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A Study to Assess the Pharmacokinetics of a Modified-release Tacrolimus Based Immunosuppression Regimen in Stable Kidney Transplant Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00282568
Recruitment Status : Completed
First Posted : January 27, 2006
Results First Posted : September 26, 2013
Last Update Posted : September 26, 2013
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Prevention
Condition Kidney Transplantation
Interventions Drug: Tacrolimus Modified Release (MR)
Drug: tacrolimus
Enrollment 70
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.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description 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.
Period Title: Pharmacokinetic Treatment Period
Started 70
Received Tacrolimus 68
Received Tacrolimus MR 67
Completed 67
Not Completed 3
Reason Not Completed
Discontinued prior to Day 1             2
Enrolled erroneously             1
Period Title: Extended Treatment Period
Started 66 [1]
Completed 42
Not Completed 24
Reason Not Completed
Adverse Event             17
Non-compliance             4
Physician Decision             1
Lost to Follow-up             2
[1]
One patient who completed the PK period did not enter the extended treatment period.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description 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.
Overall Number of Baseline Participants 66
Hide Baseline Analysis Population Description
Pharmacokinetic evaluable set defined as all patients with all five complete pharmacokinetic profiles (two tacrolimus and three tacrolimus MR).
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 66 participants
46.9  (12.37)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 66 participants
Female
24
  36.4%
Male
42
  63.6%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 66 participants
White 53
Black 12
Asian 1
Reason for End Stage Renal Disease  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 66 participants
Glomerulonephritis 16
Polycystic Kidney Disease 8
Hypertensive Nephrosclerosis 6
Immunoglobulin A Nephropathy 6
Diabetes 6
Systemic Lupus Erythematosis 5
Focal Segmental Glomerulonephritis 5
Tubular and Interstitial Disease 3
Unknown 1
Other 10
Type of Current Transplant  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 66 participants
Cadaver 43
Living Related Donor 18
Living Nonrelated Donor 5
Re-transplant  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 66 participants
No 61
Yes 5
History of Pre-Study Dialysis  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 66 participants
No 12
Yes 54
1.Primary Outcome
Title Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
Day 1: Tacrolimus 215.1  (59.4)
Day 7: Tacrolimus 206.6  (58.4)
Day 14: Tacrolimus MR 200.7  (57.5)
Day 21: Tacrolimus MR 197.6  (47.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tacrolimus Modified Release
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments If the 90% Confidence Interval for the ratio of the natural log-transformed pharmacokinetic parameters fell within an 80% to 125% range, then the exposure between the two formulations was considered to be equivalent.
Method of Estimation Estimation Parameter Ratio of means
Estimated Value 94.97
Confidence Interval (2-Sided) 90%
90.72 to 99.41
Estimation Comments Tacrolimus/tacrolimus MR ratio of natural log transformed means expressed as a percent.
2.Primary Outcome
Title Maximum Observed Concentration (Cmax) of Tacrolimus
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
The number of participants analyzed represents the Pharmacokinetic evaluable set.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Mean (Standard Deviation)
Unit of Measure: ng/mL
Day 1: Tacrolimus 17.2  (7.2)
Day 7: Tacrolimus 16.0  (6.5)
Day 14: Tacrolimus MR 14.3  (4.7)
Day 21: Tacrolimus MR 14.2  (5.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tacrolimus Modified Release
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments If the 90% CI for the ratio of the natural log-transformed pharmacokinetic parameters fell within an 80% to 125% range, then the exposure between the two formulations was considered to be equivalent.
Method of Estimation Estimation Parameter Ratio of means
Estimated Value 88.15
Confidence Interval (2-Sided) 90%
82.69 to 93.96
Estimation Comments Tacrolimus/tacrolimus MR ratio of natural log transformed means expressed as a percent.
3.Primary Outcome
Title Minimum Concentration of Tacrolimus (Cmin)
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Mean (Standard Deviation)
Unit of Measure: ng/mL
Day 1: Tacrolimus 6.96  (1.90)
Day 7: Tacrolimus 6.73  (1.99)
Day 14: Tacrolimus MR 6.08  (1.80)
Day 21: Tacrolimus MR 5.83  (1.63)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tacrolimus Modified Release
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments If the 90% CI for the ratio of the natural log-transformed pharmacokinetic parameters fell within an 80% to 125% range, then the exposure between the two formulations was considered to be equivalent.
Method of Estimation Estimation Parameter Ratio of means
Estimated Value 87.20
Confidence Interval (2-Sided) 90%
82.72 to 91.93
Estimation Comments Tacrolimus/tacrolimus MR ratio of natural log transformed means expressed as a percent.
4.Primary Outcome
Title Time to Maximum Observed Concentration of Tacrolimus (Tmax)
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Mean (Standard Deviation)
Unit of Measure: hours
Day 1: Tacrolimus 1.9  (1.8)
Day 7: Tacrolimus 2.0  (1.7)
Day 14: Tacrolimus MR 3.1  (2.3)
Day 21: Tacrolimus MR 2.7  (2.1)
5.Primary Outcome
Title Patient Survival
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
95.45
(90.43 to 100.00)
6.Primary Outcome
Title Graft Survival
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
86.36
(78.08 to 94.64)
7.Secondary Outcome
Title Percentage of Participants With Biopsy-confirmed Acute Rejection
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Modified full analysis set
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
10.61
(3.18 to 18.03)
8.Secondary Outcome
Title Change From Baseline in Serum Creatinine
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 67
Mean (Standard Deviation)
Unit of Measure: mg/dL
Baseline [N= 67] 1.37  (0.501)
Change from Baseline at Day 35 [N=66] 0.09  (0.350)
Change from Baseline at EOT [N=67] 0.57  (2.322)
9.Secondary Outcome
Title Change From Baseline in Creatinine Clearance
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Modified safety analysis set
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 67
Mean (Standard Deviation)
Unit of Measure: mL/minute
Baseline [N= 67] 62.29  (17.531)
Change from Baseline at Day 35 [N=66] -2.32  (5.500)
Change from Baseline at EOT [N=67] -5.41  (13.335)
10.Secondary Outcome
Title Time to Event for Patient Non Survival
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the modified full analysis set who died on study.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 3
Median (Full Range)
Unit of Measure: days
1754.00
(1063.0 to 1799.0)
11.Secondary Outcome
Title Time to Event for Graft Non Survival
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the modified full analysis set with graft loss.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 9
Median (Full Range)
Unit of Measure: days
1526.00
(130.0 to 2113.0)
12.Secondary Outcome
Title Time to First Biopsy-confirmed Acute Rejection
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the modified full analysis set with a biopsy-confirmed acute rejection.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 7
Median (Full Range)
Unit of Measure: days
727.00
(163.0 to 1762.0)
13.Secondary Outcome
Title Grade of Biopsy-confirmed Acute Rejection Episodes
Hide Description

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).
Hide Outcome Measure Data
Hide Analysis Population Description
Participants in the modified full analysis set with a biopsy-confirmed acute rejection.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 7
Measure Type: Number
Unit of Measure: participants
Grade IA 3
Grade IB 1
Grade IIA 2
Grade IIB 1
Grade III 0
14.Secondary Outcome
Title Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Modified full analysis set
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Measure Type: Number
Unit of Measure: participants
4
15.Secondary Outcome
Title Number of Participants With Multiple Rejection Episodes
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Modified full analysis set
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Measure Type: Number
Unit of Measure: participants
2
16.Secondary Outcome
Title Number of Participants With Clinically Treated Acute Rejection Episodes
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Modified full analysis set
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Measure Type: Number
Unit of Measure: participants
7
17.Secondary Outcome
Title Number of Participants With Chronic Rejection
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
18.Secondary Outcome
Title Number of Participants With Treatment Failure
Hide Description 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).
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[Not Specified]
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
19.Secondary Outcome
Title Primary Reason for Graft Loss
Hide Description 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).
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Participants in the modified full analysis set with graft loss.
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 9
Measure Type: Number
Unit of Measure: participants
Donor GBM disease 1
Drug induced nephropathy 1
Polyoma virus 1
Renal insufficiency 1
Non-compliance with study medication 1
Recurrent disease 1
Death 3
20.Secondary Outcome
Title Number of Participants Returning to Permanent Dialysis
Hide Description Permanent dialysis defined as dialysis for longer than 30 days.
Time Frame From enrollment until the end of study (up to 60 months).
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Modified full analysis set
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 66
Measure Type: Number
Unit of Measure: participants
3
21.Secondary Outcome
Title Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs
Hide Description

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).
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Hide Analysis Population Description
Modified safety analysis set
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 67
Measure Type: Number
Unit of Measure: participants
Any adverse event 66
Any serious adverse event 39
Adverse event leading to discontinuation 16
Adverse Event leading to dose changes 29
Death 3
Time Frame From the first dose of tacrolimus MR formulation through the day of last dose plus 10 days (approximately 60 months).
Adverse Event Reporting Description Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus MR during the pharmacokinetic period of the study.
 
Arm/Group Title Tacrolimus Modified Release
Hide Arm/Group Description 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.
All-Cause Mortality
Tacrolimus Modified Release
Affected / at Risk (%)
Total   --/-- 
Hide Serious Adverse Events
Tacrolimus Modified Release
Affected / at Risk (%)
Total   39/67 (58.21%) 
Blood and lymphatic system disorders   
Anaemia  1  1/67 (1.49%) 
Leukopenia  1  1/67 (1.49%) 
Cardiac disorders   
Angina pectoris  1  1/67 (1.49%) 
Angina unstable  1  1/67 (1.49%) 
Atrial Fibrillation  1  1/67 (1.49%) 
Cardiac arrest  1  1/67 (1.49%) 
Cardiac failure  1  1/67 (1.49%) 
Cardiac failure congestive  1  1/67 (1.49%) 
Myocardial infarction  1  1/67 (1.49%) 
Gastrointestinal disorders   
Abdominal pain  1  2/67 (2.99%) 
Nausea  1  2/67 (2.99%) 
Vomiting  1  2/67 (2.99%) 
Abdominal pain lower  1  1/67 (1.49%) 
Abdominal strangulated hernia  1  1/67 (1.49%) 
Anal ulcer  1  1/67 (1.49%) 
Coeliac disease  1  1/67 (1.49%) 
Diarrhoea haemorrhagic  1  1/67 (1.49%) 
Dysphagia  1  1/67 (1.49%) 
Gastritis  1  1/67 (1.49%) 
Gastrointestinal haemorrhage  1  1/67 (1.49%) 
Intestinal perforation  1  1/67 (1.49%) 
Palatal dysplasia  1  1/67 (1.49%) 
Small intestinal obstruction  1  1/67 (1.49%) 
General disorders   
Chest pain  1  2/67 (2.99%) 
Pyrexia  1  2/67 (2.99%) 
Asthenia  1  1/67 (1.49%) 
Fatigue  1  1/67 (1.49%) 
Malaise  1  1/67 (1.49%) 
Pelvic mass  1  1/67 (1.49%) 
Immune system disorders   
Amyloidosis  1  1/67 (1.49%) 
Kidney transplant rejection  1  1/67 (1.49%) 
Infections and infestations   
Cellulitis  1  4/67 (5.97%) 
Escherichia urinary tract infection  1  4/67 (5.97%) 
Pyelonephritis  1  3/67 (4.48%) 
Abscess limb  1  2/67 (2.99%) 
Bronchitis  1  2/67 (2.99%) 
Urosepsis  1  2/67 (2.99%) 
Viral infection  1  2/67 (2.99%) 
Cellulitis staphylococcal  1  1/67 (1.49%) 
Clostridium colitis  1  1/67 (1.49%) 
Gastroenteritis  1  1/67 (1.49%) 
Gastroenteritis viral  1  1/67 (1.49%) 
Hepatitis c  1  1/67 (1.49%) 
Herpes zoster  1  1/67 (1.49%) 
Human polyomavirus infection  1  1/67 (1.49%) 
Influenza  1  1/67 (1.49%) 
Orchitis  1  1/67 (1.49%) 
Pneumonia  1  1/67 (1.49%) 
Pneumonitis cryptococcal  1  1/67 (1.49%) 
Pyelonephritis acute  1  1/67 (1.49%) 
Sepsis syndrome  1  1/67 (1.49%) 
Tracheobronchitis  1  1/67 (1.49%) 
Urinary tract infection  1  1/67 (1.49%) 
Urinary tract infection bacterial  1  1/67 (1.49%) 
Injury, poisoning and procedural complications   
Arteriovenous graft site complications  1  1/67 (1.49%) 
Complications of transplant surgery  1  1/67 (1.49%) 
Drug toxicity  1  1/67 (1.49%) 
Incisional hernia  1  1/67 (1.49%) 
Injury  1  1/67 (1.49%) 
Intentional misuse  1  1/67 (1.49%) 
Medication error  1  1/67 (1.49%) 
Post procedural diarrhoea  1  1/67 (1.49%) 
Renal injury  1  1/67 (1.49%) 
Tibia fracture  1  1/67 (1.49%) 
Upper limb fracture  1  1/67 (1.49%) 
Investigations   
Blood creatinine increased  1  2/67 (2.99%) 
Weight decreased  1  2/67 (2.99%) 
Metabolism and nutrition disorders   
Dehydration  1  5/67 (7.46%) 
Diabetic ketoacidosis  1  2/67 (2.99%) 
Fluid overload  1  1/67 (1.49%) 
Gout  1  1/67 (1.49%) 
Hyperkalaemia  1  1/67 (1.49%) 
Hypervolaemia  1  1/67 (1.49%) 
Hypovolaemia  1  1/67 (1.49%) 
Musculoskeletal and connective tissue disorders   
Localised osteoarthritis  1  2/67 (2.99%) 
Aseptic necrosis bone  1  1/67 (1.49%) 
Flank pain  1  1/67 (1.49%) 
Intervertebral disc protrusion  1  1/67 (1.49%) 
Myopathy  1  1/67 (1.49%) 
Osteoarthritis  1  1/67 (1.49%) 
Rhabdomyolysis  1  1/67 (1.49%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Squamous cell carcinoma of skin  1  4/67 (5.97%) 
Basal cell carcinoma  1  2/67 (2.99%) 
Prostate cancer  1  2/67 (2.99%) 
Bladder cancer  1  1/67 (1.49%) 
Bowen's disease  1  1/67 (1.49%) 
Lung neoplasm malignant  1  1/67 (1.49%) 
Lung Nodule  1  1/67 (1.49%) 
Lymphoproliferative disorder  1  1/67 (1.49%) 
Papilloma  1  1/67 (1.49%) 
Renal cell carcinoma stage unspecified  1  1/67 (1.49%) 
Tonsil cancer  1  1/67 (1.49%) 
Tumour lysis syndrome  1  1/67 (1.49%) 
Pregnancy, puerperium and perinatal conditions   
Ectopic pregnancy  1  1/67 (1.49%) 
Renal and urinary disorders   
Renal failure acute  1  7/67 (10.45%) 
Haematuria  1  2/67 (2.99%) 
Renal insufficiency  1  2/67 (2.99%) 
Glomerulonephritis focal  1  1/67 (1.49%) 
Renal failure chronic  1  1/67 (1.49%) 
Tubulointestitial nephritis  1  1/67 (1.49%) 
Reproductive system and breast disorders   
Vulvar Dysplasia  1  1/67 (1.49%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  2/67 (2.99%) 
Bronchospasm  1  1/67 (1.49%) 
Dysphonia  1  1/67 (1.49%) 
Pneumothorax  1  1/67 (1.49%) 
Social circumstances   
Pregnancy of partner  1  1/67 (1.49%) 
Surgical and medical procedures   
Renal transplant  1  1/67 (1.49%) 
Vascular disorders   
Malignant hypertension  1  2/67 (2.99%) 
Gangrene  1  1/67 (1.49%) 
Hypertension  1  1/67 (1.49%) 
Hypotension  1  1/67 (1.49%) 
Peripheral ischaemia  1  1/67 (1.49%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (6.1)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tacrolimus Modified Release
Affected / at Risk (%)
Total   48/67 (71.64%) 
Gastrointestinal disorders   
Diarrhoea  1  12/67 (17.91%) 
Nausea  1  4/67 (5.97%) 
Vomiting  1  4/67 (5.97%) 
General disorders   
Oedema Peripheral  1  6/67 (8.96%) 
Infections and infestations   
Upper respiratory tract infection  1  18/67 (26.87%) 
Sinusitis  1  9/67 (13.43%) 
Escherichia urinary tract infection  1  8/67 (11.94%) 
Nasopharyngitis  1  8/67 (11.94%) 
Influenza  1  7/67 (10.45%) 
Urinary tract infection bacterial  1  6/67 (8.96%) 
Urinary tract infection  1  5/67 (7.46%) 
Herpes zoster  1  4/67 (5.97%) 
Pneumonia  1  4/67 (5.97%) 
Urinary tract infection enterococcal  1  4/67 (5.97%) 
Investigations   
Blood creatinine increased  1  6/67 (8.96%) 
Nervous system disorders   
Headache  1  5/67 (7.46%) 
Respiratory, thoracic and mediastinal disorders   
Pharyngolaryngeal pain  1  5/67 (7.46%) 
Cough  1  4/67 (5.97%) 
Vascular disorders   
Hypertension  1  7/67 (10.45%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (6.1)
Company makes no warranties or representations of any kind as to the posting, expressed or implied, including warranties of merchantability and fitness for a particular purpose, and shall not be liable for any damages.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data or until 18 months have elapsed following study completion. Sponsor must receive a site’s manuscript at least 30 days prior to publication to ensure that no confidential information of Sponsor is included in the document.
Results Point of Contact
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Name/Title: Vice President, Therapeutic Area Head, Transplantation
Organization: Astellas Pharma Global Development, Inc.
EMail: ClinicalTrials.Disclosure@us.astellas.com
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Responsible Party: Astellas Pharma Inc
ClinicalTrials.gov Identifier: NCT00282568    
Other Study ID Numbers: 02-0-131
First Submitted: January 25, 2006
First Posted: January 27, 2006
Results First Submitted: July 25, 2013
Results First Posted: September 26, 2013
Last Update Posted: September 26, 2013