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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
70
Oral
Oral
Unnamed facility
San Diego, California, United States
Unnamed facility
Miami, Florida, United States
Unnamed facility
Minneapolis, Minnesota, United States
Unnamed facility
Cincinnati, Ohio, United States
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.
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.
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.
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.
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).
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Unnamed facility
Portland, Oregon, United States
Unnamed facility
Madison, Wisconsin, United States
Unnamed facility
Milwaukee, Wisconsin, United States
Unnamed facility
Edmonton, Alberta, Canada
Unnamed facility
Toronto, Ontario, Canada
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).