Kidney Transplantation
Conditions
Keywords
De Novo Kidney Transplant, cyclosporine, Prograf®, mycophenolate mofetil, tacrolimus
Brief summary
The purpose of this study is to compare the safety and efficacy of tacrolimus/mycophenolate mofetil (MMF), cyclosporine/MMF and tacrolimus modified release/MMF in de novo kidney transplant recipients.
Detailed description
This was a 3 arm randomized, open-label, comparative, multi-center study in de novo kidney transplant recipients at 60 centers in the U.S., Canada and Brazil. The study consisted of a 1-year post-transplant efficacy and safety study with a clinical continuation phase of a minimum of 2 years or until commercial availability of tacrolimus modified release, unless the Data Safety Monitoring Board or sponsor specified otherwise.
Interventions
The target range for whole blood tacrolimus trough concentrations was 7 to 16 ng/mL for days 0 through 90, and 5 to 15 ng/mL thereafter.
DRUGTacrolimus
The target range for whole blood tacrolimus trough concentrations was the recommended trough concentration range for Prograf: 7 to 16 ng/mL for days 0 through 90 and 5 to 15 ng/mL thereafter.
The target range for whole blood cyclosporine trough concentrations was 125 to 400 ng/mL for days 0 through 90, and 100 to 300 ng/mL thereafter.
DRUGmycophenolate mofetil
Oral
Sponsors
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Recipient of a primary or retransplanted non-human leukocyte antigen (HLA)-identical living or non-HLA-identical cadaveric kidney transplant * Age greater or equal to 12 years
Exclusion criteria
* Recipient or donor is known seropositive for human immunodeficiency virus (HIV) * Has current malignancy or history of malignancy * Has significant liver disease * Has uncontrolled concomitant infection or any other unstable medical condition * Is receiving everolimus or enteric coated mycophenolic acid at any time during the study * Received kidney with a cold ischemia time of equal or more than 36 hours * Received kidney transplant from a cadaveric donor equal or more than 60 years of age * Received intravenous immunoglobulin (IVIG) therapy prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Efficacy Failure | one year | Efficacy failure is defined as any participant who died, experienced a graft failure (permanent return to dialysis \[\> 30 days\] or retransplant), had a biopsy-confirmed (Banff Grade ≥ I) acute rejection (BCAR), or was lost to follow-up. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Graft Survival at One Year | One year | Graft survival defined as any participant who did not meet the criteria for graft loss, where graft loss is defined as any re-transplant, permanent return to dialysis (\> 30 days), patient death, or participant whose outcome at one year was unknown. Participants were only counted once regardless of how many criteria were met. |
| Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months | Six months and 12 months | Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. Acute rejection is defined as a grade ≥ I. |
| Time to First Biopsy-confirmed Acute Rejection Episode | one year | Time to first biopsy-confirmed acute rejection episode defined as the number of days from skin closure (Day 0) to the date of biopsy. Rejection episodes were confirmed by biopsy by the clinical site pathologist and graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. Acute rejection is defined as a grade ≥ I. |
| Number of Participants Requiring Anti-lymphocyte Antibody Therapy for Treatment of Rejection | one year | Rejection episodes were confirmed by biopsy by the clinical site pathologist. Participants with histologically-proven Banff Grade II or III rejection or participants with steroid-resistant rejection were treated with anti-lymphocyte antibody treatment according to institutional practice. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. |
| Severity of Acute Rejection | one year | Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade IA: Significant interstitial infiltration and foci of moderate tubulitis; Grade IB: Significant interstitial infiltration and foci of severe tubulitis; Grade IIA: Mild to moderate intimal arteritis in at least 1 arterial cross section Grade IIB: Severe intimal arteritis comprising \>25% of the luminal area lost in at least 1 arterial cross section; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. |
| Number of Participants Experiencing Multiple Rejection Episodes | one year | This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated. |
| Patient Survival at One Year | One year | Patient survival is defined as any participant who is known to be alive one year after the skin closure date. Participants who died or whose outcome was unknown at one year were considered to be non-survivors. |
| Number of Participants With Treatment Failure | one year | Treatment failure was defined as the discontinuation of randomized study drug for any reason. Participants who met the definition of treatment failure were to be followed throughout the 12-month treatment period. |
| Number of Participants Who Crossed Over Due to Treatment Failure | one year | Participants were allowed to cross over to an alternative primary immunosuppressive regimen (either to the tacrolimus or cyclosporine treatment arms) to address an adverse event which led to randomized study drug discontinuation or in the case of severe or refractory rejection. Crossover to the modified release tacrolimus treatment arm was not permitted. |
| Change From Month 1 in Serum Creatinine at Month 6 and Month 12 | Month 1, Month 6, and Month 12 | Renal function was assessed by the change from Month 1 in serum creatinine six months and 12 months after transplant. |
| Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 | Month 1, Month 6, and Month 12 | Renal function was assessed by creatinine clearance, calculated using the Cockcroft-Gault formula. |
| Kaplan-Meier Estimate of Patient Survival at the End of the Study | End of study (maximum time on study was 1,941 days). | Patient survival was defined as any participant who was alive at the end of the study. Patient survival was censored at the time of last follow-up contact. |
| Kaplan-Meier Estimate of Graft Survival at the End of the Study | End of study (maximum time on study was 1,941 days). | Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was any retransplant or the permanent return to dialysis (more than 30 days) or patient death. Graft survival was censored at the time of last follow-up contact. |
| Number of Participants With Clinically Treated Acute Rejection Episodes | one year | A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy. |
Countries
Brazil, Canada, United States
Participant flow
Recruitment details
De novo kidney transplant recipients 12 years of age and older were randomized in a 1:1:1 ratio to 1 of 3 treatment arms.
Pre-assignment details
This study was a 1-year safety and efficacy study followed by a clinical continuation phase that continued until the sponsor discontinued the study in March 2009.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus Participants received a first dose of tacrolimus between 0.075 and 0.10 mg/kg twice daily, orally prior to or within 48 hours of the completion of the transplant procedure, and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study. | 212 |
| Tacrolimus Modified Release Participants received a first dose of tacrolimus modified release between 0.15 and 0.20 mg/kg/day, given as a single oral dose in the morning, prior to or within 48 hours following the completion of the transplant procedure, and subsequently as once daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study. | 214 |
| Cyclosporine Participants received a first dose of cyclosporine between 4 to 5 mg/kg orally prior to or within 48 hours following the completion of the transplant procedure and subsequently as twice daily oral doses adjusted based on clinical evidence of efficacy, blood concentrations of tacrolimus and adverse events. Participants also received 1.0 g mycophenolate mofetil orally twice daily throughout the study. | 212 |
| Total | 638 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Clinical Continuation Phase | Adverse Event | 12 | 21 | 14 |
| Clinical Continuation Phase | Discharged to nursing home | 0 | 1 | 0 |
| Clinical Continuation Phase | Graft Failure | 5 | 5 | 2 |
| Clinical Continuation Phase | Immunosuppressive treatment crossover | 0 | 3 | 6 |
| Clinical Continuation Phase | Incorrect study drug dispensed | 0 | 1 | 0 |
| Clinical Continuation Phase | Lost to Follow-up | 6 | 3 | 6 |
| Clinical Continuation Phase | Non-compliance | 8 | 6 | 7 |
| Clinical Continuation Phase | Pancreas transplant | 1 | 0 | 0 |
| Clinical Continuation Phase | Patient opted out | 0 | 0 | 1 |
| Clinical Continuation Phase | Physician Decision | 1 | 3 | 0 |
| Clinical Continuation Phase | Ran out of study drug due to Hurricane | 0 | 1 | 0 |
| Clinical Continuation Phase | Rejection | 1 | 2 | 2 |
| Clinical Continuation Phase | Sponsor discontinued study | 113 | 129 | 79 |
| Clinical Continuation Phase | Unable to return to site for study visit | 1 | 0 | 1 |
| Clinical Continuation Phase | Withdrawal by Subject | 22 | 3 | 22 |
| One Year Post-transplant | Acute tubular necrosis | 1 | 0 | 0 |
| One Year Post-transplant | Adverse Event | 23 | 19 | 37 |
| One Year Post-transplant | Converted to rapamycin | 1 | 0 | 0 |
| One Year Post-transplant | Crossover secondary to possible toxicity | 0 | 1 | 0 |
| One Year Post-transplant | Did not receive study drug | 7 | 12 | 11 |
| One Year Post-transplant | Graft Failure | 3 | 2 | 1 |
| One Year Post-transplant | Incorrect study drug dispensed | 0 | 1 | 0 |
| One Year Post-transplant | Lost to Follow-up | 1 | 0 | 0 |
| One Year Post-transplant | Non-compliance | 4 | 2 | 5 |
| One Year Post-transplant | Pancreas transplant | 0 | 0 | 1 |
| One Year Post-transplant | Poor absorption | 0 | 1 | 0 |
| One Year Post-transplant | Rejection | 0 | 1 | 16 |
| One Year Post-transplant | Withdrawal by Subject | 0 | 4 | 1 |
Baseline characteristics
| Characteristic | Tacrolimus | Tacrolimus Modified Release | Cyclosporine | Total |
|---|---|---|---|---|
| Age Continuous | 48.62 years STANDARD_DEVIATION 12.855 | 47.84 years STANDARD_DEVIATION 12.995 | 47.63 years STANDARD_DEVIATION 12.953 | 48.03 years STANDARD_DEVIATION 12.921 |
| Previous Transplant No | 205 participants | 206 participants | 203 participants | 614 participants |
| Previous Transplant Yes | 7 participants | 8 participants | 9 participants | 24 participants |
| Primary Diagnosis Congenital/ Hereditary Nephropathy | 7 participants | 7 participants | 13 participants | 27 participants |
| Primary Diagnosis Diabetic Nephropathy | 46 participants | 38 participants | 46 participants | 130 participants |
| Primary Diagnosis Glomerulonephritis | 44 participants | 43 participants | 43 participants | 130 participants |
| Primary Diagnosis Nephrosclerosis/ Hypertensive Nephropathy | 54 participants | 56 participants | 43 participants | 153 participants |
| Primary Diagnosis Other | 5 participants | 5 participants | 6 participants | 16 participants |
| Primary Diagnosis Polycycstic Kidney Disease | 20 participants | 26 participants | 20 participants | 66 participants |
| Primary Diagnosis Reflux | 1 participants | 0 participants | 1 participants | 2 participants |
| Primary Diagnosis Systemic Vasculitis | 9 participants | 10 participants | 7 participants | 26 participants |
| Primary Diagnosis Tubular/ Interstitial Disease | 9 participants | 5 participants | 16 participants | 30 participants |
| Primary Diagnosis Unknown | 17 participants | 24 participants | 17 participants | 58 participants |
| Race/Ethnicity, Customized Asian | 5 participants | 5 participants | 8 participants | 18 participants |
| Race/Ethnicity, Customized Black | 51 participants | 41 participants | 36 participants | 128 participants |
| Race/Ethnicity, Customized Other | 4 participants | 8 participants | 5 participants | 17 participants |
| Race/Ethnicity, Customized White | 152 participants | 160 participants | 163 participants | 475 participants |
| Sex: Female, Male Female | 76 Participants | 76 Participants | 82 Participants | 234 Participants |
| Sex: Female, Male Male | 136 Participants | 138 Participants | 130 Participants | 404 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 208 / 212 | 212 / 214 | 208 / 212 |
| serious Total, serious adverse events | 148 / 212 | 141 / 214 | 139 / 212 |
Outcome results
Primary
Percentage of Participants With Efficacy Failure
Efficacy failure is defined as any participant who died, experienced a graft failure (permanent return to dialysis \[\> 30 days\] or retransplant), had a biopsy-confirmed (Banff Grade ≥ I) acute rejection (BCAR), or was lost to follow-up. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set, defined as all randomized patients who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Percentage of Participants With Efficacy Failure | 15.1 percentage of participants |
| Tacrolimus Modified Release | Percentage of Participants With Efficacy Failure | 14.0 percentage of participants |
| Cyclosporine | Percentage of Participants With Efficacy Failure | 17.0 percentage of participants |
95.2% CI: [-8.9, 5.2]
95.2% CI: [-9.9, 4]
Secondary
Change From Month 1 in Creatinine Clearance at Month 6 and Month 12
Renal function was assessed by creatinine clearance, calculated using the Cockcroft-Gault formula.
Time frame: Month 1, Month 6, and Month 12
Population: The number of participants analyzed represents the full analysis set with available data at Month 1 and at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus | Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 | At 6 months [N=184, 184, 167] | 0.83 mL/min | Standard Deviation 13.77 |
| Tacrolimus | Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 | At 12 months [N=173, 182, 145] | 1.50 mL/min | Standard Deviation 16.07 |
| Tacrolimus Modified Release | Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 | At 6 months [N=184, 184, 167] | 0.47 mL/min | Standard Deviation 12.9 |
| Tacrolimus Modified Release | Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 | At 12 months [N=173, 182, 145] | 2.62 mL/min | Standard Deviation 14.32 |
| Cyclosporine | Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 | At 6 months [N=184, 184, 167] | -1.79 mL/min | Standard Deviation 14.09 |
| Cyclosporine | Change From Month 1 in Creatinine Clearance at Month 6 and Month 12 | At 12 months [N=173, 182, 145] | -0.25 mL/min | Standard Deviation 14.54 |
Secondary
Change From Month 1 in Serum Creatinine at Month 6 and Month 12
Renal function was assessed by the change from Month 1 in serum creatinine six months and 12 months after transplant.
Time frame: Month 1, Month 6, and Month 12
Population: The number of participants analyzed represents the full analysis set with available data at Month 1 and at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus | Change From Month 1 in Serum Creatinine at Month 6 and Month 12 | At 6 months [N=184, 184, 169] | -0.09 mg/dL | Standard Deviation 0.63 |
| Tacrolimus | Change From Month 1 in Serum Creatinine at Month 6 and Month 12 | At 12 months [N=173, 182, 147] | -0.08 mg/dL | Standard Deviation 0.76 |
| Tacrolimus Modified Release | Change From Month 1 in Serum Creatinine at Month 6 and Month 12 | At 6 months [N=184, 184, 169] | -0.08 mg/dL | Standard Deviation 0.56 |
| Tacrolimus Modified Release | Change From Month 1 in Serum Creatinine at Month 6 and Month 12 | At 12 months [N=173, 182, 147] | -0.14 mg/dL | Standard Deviation 0.62 |
| Cyclosporine | Change From Month 1 in Serum Creatinine at Month 6 and Month 12 | At 6 months [N=184, 184, 169] | -0.01 mg/dL | Standard Deviation 0.53 |
| Cyclosporine | Change From Month 1 in Serum Creatinine at Month 6 and Month 12 | At 12 months [N=173, 182, 147] | -0.04 mg/dL | Standard Deviation 0.53 |
Secondary
Graft Survival at One Year
Graft survival defined as any participant who did not meet the criteria for graft loss, where graft loss is defined as any re-transplant, permanent return to dialysis (\> 30 days), patient death, or participant whose outcome at one year was unknown. Participants were only counted once regardless of how many criteria were met.
Time frame: One year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Graft Survival at One Year | 91.5 percentage of participants |
| Tacrolimus Modified Release | Graft Survival at One Year | 95.3 percentage of participants |
| Cyclosporine | Graft Survival at One Year | 95.3 percentage of participants |
95% CI: [-8.5, 0.9]
95% CI: [-4, 4.1]
Secondary
Kaplan-Meier Estimate of Graft Survival at the End of the Study
Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was any retransplant or the permanent return to dialysis (more than 30 days) or patient death. Graft survival was censored at the time of last follow-up contact.
Time frame: End of study (maximum time on study was 1,941 days).
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Kaplan-Meier Estimate of Graft Survival at the End of the Study | 82.7 percentage of participants |
| Tacrolimus Modified Release | Kaplan-Meier Estimate of Graft Survival at the End of the Study | 84.7 percentage of participants |
| Cyclosporine | Kaplan-Meier Estimate of Graft Survival at the End of the Study | 83.9 percentage of participants |
95% CI: [-9.1, 6.6]
95% CI: [-7.1, 8.6]
Secondary
Kaplan-Meier Estimate of Patient Survival at the End of the Study
Patient survival was defined as any participant who was alive at the end of the study. Patient survival was censored at the time of last follow-up contact.
Time frame: End of study (maximum time on study was 1,941 days).
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Kaplan-Meier Estimate of Patient Survival at the End of the Study | 91.2 percentage of participants |
| Tacrolimus Modified Release | Kaplan-Meier Estimate of Patient Survival at the End of the Study | 93.2 percentage of participants |
| Cyclosporine | Kaplan-Meier Estimate of Patient Survival at the End of the Study | 91.7 percentage of participants |
95% CI: [-6.5, 5.5]
95% CI: [-3.9, 6.9]
Secondary
Number of Participants Experiencing Multiple Rejection Episodes
This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Number of Participants Experiencing Multiple Rejection Episodes | 2 participants |
| Tacrolimus Modified Release | Number of Participants Experiencing Multiple Rejection Episodes | 4 participants |
| Cyclosporine | Number of Participants Experiencing Multiple Rejection Episodes | 8 participants |
Secondary
Number of Participants Requiring Anti-lymphocyte Antibody Therapy for Treatment of Rejection
Rejection episodes were confirmed by biopsy by the clinical site pathologist. Participants with histologically-proven Banff Grade II or III rejection or participants with steroid-resistant rejection were treated with anti-lymphocyte antibody treatment according to institutional practice. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Number of Participants Requiring Anti-lymphocyte Antibody Therapy for Treatment of Rejection | 6 participants |
| Tacrolimus Modified Release | Number of Participants Requiring Anti-lymphocyte Antibody Therapy for Treatment of Rejection | 8 participants |
| Cyclosporine | Number of Participants Requiring Anti-lymphocyte Antibody Therapy for Treatment of Rejection | 18 participants |
Secondary
Number of Participants Who Crossed Over Due to Treatment Failure
Participants were allowed to cross over to an alternative primary immunosuppressive regimen (either to the tacrolimus or cyclosporine treatment arms) to address an adverse event which led to randomized study drug discontinuation or in the case of severe or refractory rejection. Crossover to the modified release tacrolimus treatment arm was not permitted.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Number of Participants Who Crossed Over Due to Treatment Failure | 6 participants |
| Tacrolimus Modified Release | Number of Participants Who Crossed Over Due to Treatment Failure | 10 participants |
| Cyclosporine | Number of Participants Who Crossed Over Due to Treatment Failure | 39 participants |
Secondary
Number of Participants With Clinically Treated Acute Rejection Episodes
A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Number of Participants With Clinically Treated Acute Rejection Episodes | 25 participants |
| Tacrolimus Modified Release | Number of Participants With Clinically Treated Acute Rejection Episodes | 39 participants |
| Cyclosporine | Number of Participants With Clinically Treated Acute Rejection Episodes | 45 participants |
Secondary
Number of Participants With Treatment Failure
Treatment failure was defined as the discontinuation of randomized study drug for any reason. Participants who met the definition of treatment failure were to be followed throughout the 12-month treatment period.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Number of Participants With Treatment Failure | 33 participants |
| Tacrolimus Modified Release | Number of Participants With Treatment Failure | 31 participants |
| Cyclosporine | Number of Participants With Treatment Failure | 61 participants |
Secondary
Patient Survival at One Year
Patient survival is defined as any participant who is known to be alive one year after the skin closure date. Participants who died or whose outcome was unknown at one year were considered to be non-survivors.
Time frame: One year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus | Patient Survival at One Year | 93.9 percentage of participants |
| Tacrolimus Modified Release | Patient Survival at One Year | 97.2 percentage of participants |
| Cyclosporine | Patient Survival at One Year | 97.2 percentage of participants |
95% CI: [-7.2, 0.6]
95% CI: [-3.1, 3.2]
Secondary
Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months
Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. Acute rejection is defined as a grade ≥ I.
Time frame: Six months and 12 months
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months | At 6 Months | 3.8 percentage of participants |
| Tacrolimus | Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months | At 12 Months | 7.5 percentage of participants |
| Tacrolimus Modified Release | Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months | At 6 Months | 7.9 percentage of participants |
| Tacrolimus Modified Release | Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months | At 12 Months | 10.3 percentage of participants |
| Cyclosporine | Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months | At 6 Months | 11.8 percentage of participants |
| Cyclosporine | Percentage of Participants With Biopsy Confirmed Acute Rejection at 6 and 12 Months | At 12 Months | 13.7 percentage of participants |
Comparison: Comparison of tacrolimus with cyclosporine at 6 months95% CI: [-13.1, -3]
Comparison: Comparison of Tacrolimus Modified Release with Cyclosporine at 6 months95% CI: [-9.5, 1.8]
Comparison: Comparison of tacrolimus with cyclosporine at 12 months95% CI: [-12, -0.3]
Comparison: Comparison of Tacrolimus Modified Release with Cyclosporine at 12 months95% CI: [-9.6, 2.8]
Secondary
Severity of Acute Rejection
Rejection episodes were confirmed by biopsy by the clinical site pathologist. Biopsies were graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade IA: Significant interstitial infiltration and foci of moderate tubulitis; Grade IB: Significant interstitial infiltration and foci of severe tubulitis; Grade IIA: Mild to moderate intimal arteritis in at least 1 arterial cross section Grade IIB: Severe intimal arteritis comprising \>25% of the luminal area lost in at least 1 arterial cross section; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set with a biopsy-confirmed acute rejection episode during one year.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus | Severity of Acute Rejection | Grade II-B | 1 participants |
| Tacrolimus | Severity of Acute Rejection | Grade II-A | 3 participants |
| Tacrolimus | Severity of Acute Rejection | Grade I-A | 8 participants |
| Tacrolimus | Severity of Acute Rejection | Grade I-B | 4 participants |
| Tacrolimus | Severity of Acute Rejection | Grade III | 0 participants |
| Tacrolimus Modified Release | Severity of Acute Rejection | Grade II-A | 6 participants |
| Tacrolimus Modified Release | Severity of Acute Rejection | Grade I-A | 11 participants |
| Tacrolimus Modified Release | Severity of Acute Rejection | Grade I-B | 3 participants |
| Tacrolimus Modified Release | Severity of Acute Rejection | Grade II-B | 1 participants |
| Tacrolimus Modified Release | Severity of Acute Rejection | Grade III | 1 participants |
| Cyclosporine | Severity of Acute Rejection | Grade III | 2 participants |
| Cyclosporine | Severity of Acute Rejection | Grade II-B | 1 participants |
| Cyclosporine | Severity of Acute Rejection | Grade I-A | 14 participants |
| Cyclosporine | Severity of Acute Rejection | Grade II-A | 6 participants |
| Cyclosporine | Severity of Acute Rejection | Grade I-B | 6 participants |
Secondary
Time to First Biopsy-confirmed Acute Rejection Episode
Time to first biopsy-confirmed acute rejection episode defined as the number of days from skin closure (Day 0) to the date of biopsy. Rejection episodes were confirmed by biopsy by the clinical site pathologist and graded according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. Acute rejection is defined as a grade ≥ I.
Time frame: one year
Population: The number of participants analyzed represents the full analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tacrolimus | Time to First Biopsy-confirmed Acute Rejection Episode | 156.00 days |
| Tacrolimus Modified Release | Time to First Biopsy-confirmed Acute Rejection Episode | 11.00 days |
| Cyclosporine | Time to First Biopsy-confirmed Acute Rejection Episode | 52.00 days |