A Study of Modigraf® (Tacrolimus Granules) to Evaluate the Pharmacokinetics and Long-term Safety and Efficacy in De Novo Pediatric Allograft Liver and Kidney Transplantation Recipients

Astellas Pharma China, Inc.55 enrolled

Overview

The purpose of this study is to determine the pharmacokinetics of tacrolimus following oral administration of Modigraf, after the first oral dose and at steady state in pediatric participants undergoing de novo allograft liver or kidney transplantation. This study will also observe the safety and efficacy of Modigraf in de novo pediatric allograft liver and kidney transplantation recipients.

Pediatric participants will be treated with a Modigraf (tacrolimus granules) based immunosuppressive regimen for 12 months.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Liver Transplantation Kidney Transplantation

Interventions

Eligibility

Sex: ALLMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participant's parent(s) or their legal representative(s), and participant where applicable agrees not to participate in another interventional study while participating in the present study from 1 month before screening to the end of the study. Exclusion Criteria: * Participant has previously received another organ transplant. * Participant has a high immunological risk, defined as a panel reactive antibody (PRA) score \> 50% in the previous 6 months (only applicable for kidney transplantation recipients). * Cold ischemia time of the donor kidney longer than 30 hours (only applicable for kidney transplantation recipients). * Bilateral kidney transplantation recipients (only applicable for kidney transplantation recipients). * Participant receives an ABO incompatible donor organ. * Participant has significant kidney impairment, defined as having serum creatinine ≥ 230 μmol/L (≥ 2.6 mg/dL) prior to transplantation (not applicable for kidney transplantation recipients). * Participant has significant liver disease, defined as having elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and/or total bilirubin (TBL) levels 3 times the upper value of the normal range prior to transplantation (not applicable for liver transplantation recipients). * Participants with malignancies or a history of malignancy within the last 5 years. * Participant has a significant, uncontrolled systemic infection and/or severe diarrhea, vomiting, active upper gastrointestinal disorder that may affect the absorption of tacrolimus or has an active peptic ulcer. * Recipient or donor known to be human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) positive. * Participant requires systemic immunosuppressive medication for any indication other than transplantation. * Participants taking or requiring to be treated with medication or substances prohibited by this protocol. * Known allergy or intolerance to steroids, macrolide antibiotics, basiliximab, or tacrolimus. * Participants with severe primary disease/complications/poor general condition which may be unsuitable for participating in this study. * Participant is currently participating in another clinical trial and/or has been taking any other study drug within 1 month prior to screening. * Participant is unlikely to comply with the visits scheduled in the protocol.

Locations (4)

Site CN86003

Beijing, China

Site CN86002

Guangzhou, China

Site CN86001

Shanghai, China

Site CN86004

Wuhan, China

Outcomes

Primary Outcomes

Pharmacokinetics (PK) of tacrolimus granules in whole blood: area under the blood concentration - time curve for a dosing interval (AUCtau) on Day 1

AUCtau is recorded from the pharmacokinetic (PK) whole blood samples collected.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1

PK of tacrolimus granules in whole blood: AUCtau on Day 7

AUCtau is recorded from the PK blood samples collected.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

PK of tacrolimus granules in whole blood: maximum concentration (Cmax) on Day 1

Cmax is recorded from the PK blood samples collected. Cmax is maximum concentration observed in an observation period.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1

PK of tacrolimus granules in whole blood: Cmax on Day 7

Cmax is recorded from the PK blood samples collected. Cmax is maximum concentration observed in an observation period.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

PK of tacrolimus granules in Whole Blood: Time of Maximum Concentration (Tmax) on Day 1

Tmax is recorded from the PK blood samples collected. Tmax is time of maximum concentration in an observation period.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1

PK of tacrolimus granules in Whole Blood: Tmax on Day 7

Tmax is recorded from the PK blood samples collected. Tmax is time of maximum concentration in an observation period.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

PK of tacrolimus granules in whole blood: Trough blood concentration (Ctrough) on Day 1

Ctrough is recorded from the PK blood samples collected.

Time frame: Pre-dose on day 1

PK of granules tacrolimus in whole blood: Ctrough on Day 7

Ctrough is recorded from the PK blood samples collected.

Time frame: Pre-dose on day 7

Correlation between Ctrough and AUCtau of tacrolimus granules PK parameters in whole blood on Day 1

The correlation between Ctrough and AUCtau PK parameters will be assessed by Pearson's coefficient at each sample time by visit.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1

Percentage of Participants With Acute Rejection (AR)

Time frame: From first dose to month 12

Number of Participants who Died

Number of participant who died is recorded during 12 months' post-transplant; any cause of death is taken into account.

Time frame: From first dose to month 12

Number of Participants with Graft Failure

Graft failure is defined as graft dysfunction, including re-transplantation or death, during the study period. A graft dysfunction to permanent dialysis in kidney transplantation is also considered as graft failure.

Time frame: From first dose to month 12

Number of Dose Adjustments Throughout the Study Period

The dose adjustments required for the organ transplant is reported.

Time frame: From first dose to month 12

Number of Participants with Treatment Emergent Adverse Events (AEs)

An AE is defined as any untoward medical occurrence in a participant given a study drug not necessarily linked to this treatment. An AE can be any unfavorable and unintended sign (e.g., abnormal laboratory finding; abnormal laboratory test result or other safety assessment, symptom, or disease) temporally associated with the use of study drug whether or not considered related to the study drug. Treatment emergent adverse event (TEAE) is defined as AE observed after administering the study drug.

Time frame: From first dose to month 12

Whole Blood Trough Levels of Tacrolimus

Tacrolimus whole blood trough levels are routinely monitored from whole blood samples, using a local assay method, for example EMITÒ or Liquid-Chromatography-Mass-Spectrometry-Mass-Spectrometry (LC-MS-MS) in the local laboratories. Mean trough levels of tacrolimus from day 1 through month 12 are reported.

Time frame: From day 1 through month 12 (predose)

Correlation between Ctrough and AUCtau of tacrolimus granules in whole blood on Day 7

The correlation between Ctrough and AUCtau is assessed by Pearson's coefficient at each sample time by visit.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

PK of tacrolimus granules in Whole Blood: Dose-normalized AUCtau on Day 1

Dose-normalized AUCtau is AUCtau normalized with the dose just prior to blood sampling. Dose-normalized AUCtau is calculated as AUCtau/dose.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1

PK of tacrolimus granules in Whole Blood: Dose-normalized AUCtau on Day 7

Dose-normalized AUCtau is AUCtau normalized with the dose just prior to blood sampling. Dose-normalized AUCtau is calculated as AUCtau/dose.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

PK of tacrolimus granules in Whole Blood: Dose-normalized Cmax on Day 1

Dose-normalized Cmax is Cmax normalized with the dose just prior to blood sampling. Dose-normalized Cmax is calculated as Cmax/dose.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1

PK of tacrolimus granules in Whole Blood: Dose-normalized Cmax on Day 7

Dose-normalized Cmax is Cmax normalized with the dose just prior to blood sampling. Dose-normalized Cmax is calculated as Cmax/dose.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

PK of tacrolimus granules in Whole Blood: Dose-normalized Ctrough on Day 1

Ctrough normalized with the dose just prior to blood sampling. Dose-normalized Ctrough is calculated as Ctrough/dose.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1

PK of tacrolimus granules in Whole Blood: Dose-normalized Ctrough on Day 7

Ctrough normalized with the dose just prior to blood sampling. Dose-normalized Ctrough is calculated as Ctrough/dose.

Time frame: Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

Percentage of Participants With Biopsy-Proven Acute Rejections (BPAR)

AR is an immune response against the donor graft that causes tissue impairment and potential failure. The criteria for rejection is performed by the local histopathologist following the "Histological Grading of Liver Biopsies for Rejection", the "Banff diagnostic categories for renal allograft biopsies". A BPAR episode is defined as any AR episode confirmed by biopsy.

Time frame: From first dose to month 12

Percentage of Participants With Clinically Suspected Rejection

AR is an immune response against the donor graft that causes tissue impairment and potential failure. The criteria for rejection is performed by the local histopathologist following the "Histological Grading of Liver Biopsies for Rejection", the "Banff diagnostic categories for renal allograft biopsies". An AR is clinically suspected in participants who experienced an increase in serum creatinine, after the exclusion of other causes of graft dysfunction (generally with biopsy).

Time frame: From first dose to month 12