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

A Multicenter, Open-label, Non-comparative 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

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.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation; Kidney Transplantation
• Intervention / Treatment: Drug: Tacrolimus granules

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Site CN86003
  • Guangzhou, China
    • Site CN86002
  • Shanghai, China
    • Site CN86001
  • Wuhan, China
    • Site CN86004

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liver Transplant; Pediatric participants who undergo de novo allograft liver transplantation receive initial daily dose of 0.2 milligram per kilogram (mg/kg) of body weight oral suspension of tacrolimus granules post-operatively for 12 months.	Drug: Tacrolimus granules; Oral; Other Names: Modigraf
Experimental: Kidney Transplant; Pediatric participants who undergo de novo allograft kidney transplantation receive initial daily dose of 0.2 mg/kg of body weight oral suspension of tacrolimus granules post-operatively for 12 months.	Drug: Tacrolimus granules; Oral; Other Names: Modigraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK of tacrolimus granules in whole blood: Trough blood concentration (Ctrough) on Day 1	Ctrough is recorded from the PK blood samples collected.	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.	Pre-dose on day 7
Percentage of Participants With Acute Rejection (AR)	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".	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.	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.	From first dose to month 12
Number of Dose Adjustments Throughout the Study Period	The dose adjustments required for the organ transplant is reported.	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.	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.	From day 1 through month 12 (predose)
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.	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).	From first dose to month 12
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.	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.	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.	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.	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.	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.	Predose, 0.5, 1, 2, 8, 12 hours post 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.	Predose, 0.5, 1, 2, 8, 12 hours post dose on day 1
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.	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.	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.	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.	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.	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.	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.	Predose, 0.5, 1, 2, 8, 12 hours post dose on day 7

Collaborators and Investigators

• Sponsor: Astellas Pharma China, Inc.
• Investigators: Study Director: Manager Medical Science, Astellas Pharma China, Inc.

Publications and helpful links

Helpful Links

• Link to results and other applicable study documents on the Astellas Clinical Trials website
• Link to plain language summary of the study on the Trial Results Summaries website

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2022
• Primary Completion (Actual): March 6, 2024
• Study Completion (Actual): March 6, 2024

Study Registration Dates

• First Submitted: November 29, 2021
• First Submitted That Met QC Criteria: November 29, 2021
• First Posted (Actual): December 10, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 13, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Pediatric; Pharmacokinetics; Tacrolimus; Kidney Transplantation; Liver Transplantation; Modigraf
• Additional Relevant MeSH Terms: Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: F506-CL-0405; CTR20212678 (Registry Identifier: ChinaDrugTrials.org.cn); 2022-002350-68 (Registry Identifier: EudraCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No