of participants |
Comparison: Chi-square test was used to test the difference.p-value: 0.985Chi-squared
Secondary
Percentage of Participants With Graft Survival
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: Month 12
Population: PP4 population included all participants who had completed study, also included those who dropped out of the study due to the occurrence of graft loss.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CsA+Rapamune+CS | Percentage of Participants With Graft Survival | 94.1 percentage of participants |
| CsA+MMF+CS | Percentage of Participants With Graft Survival | 93.8 percentage of participants |
Comparison: Fisher's exact test was used to test the difference.p-value: 0.999Fisher Exact
Secondary
Serum Creatinine Level
Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. An increased level of creatinine in the blood indicates decreased kidney function. Normal adult blood levels of creatinine are 0.5 to 1.1 milligram per deciliter (mg/dL) for females and 0.6 to 1.2 mg/dL for males; however, the normal values are age-dependent as elderly patients typically have smaller muscle mass.
Time frame: Month 3, 6, 12
Population: PP1 population. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure. 'n' is number of participants evaluable at specific time points for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CsA+Rapamune+CS | Serum Creatinine Level | Month 3 (n=102, 94) | 1.4 mg/dL | Standard Deviation 0.4 |
| CsA+Rapamune+CS | Serum Creatinine Level | Month 6 (n=101, 92) | 1.2 mg/dL | Standard Deviation 0.3 |
| CsA+Rapamune+CS | Serum Creatinine Level | Month 12 (n=98, 91) | 1.2 mg/dL | Standard Deviation 0.3 |
| CsA+MMF+CS | Serum Creatinine Level | Month 3 (n=102, 94) | 1.4 mg/dL | Standard Deviation 0.4 |
| CsA+MMF+CS | Serum Creatinine Level | Month 6 (n=101, 92) | 1.3 mg/dL | Standard Deviation 0.4 |
| CsA+MMF+CS | Serum Creatinine Level | Month 12 (n=98, 91) | 1.3 mg/dL | Standard Deviation 0.3 |
Comparison: Month 3: One-way analysis of variance (ANOVA) was used to test the difference.p-value: 0.87ANOVA
Comparison: Month 6: One-way ANOVA was used to test the difference.p-value: 0.381ANOVA
Comparison: Month 12: One-way ANOVA was used to test the difference.p-value: 0.096ANOVA