Kidney Transplantation
Conditions
Keywords
Pharmacokinetics, Therapy, Immunosuppression, Drugs, Investigational, Adult
Brief summary
A study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable kidney transplant patients converted from a Prograf® based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.
Detailed description
This is a Phase II open-label, multi-center conversion study in stable, adult kidney transplant recipients to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable kidney transplant patients converted from a Prograf® based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.
Interventions
Oral
DRUGtacrolimus
Oral
Sponsors
Astellas Pharma Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patient is currently receiving Prograf ® based immunosuppressive therapy for kidney transplantation. * Patient has stable whole blood trough level concentrations of Prograf® and is clinically stable
Exclusion criteria
* Patient has previously received an organ transplant other than a kidney * Patient is currently receiving sirolimus immunosuppression therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. | The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state using the trapezoidal rule. |
| Maximum Observed Concentration (Cmax) of Tacrolimus | For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. | The maximum concentration was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation. |
| Minimum Concentration of Tacrolimus (Cmin) | Days 1 and 7 (tacrolimus) and Days 14 and 21 (tacrolimus MR), 24 hours post-dose. | The trough (minimum) concentration of tacrolimus determined from the tacrolimus whole blood concentration value at the 24-hour time point post- dose, prior to receiving the next dose. |
| Time to Maximum Observed Concentration of Tacrolimus (Tmax) | For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. | The time to reach the maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation. |
| Patient Survival | From enrollment until the end of study (up to 60 months). | Patient Survival defined as any participant who did not die by the time of analysis. |
| Graft Survival | From enrollment until the end of study (up to 60 months). | Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participants death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Grade of Biopsy-confirmed Acute Rejection Episodes | From enrollment until the end of study (up to 60 months). | Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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. For participants with more than one biopsy-confirmed acute rejection episode, the worst case grade is reported. |
| Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection | From enrollment until the end of study (up to 60 months). | Steroid-resistant rejection episodes were treated with anti-lymphocyte antibodies. If a participant had a histologically proven Banff Grade II or III rejection, they could be initiated on anti-lymphocyte antibody treatment per institutional practice. Biopsies were graded by the pathologist at the clinical site 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. |
| Number of Participants With Multiple Rejection Episodes | From enrollment until the end of study (up to 60 months). | This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated. |
| Number of Participants With Clinically Treated Acute Rejection Episodes | From enrollment until the end of study (up to 60 months). | A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy. |
| Percentage of Participants With Biopsy-confirmed Acute Rejection | From enrollment until the end of study (up to 60 months). | Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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. |
| Number of Participants With Treatment Failure | From enrollment until the end of study (up to 60 months). | Treatment failure was defined as discontinuation of study drug for any reason. Due to discontinuation of the study by the sponsor, treatment failure was not analyzed. |
| Primary Reason for Graft Loss | From enrollment until the end of study (up to 60 months). | The primary reason for graft loss was recorded by the Investigator. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis) or death. GBM = glomerular basement membrane. |
| Number of Participants Returning to Permanent Dialysis | From enrollment until the end of study (up to 60 months). | Permanent dialysis defined as dialysis for longer than 30 days. |
| Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | From the first dose of tacrolimus MR formulation through the day of last dose plus 10 days (approximately 60 months). | An adverse event was defined as any reaction, side effect or other untoward medical occurrence, regardless of the relationship to study drug which occurred during the conduct of a clinical study. Clinically significant adverse changes in clinical status, routine laboratory studies or physical examinations were considered adverse events. A serious adverse event was any adverse event occurring at any dose that resulted in any of the following outcomes: * Death * Life-threatening adverse event * Inpatient hospitalization or prolongation of existing hospitalization * Persistent or significant disability or incapacity * Congenital abnormality or birth defect * Important medical event. |
| Number of Participants With Chronic Rejection | From enrollment until the end of study (up to 60 months). | Due to the low number of participants with biopsy-confirmed acute rejection episodes, chronic rejection was not analyzed. |
| Change From Baseline in Serum Creatinine | Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months). | Renal function was assessed using serum creatinine levels over the course of the study. |
| Change From Baseline in Creatinine Clearance | Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months). | Renal function was assessed using creatinine clearance levels calculated using the Cockcroft-Gault formula, over the course of the study. |
| Time to Event for Patient Non Survival | From enrollment until the end of study (up to 60 months). | For participants who died on study, the median number of days from enrollment to death due to any cause. |
| Time to Event for Graft Non Survival | From enrollment until the end of study (up to 60 months). | For participants with graft loss, the median number of days from enrollment to graft loss. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participant death. |
| Time to First Biopsy-confirmed Acute Rejection | From enrollment until the end of study (up to 60 months). | For participants with a biopsy-confirmed acute rejection, the median number of days from enrollment to the date of biopsy confirmation. Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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. |
Countries
Canada, United States
Participant flow
Recruitment details
Stable, adult kidney transplant recipients being treated with tacrolimus (Prograf)-based immunosuppressive regimen.
Pre-assignment details
Pharmacokinetic (PK) treatment period was from Day 1 - 35. Participants who completed the PK period were eligible to continue receiving tacrolimus MR in the extended treatment period, from Day 36 up to 60 months.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus Modified Release Participants were enrolled into the study on their stable twice-daily (bid) dose of tacrolimus on Day 1 and continued to receive a stable bid dose of tacrolimus through Day 7. Participants then converted to Tacrolimus Modified Release (MR), administered once daily at an equivalent dose to the patient's previous stable total daily dose of tacrolimus. Participants who completed the 4-week pharmacokinetic treatment period with tacrolimus MR could continue receiving tacrolimus MR as part of the extended treatment period of the study. Dose adjustments were allowed in order to maintain tacrolimus trough concentrations within the target range of 5 to 15 ng/mL and for clinical reasons. | 66 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extended Treatment Period | Adverse Event | 17 |
| Extended Treatment Period | Lost to Follow-up | 2 |
| Extended Treatment Period | Non-compliance | 4 |
| Extended Treatment Period | Physician Decision | 1 |
| Pharmacokinetic Treatment Period | Discontinued prior to Day 1 | 2 |
| Pharmacokinetic Treatment Period | Enrolled erroneously | 1 |
Baseline characteristics
| Characteristic | Tacrolimus Modified Release |
|---|---|
| Age Continuous | 46.9 years STANDARD_DEVIATION 12.37 |
| History of Pre-Study Dialysis No | 12 participants |
| History of Pre-Study Dialysis Yes | 54 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black | 12 participants |
| Race/Ethnicity, Customized White | 53 participants |
| Reason for End Stage Renal Disease Diabetes | 6 participants |
| Reason for End Stage Renal Disease Focal Segmental Glomerulonephritis | 5 participants |
| Reason for End Stage Renal Disease Glomerulonephritis | 16 participants |
| Reason for End Stage Renal Disease Hypertensive Nephrosclerosis | 6 participants |
| Reason for End Stage Renal Disease Immunoglobulin A Nephropathy | 6 participants |
| Reason for End Stage Renal Disease Other | 10 participants |
| Reason for End Stage Renal Disease Polycystic Kidney Disease | 8 participants |
| Reason for End Stage Renal Disease Systemic Lupus Erythematosis | 5 participants |
| Reason for End Stage Renal Disease Tubular and Interstitial Disease | 3 participants |
| Reason for End Stage Renal Disease Unknown | 1 participants |
| Re-transplant No | 61 participants |
| Re-transplant Yes | 5 participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 42 Participants |
| Type of Current Transplant Cadaver | 43 participants |
| Type of Current Transplant Living Nonrelated Donor | 5 participants |
| Type of Current Transplant Living Related Donor | 18 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 48 / 67 |
| serious Total, serious adverse events | 39 / 67 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus
The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state using the trapezoidal rule.
Time frame: For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
Population: The number of participants analyzed represents the Pharmacokinetic evaluable set, defined as patients with all five complete pharmacokinetic profiles (two tacrolimus and three tacrolimus MR).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Modified Release | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 1: Tacrolimus | 215.1 ng*hr/mL | Standard Deviation 59.4 |
| Tacrolimus Modified Release | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 7: Tacrolimus | 206.6 ng*hr/mL | Standard Deviation 58.4 |
| Tacrolimus Modified Release | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 14: Tacrolimus MR | 200.7 ng*hr/mL | Standard Deviation 57.5 |
| Tacrolimus Modified Release | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 21: Tacrolimus MR | 197.6 ng*hr/mL | Standard Deviation 47.5 |
Comparison: The method of analysis of variance with repeated measures was used for the comparisons of AUC0-24. Exposure at steady state was used for tacrolimus (steady state was defined as days 1 and 7) and for tacrolimus MR (steady state was defined as days 14 and 21). The natural log (ln) was used to transform AUC0-24 prior to analysis and the results were transformed back to the original scale for the presentation of results.90% CI: [90.72, 99.41]
Primary
Graft Survival
Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participants death.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set, defined as all patients who took at least one dose of tacrolimus MR during the extension portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus Modified Release | Graft Survival | 86.36 percentage of participants |
Primary
Maximum Observed Concentration (Cmax) of Tacrolimus
The maximum concentration was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.
Time frame: For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
Population: The number of participants analyzed represents the Pharmacokinetic evaluable set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Modified Release | Maximum Observed Concentration (Cmax) of Tacrolimus | Day 1: Tacrolimus | 17.2 ng/mL | Standard Deviation 7.2 |
| Tacrolimus Modified Release | Maximum Observed Concentration (Cmax) of Tacrolimus | Day 7: Tacrolimus | 16.0 ng/mL | Standard Deviation 6.5 |
| Tacrolimus Modified Release | Maximum Observed Concentration (Cmax) of Tacrolimus | Day 14: Tacrolimus MR | 14.3 ng/mL | Standard Deviation 4.7 |
| Tacrolimus Modified Release | Maximum Observed Concentration (Cmax) of Tacrolimus | Day 21: Tacrolimus MR | 14.2 ng/mL | Standard Deviation 5.1 |
Comparison: The method of analysis of variance with repeated measures was used for the comparisons of Cmax. Exposure at steady state was used for tacrolimus (steady state was defined as days 1 and 7) and for tacrolimus MR (steady state was defined as days 14 and 21). The natural log (ln) was used to transform Cmax prior to analysis and the results were transformed back to the original scale for the presentation of results.90% CI: [82.69, 93.96]
Primary
Minimum Concentration of Tacrolimus (Cmin)
The trough (minimum) concentration of tacrolimus determined from the tacrolimus whole blood concentration value at the 24-hour time point post- dose, prior to receiving the next dose.
Time frame: Days 1 and 7 (tacrolimus) and Days 14 and 21 (tacrolimus MR), 24 hours post-dose.
Population: The number of participants analyzed represents the trough evaluable set defined as all patients with replicate trough measurements for both tacrolimus and tacrolimus MR.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Modified Release | Minimum Concentration of Tacrolimus (Cmin) | Day 1: Tacrolimus | 6.96 ng/mL | Standard Deviation 1.9 |
| Tacrolimus Modified Release | Minimum Concentration of Tacrolimus (Cmin) | Day 7: Tacrolimus | 6.73 ng/mL | Standard Deviation 1.99 |
| Tacrolimus Modified Release | Minimum Concentration of Tacrolimus (Cmin) | Day 14: Tacrolimus MR | 6.08 ng/mL | Standard Deviation 1.8 |
| Tacrolimus Modified Release | Minimum Concentration of Tacrolimus (Cmin) | Day 21: Tacrolimus MR | 5.83 ng/mL | Standard Deviation 1.63 |
Comparison: The method of analysis of variance with repeated measures was used for the comparisons of Cmin. Exposure at steady state was used for tacrolimus (steady state was defined as days 1 and 7) and for tacrolimus MR (steady state was defined as days 14 and 21). The natural log (ln) was used to transform Cmin prior to analysis and the results were transformed back to the original scale for the presentation of results.90% CI: [82.72, 91.93]
Primary
Patient Survival
Patient Survival defined as any participant who did not die by the time of analysis.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set, defined as all patients who took at least one dose of tacrolimus MR during the extension portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus Modified Release | Patient Survival | 95.45 percentage of participants |
Primary
Time to Maximum Observed Concentration of Tacrolimus (Tmax)
The time to reach the maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.
Time frame: For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
Population: The number of participants analyzed represents the trough evaluable set defined as all patients with replicate trough measurements for both tacrolimus and tacrolimus MR.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Modified Release | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 1: Tacrolimus | 1.9 hours | Standard Deviation 1.8 |
| Tacrolimus Modified Release | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 7: Tacrolimus | 2.0 hours | Standard Deviation 1.7 |
| Tacrolimus Modified Release | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 14: Tacrolimus MR | 3.1 hours | Standard Deviation 2.3 |
| Tacrolimus Modified Release | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 21: Tacrolimus MR | 2.7 hours | Standard Deviation 2.1 |
Secondary
Change From Baseline in Creatinine Clearance
Renal function was assessed using creatinine clearance levels calculated using the Cockcroft-Gault formula, over the course of the study.
Time frame: Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months).
Population: Modified safety analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Modified Release | Change From Baseline in Creatinine Clearance | Baseline [N= 67] | 62.29 mL/minute | Standard Deviation 17.531 |
| Tacrolimus Modified Release | Change From Baseline in Creatinine Clearance | Change from Baseline at Day 35 [N=66] | -2.32 mL/minute | Standard Deviation 5.5 |
| Tacrolimus Modified Release | Change From Baseline in Creatinine Clearance | Change from Baseline at EOT [N=67] | -5.41 mL/minute | Standard Deviation 13.335 |
Secondary
Change From Baseline in Serum Creatinine
Renal function was assessed using serum creatinine levels over the course of the study.
Time frame: Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months).
Population: Modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and at least one dose of tacrolimus MR during the pharmacokinetic portion of the study. N indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Modified Release | Change From Baseline in Serum Creatinine | Baseline [N= 67] | 1.37 mg/dL | Standard Deviation 0.501 |
| Tacrolimus Modified Release | Change From Baseline in Serum Creatinine | Change from Baseline at Day 35 [N=66] | 0.09 mg/dL | Standard Deviation 0.35 |
| Tacrolimus Modified Release | Change From Baseline in Serum Creatinine | Change from Baseline at EOT [N=67] | 0.57 mg/dL | Standard Deviation 2.322 |
Secondary
Grade of Biopsy-confirmed Acute Rejection Episodes
Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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. For participants with more than one biopsy-confirmed acute rejection episode, the worst case grade is reported.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Participants in the modified full analysis set with a biopsy-confirmed acute rejection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus Modified Release | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade IA | 3 participants |
| Tacrolimus Modified Release | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade IB | 1 participants |
| Tacrolimus Modified Release | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade IIA | 2 participants |
| Tacrolimus Modified Release | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade IIB | 1 participants |
| Tacrolimus Modified Release | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade III | 0 participants |
Secondary
Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection
Steroid-resistant rejection episodes were treated with anti-lymphocyte antibodies. If a participant had a histologically proven Banff Grade II or III rejection, they could be initiated on anti-lymphocyte antibody treatment per institutional practice. Biopsies were graded by the pathologist at the clinical site 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: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus Modified Release | Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection | 4 participants |
Secondary
Number of Participants Returning to Permanent Dialysis
Permanent dialysis defined as dialysis for longer than 30 days.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus Modified Release | Number of Participants Returning to Permanent Dialysis | 3 participants |
Secondary
Number of Participants With Chronic Rejection
Due to the low number of participants with biopsy-confirmed acute rejection episodes, chronic rejection was not analyzed.
Time frame: From enrollment until the end of study (up to 60 months).
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: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus Modified Release | Number of Participants With Clinically Treated Acute Rejection Episodes | 7 participants |
Secondary
Number of Participants With 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: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus Modified Release | Number of Participants With Multiple Rejection Episodes | 2 participants |
Secondary
Number of Participants With Treatment Failure
Treatment failure was defined as discontinuation of study drug for any reason. Due to discontinuation of the study by the sponsor, treatment failure was not analyzed.
Time frame: From enrollment until the end of study (up to 60 months).
Secondary
Percentage of Participants With Biopsy-confirmed Acute Rejection
Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus Modified Release | Percentage of Participants With Biopsy-confirmed Acute Rejection | 10.61 percentage of participants |
Secondary
Primary Reason for Graft Loss
The primary reason for graft loss was recorded by the Investigator. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis) or death. GBM = glomerular basement membrane.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Participants in the modified full analysis set with graft loss.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus Modified Release | Primary Reason for Graft Loss | Donor GBM disease | 1 participants |
| Tacrolimus Modified Release | Primary Reason for Graft Loss | Drug induced nephropathy | 1 participants |
| Tacrolimus Modified Release | Primary Reason for Graft Loss | Polyoma virus | 1 participants |
| Tacrolimus Modified Release | Primary Reason for Graft Loss | Renal insufficiency | 1 participants |
| Tacrolimus Modified Release | Primary Reason for Graft Loss | Non-compliance with study medication | 1 participants |
| Tacrolimus Modified Release | Primary Reason for Graft Loss | Recurrent disease | 1 participants |
| Tacrolimus Modified Release | Primary Reason for Graft Loss | Death | 3 participants |
Secondary
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs
An adverse event was defined as any reaction, side effect or other untoward medical occurrence, regardless of the relationship to study drug which occurred during the conduct of a clinical study. Clinically significant adverse changes in clinical status, routine laboratory studies or physical examinations were considered adverse events. A serious adverse event was any adverse event occurring at any dose that resulted in any of the following outcomes: * Death * Life-threatening adverse event * Inpatient hospitalization or prolongation of existing hospitalization * Persistent or significant disability or incapacity * Congenital abnormality or birth defect * Important medical event.
Time frame: From the first dose of tacrolimus MR formulation through the day of last dose plus 10 days (approximately 60 months).
Population: Modified safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus Modified Release | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Any adverse event | 66 participants |
| Tacrolimus Modified Release | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Any serious adverse event | 39 participants |
| Tacrolimus Modified Release | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Adverse event leading to discontinuation | 16 participants |
| Tacrolimus Modified Release | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Adverse Event leading to dose changes | 29 participants |
| Tacrolimus Modified Release | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Death | 3 participants |
Secondary
Time to Event for Graft Non Survival
For participants with graft loss, the median number of days from enrollment to graft loss. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participant death.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Participants in the modified full analysis set with graft loss.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tacrolimus Modified Release | Time to Event for Graft Non Survival | 1526.00 days |
Secondary
Time to Event for Patient Non Survival
For participants who died on study, the median number of days from enrollment to death due to any cause.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Participants in the modified full analysis set who died on study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tacrolimus Modified Release | Time to Event for Patient Non Survival | 1754.00 days |
Secondary
Time to First Biopsy-confirmed Acute Rejection
For participants with a biopsy-confirmed acute rejection, the median number of days from enrollment to the date of biopsy confirmation. Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site 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: From enrollment until the end of study (up to 60 months).
Population: Participants in the modified full analysis set with a biopsy-confirmed acute rejection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tacrolimus Modified Release | Time to First Biopsy-confirmed Acute Rejection | 727.00 days |