Liver Transplantation
Conditions
Keywords
Pharmacokinetics, Therapy, Immunosuppression, Drugs, Investigational, Adult
Brief summary
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.
Detailed description
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.
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 liver 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 liver * 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 | 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. | 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. |
| Minimum Observed Concentration of Tacrolimus (Cmin) | Days 14 and 42 at 12 hours post-dose (tacrolimus) and Days 28 and 56 at 24 hours post-dose (for tacrolimus MR). | 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. |
| Patient Survival | From enrollment until the end of study (up to 60 months). | Patient survival was defined as any participant known to be alive at 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 participant death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 the first dose of study drug to graft loss. Graft loss was defined as graft failure (re-transplant) 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 (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. |
| 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 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. |
| 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. |
| 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. |
| Maximum Observed Concentration of Tacrolimus (Cmax) | 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. | The maximum concentration was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR treatment periods at steady state, without interpolation. |
| 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 participant death. |
| Change From Baseline in Alanine Aminotransferase (ALT) | 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). | Hepatic function was assessed by measuring alanine aminotransferase levels over the course of the study. |
| Change From Baseline in Aspartate Aminotransferase (AST) | 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). | Hepatic function was assessed by measuring aspartate aminotransferase levels over the course of the study. |
| Change From Baseline in Total Bilirubin | 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). | Hepatic function was assessed by measuring total bilirubin over the course of the study. |
| Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). | 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. |
| 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. |
| Time to Maximum Observed Concentration of Tacrolimus (Tmax) | 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 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. |
| 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 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 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 first dose of study drug to death due to any cause. |
Countries
United States
Participant flow
Recruitment details
Stable liver transplant recipients aged 18 to 65 years who were on a stable dose of tacrolimus based immunosuppressive regimen.
Pre-assignment details
Pharmacokinetic (PK) treatment period was 56 days. Participants who completed the PK period were eligible to continue receiving tacrolimus MR in the extended treatment period, from Day 57 up to 60 months.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus MR After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study.
Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons. | 62 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extension Treatment Period | Adverse Event | 15 |
| Extension Treatment Period | Non-compliance | 2 |
| Extension Treatment Period | Physician Decision | 1 |
| Extension Treatment Period | Withdrawal by Subject | 4 |
| Pharmacokinetic Treatment Period | Adverse Event | 3 |
| Pharmacokinetic Treatment Period | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Tacrolimus MR |
|---|---|
| Age Continuous | 50.3 years STANDARD_DEVIATION 8.97 |
| Race/Ethnicity, Customized Black | 4 participants |
| Race/Ethnicity, Customized Pacific Islander | 1 participants |
| Race/Ethnicity, Customized White | 57 participants |
| Reason for End Stage Liver Disease Alcoholic Liver Disease | 11 participants |
| Reason for End Stage Liver Disease Alpha-1 Anti-Trypsin Deficiency | 3 participants |
| Reason for End Stage Liver Disease Autoimmune Disease | 4 participants |
| Reason for End Stage Liver Disease Cryptogenic Cirrhosis | 2 participants |
| Reason for End Stage Liver Disease Hepatitis B | 2 participants |
| Reason for End Stage Liver Disease Hepatitis C | 15 participants |
| Reason for End Stage Liver Disease Non-Alcoholic Steatohepatitis | 2 participants |
| Reason for End Stage Liver Disease Other | 9 participants |
| Reason for End Stage Liver Disease Primary Biliary Cirrhosis | 7 participants |
| Reason for End Stage Liver Disease Primary Sclerosing Cholangitis | 6 participants |
| Reason for End Stage Liver Disease Unknown | 1 participants |
| Re-transplant No | 56 participants |
| Re-transplant Yes | 6 participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 36 Participants |
| Type of Current Transplant Living related Donor | 3 participants |
| Type of Current Transplant Split Cadaver | 3 participants |
| Type of Current Transplant Whole Cadaver | 56 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 51 / 69 |
| serious Total, serious adverse events | 37 / 69 |
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 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.
Population: Pharmacokinetic evaluable set defined as all patients with four complete pharmacokinetic profiles (two tacrolimus and 2 tacrolimus MR).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus MR | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 14: Tacrolimus | 215.6 ng*hr/mL | Standard Deviation 77.8 |
| Tacrolimus MR | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 28: Tacrolimus MR | 184.0 ng*hr/mL | Standard Deviation 62.7 |
| Tacrolimus MR | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 42: Tacrolimus | 202.4 ng*hr/mL | Standard Deviation 53.3 |
| Tacrolimus MR | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | Day 56: Tacrolimus MR | 187.9 ng*hr/mL | Standard Deviation 58.1 |
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 14 and 42) and for tacrolimus MR (steady state was defined as days 28 and 56). 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: [85.42, 92.29]
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 participant death.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus MR | Graft Survival | 90.77 percentage of participants |
Primary
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).
Population: Pharmacokinetic evaluable set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus MR | Minimum Observed Concentration of Tacrolimus (Cmin) | Day 14: Tacrolimus | 7.1 ng/mL | Standard Deviation 2.5 |
| Tacrolimus MR | Minimum Observed Concentration of Tacrolimus (Cmin) | Day 28: Tacrolimus MR | 5.5 ng/mL | Standard Deviation 1.8 |
| Tacrolimus MR | Minimum Observed Concentration of Tacrolimus (Cmin) | Day 42: Tacrolimus | 6.8 ng/mL | Standard Deviation 1.8 |
| Tacrolimus MR | Minimum Observed Concentration of Tacrolimus (Cmin) | Day 56: Tacrolimus MR | 5.8 ng/mL | Standard Deviation 1.8 |
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 14 and 42) and for tacrolimus MR (steady state was defined as days 28 and 56). 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: [77.88, 85.08]
Primary
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).
Population: Modified full analysis set, defined as all patients who took at least one dose of tacrolimus MR during the extended treatment period of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus MR | Patient Survival | 92.31 percentage of participants |
Secondary
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).
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 MR | Change From Baseline in Alanine Aminotransferase (ALT) | Baseline [N= 69] | 38.5 U/L | Standard Deviation 22.38 |
| Tacrolimus MR | Change From Baseline in Alanine Aminotransferase (ALT) | Change from Baseline at Day 56 [N=67] | 14.4 U/L | Standard Deviation 79.16 |
| Tacrolimus MR | Change From Baseline in Alanine Aminotransferase (ALT) | Change from Baseline at EOT [N=68] | 13.3 U/L | Standard Deviation 60.6 |
Secondary
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).
Population: Modified safety analysis set. N indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus MR | Change From Baseline in Aspartate Aminotransferase (AST) | Baseline [N= 69] | 33.4 U/L | Standard Deviation 17.94 |
| Tacrolimus MR | Change From Baseline in Aspartate Aminotransferase (AST) | Change from Baseline at Day 56 [N=67] | 3.6 U/L | Standard Deviation 23.32 |
| Tacrolimus MR | Change From Baseline in Aspartate Aminotransferase (AST) | Change from Baseline at EOT [N=68] | 10.6 U/L | Standard Deviation 55.05 |
Secondary
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).
Population: Modified safety analysis set. N indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus MR | Change From Baseline in Total Bilirubin | Baseline [N= 69] | 0.74 mg/dL | Standard Deviation 0.604 |
| Tacrolimus MR | Change From Baseline in Total Bilirubin | Change from Baseline at Day 56 [N=67] | 0.03 mg/dL | Standard Deviation 0.657 |
| Tacrolimus MR | Change From Baseline in Total Bilirubin | Change from Baseline at EOT [N=68] | 1.04 mg/dL | Standard Deviation 5.948 |
Secondary
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).
Population: Participants in the modified full analysis set with a biopsy-confirmed acute rejection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus MR | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade I | 4 participants |
| Tacrolimus MR | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade II | 2 participants |
| Tacrolimus MR | Grade of Biopsy-confirmed Acute Rejection Episodes | Grade III | 0 participants |
Secondary
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.
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.
Population: Pharmacokinetic evaluable set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus MR | Maximum Observed Concentration of Tacrolimus (Cmax) | Day 56: Tacrolimus MR | 14.1 ng/mL | Standard Deviation 6 |
| Tacrolimus MR | Maximum Observed Concentration of Tacrolimus (Cmax) | Day 14: Tacrolimus | 17.9 ng/mL | Standard Deviation 9.9 |
| Tacrolimus MR | Maximum Observed Concentration of Tacrolimus (Cmax) | Day 28: Tacrolimus MR | 13.3 ng/mL | Standard Deviation 5.6 |
| Tacrolimus MR | Maximum Observed Concentration of Tacrolimus (Cmax) | Day 42: Tacrolimus | 16.0 ng/mL | Standard Deviation 6.9 |
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.
Time frame: From enrollment until the end of study (up to 60 months).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus MR | Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection | 1 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 MR | Number of Participants With Clinically Treated Acute Rejection Episodes | 5 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 MR | 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 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).
Population: Modified full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tacrolimus MR | Percentage of Participants With Biopsy-confirmed Acute Rejection | 9.23 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 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 | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus MR | Primary Reason for Graft Loss | Recurrent disease | 1 participants |
| Tacrolimus MR | Primary Reason for Graft Loss | Death | 5 participants |
Secondary
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).
Population: Modified safety analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tacrolimus MR | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Any adverse event | 63 participants |
| Tacrolimus MR | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Serious adverse event | 37 participants |
| Tacrolimus MR | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Adverse event leading to discontinuation | 18 participants |
| Tacrolimus MR | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Adverse event leading to dose changes | 37 participants |
| Tacrolimus MR | Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs | Death | 5 participants |
Secondary
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).
Population: Participants in the modified full analysis set with graft loss.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tacrolimus MR | Time to Event for Graft Non-survival | 1529.50 days |
Secondary
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).
Population: Participants in the modified full analysis set who died on study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tacrolimus MR | Time to Event for Patient Non-survival | 1561.00 days |
Secondary
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).
Population: Participants in the modified full analysis set with a biopsy-confirmed acute rejection.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tacrolimus MR | Time to First Biopsy-confirmed Acute Rejection | 802.50 days |
Secondary
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.
Population: Pharmacokinetic evaluable set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus MR | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 14: Tacrolimus | 2.8 hours | Standard Deviation 4.2 |
| Tacrolimus MR | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 28: Tacrolimus MR | 3.0 hours | Standard Deviation 3.1 |
| Tacrolimus MR | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 42: Tacrolimus | 3.0 hours | Standard Deviation 4.4 |
| Tacrolimus MR | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Day 56: Tacrolimus MR | 2.7 hours | Standard Deviation 2.1 |