A Study of a Modified-Release Tacrolimus Based Immunosuppression Regimen in Stable Pediatric Liver Transplant Patients

Study Overview
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Brief Summary
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A study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable pediatric liver transplant patients converted from a Prograf® based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.

Detailed Description
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A 1 arm study to assess the pharmacokinetics, and long-term safety and effectiveness of a modified release tacrolimus based immunosuppression regimen in stable pediatric liver transplant patients converted from a Prograf® based immunosuppression regimen.

Official Title
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A Phase 2, Open-Label, Multi-center Study to Assess the Pharmacokinetics, Long-Term Safety and Tolerability of Tacrolimus in Stable Pediatric Liver Transplant Patients Converted From a Prograf® Based Immunosuppression Regimen to a Modified Release (MR) Tacrolimus Based Immunosuppression Regimen

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: tacrolimus modified release (MR)
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus MR<br>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. | Drug: tacrolimus modified release (MR)<br>* Oral<br>* Other names: Astagraf XL;Drug: tacrolimus<br>* Oral<br>* Other names: FK506;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | Day 7 at 12 hours post-dose (tacrolimus) and Day 14 at 24 hours post-dose (tacrolimus MR). | 
| Patient Survival | Patient survival was defined as any participant known to be alive at the end of the study. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. | 
| 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 | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 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. | From enrollment until the end of study (up to 54 months). | 
| 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. | From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 54 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Child, Pharmacokinetics, Immunosuppression Drugs, Hepatic transplant, Liver Transplantation