| Primary | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus | The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state using the linear trapezoidal rule. The AUC0-24 for tacrolimus was calculated as the sum of the AUC0-12 and AUC 12-24 for the morning and afternoon doses. | The pharmacokinetic evaluable set was defined as all patients who completed both pharmacokinetic profiles: one for tacrolimus, and one for tacrolimus MR. A complete pharmacokinetic profile was considered to be a profile that was adequate to determine AUC0-24, Cmax, and Cmin. | Posted | | Mean | Standard Deviation | ng*hr/mL | | For tacrolimus, Day 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, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
| | | Title | Denominators | Categories |
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| Day 7: Tacrolimus | | | | Day 14: Tacrolimus MR | | |
| | Group IDs | Group Description | Statistical Method | Statistical Comment | P-Value | P-Value Comment | Parameter Type | Parameter Value | Dispersion Type | Dispersion Value | Confidence Interval Sides | Confidence Interval % | CI Lower Limit | CI Upper Limit | CI Lower Limit Comment | CI Upper Limit Comment | Estimate Comment | Tested Non-Inferiority | Non-Inferiority Type | Non-Inferiority Comment | Other Analysis Description |
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| The method of analysis of variance was used for the comparisons of AUC0-24. Exposure at steady state was used for tacrolimus (defined as Day 7) and for tacrolimus MR (defined as Day 14). 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. | | | | | Ratio of means | 100.9 | | | 2-Sided | 90 | 90.8 | 112.1 | | | Tacrolimus/tacrolimus MR ratio of natural log transformed means expressed as a percent. | Yes | Non-Inferiority or Equivalence | |
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| Secondary | Maximum Observed Concentration of Tacrolimus (Cmax) | The maximum concentration was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR at steady state, without interpolation. | Pharmacokinetic evaluable set. | Posted | | Mean | Standard Deviation | ng/mL | | For tacrolimus, Day 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, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Pharmacokinetic evaluable set. | Posted | | Mean | Standard Deviation | ng/mL | | Day 7 at 12 hours post-dose (tacrolimus) and Day 14 at 24 hours post-dose (tacrolimus MR). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| Primary | Patient Survival | Patient survival was defined as any participant known to be alive at the end of the study. | The Modified Full Analysis Set included all patients who took at least 1 dose of tacrolimus MR formulation during the extended treatment period. | Posted | | Number | 95% Confidence Interval | percentage of participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Modified full analysis set. | Posted | | Number | 95% Confidence Interval | percentage of participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| Secondary | Time to Maximum Observed Concentration of Tacrolimus (Tmax) | Time to reach the first observed maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation. | Pharmacokinetic evaluable set. | Posted | | Median | Full Range | hours | | For tacrolimus, Day 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, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose. | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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 | Modified full analysis set. | Posted | | Number | | percentage of participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Participants in the modified full analysis set who died on study. | Posted | | Median | Full Range | days | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Participants in the modified full analysis set with graft loss. | Posted | | Median | Full Range | days | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Participants in the modified full analysis set with a biopsy-confirmed acute rejection. | Posted | | Median | Full Range | days | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Participants in the modified full analysis set with a biopsy-confirmed acute rejection. | Posted | | Number | | participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Modified full analysis set. | Posted | | Number | | participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
|---|
| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Modified full analysis set. | Posted | | Number | | participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
|---|
| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Modified full analysis set. | Posted | | Number | | participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | | Posted | | | | | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | | Posted | | | | | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| 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. | Participants in the modified full analysis set with graft loss. | Posted | | Number | | participants | | From enrollment until the end of study (up to 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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| Secondary | Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests | An adverse event (AE) 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.
| Modified safety analysis set defined as all participants who took at least 1 dose of both tacrolimus and tacrolimus MR formulation during the pharmacokinetic period of the study. | Posted | | Number | | participants | | From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 54 months). | | | | ID | Title | Description |
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| OG000 | Tacrolimus MR | Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study. |
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