A study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable liver transplant patients converted from a tacrolimus (Prograf®) based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.
A one arm study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable liver transplant patients converted from a tacrolimus (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
Palo Alto, California, United States
Unnamed facility
Denver, Colorado, United States
Unnamed facility
Baltimore, Maryland, United States
Unnamed facility
Ann Arbor, Michigan, 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 the tacrolimus and tacrolimus MR treatment periods at steady state using the linear trapezoidal rule. The AUC0-24 for tacrolimus was calculated as the sum of the AUC0-12 for the morning (0-12 hour) and afternoon (12-24 hour) doses.
Time frame: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose.
Minimum Observed Concentration of Tacrolimus (Cmin)
The trough (minimum) concentration of tacrolimus determined from the tacrolimus whole blood concentration value at the 12 hour post-dose concentration based on the evening dose (i.e., the 8 am concentration) for tacrolimus and the 24-hour time point post-dose for tacrolimus MR, prior to receiving the next dose.
Time frame: Days 14 and 42 at 12 hours post-dose (tacrolimus) and Days 28 and 56 at 24 hours post-dose (for tacrolimus MR).
Patient Survival
Patient survival was defined as any participant known to be alive at the time of analysis.
Time frame: From enrollment until the end of study (up to 60 months).
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 participant death.
Time frame: From enrollment until the end of study (up to 60 months).
Maximum Observed Concentration of Tacrolimus (Cmax)
The maximum concentration was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR treatment periods at steady state, without interpolation.
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Unnamed facility
Minneapolis, Minnesota, United States
Unnamed facility
Rochester, Minnesota, United States
Unnamed facility
New York, New York, United States
Unnamed facility
Cincinnati, Ohio, United States
Unnamed facility
Dallas, Texas, United States
Unnamed facility
Madison, Wisconsin, United States
Time frame: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose.
Time to Maximum Observed Concentration of Tacrolimus (Tmax)
Time to the first occurrence to reach the maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR treatment periods at steady state, without interpolation.
Time frame: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose.
Percentage of Participants With Biopsy-confirmed Acute Rejection
Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the pathologist at the clinical site according to the 1997 Banff criteria for grading of acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I (Mild): Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II (Moderate): Rejection infiltrate, expanding to most or all of the triads; Grade III (Severe): Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis.
Time frame: From enrollment until the end of study (up to 60 months).
Time to Event for Patient Non-survival
For participants who died on study, the median number of days from first dose of study drug 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 the first dose of study drug to graft loss. Graft loss was defined as graft failure (re-transplant) 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 (BCAR), the median number of days from the first dose of study drug to the date of biopsy confirmation. BCAR is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the clinical site pathologist according to the 1997 Banff criteria for grading acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I: Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II: Rejection infiltrate, expanding to most or all of the triads; Grade III: Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis.
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 liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the clinical site pathologist according to the 1997 Banff criteria for grading of acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I (Mild): Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II (Moderate): Rejection infiltrate, expanding to most or all of the triads; Grade III (Severe): Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis. 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.
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 participant death.
Time frame: From enrollment until the end of study (up to 60 months).
Change From Baseline in Alanine Aminotransferase (ALT)
Hepatic function was assessed by measuring alanine aminotransferase levels over the course of the study.
Time frame: Baseline (the last day of tacrolimus on Day 14 prior to the first conversion to tacrolimus MR), Day 56 (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 Aspartate Aminotransferase (AST)
Hepatic function was assessed by measuring aspartate aminotransferase levels over the course of the study.
Time frame: Baseline (the last day of tacrolimus on Day 14 prior to the first conversion to tacrolimus MR), Day 56 (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 Total Bilirubin
Hepatic function was assessed by measuring total bilirubin over the course of the study.
Time frame: Baseline (the last day of tacrolimus on Day 14 prior to the first conversion to tacrolimus MR), Day 56 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months).
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs
An adverse event is 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 last dose day plus 10 days (approximately 60 months).