Safety, Tolerability and Pharmacokinetics of Oral CellCept (Mycophenolate Mofetil) in Pediatric Liver Transplant Recipients on Concomitant Treatment With Cyclosporine and Corticosteroids

A Study of the Safety, Tolerability and Pharmacokinetics of Oral CellCept® (Mycophenolate Mofetil, MMF) in Pediatric Liver Transplant Recipients on Concomitant Treatment With Cyclosporine and Corticosteroids

The study is planned to be conducted in 2 parts. The first part (open label, multi-center, non-controlled) of the study will estimate a dose that would provide a mycophenolic acid (MPA) exposure in pediatric participant that is comparable to that achieved in adult liver transplant participants receiving the approved dose of mycophenolate mofetil (MMF, CellCept). The second part (open-label, multi-center, single-arm Phase IV study) of the study will provide the pharmacokinetics, efficacy and safety profile of the proposed dose in the immediate post-transplant period. This study will be conducted at two centers based in the United States of America. Twelve pediatric transplant participants receiving a first liver allograft from a cadaveric or living donor will be enrolled in this study. Stable pediatric liver transplant participants who are at least 6 months post-transplant and who were already receiving stable dose of MMF in combination with cyclosporine will be enrolled into the study. Participants should have received stable MMF dose according to center practice for at least seven days in order to get steady state pharmacokinetics (PK). Participants also should have received stable concomitant doses of cyclosporine (for at least 2 days) and corticosteroids per center practice. Participants will be aged between 9 months and 12 years, with at least 6 participants greater than or equal to (>/=) 9 months and less than (<) 36 months, of whom at least 2 will be <24 months.

Study Overview

• Status: Terminated
• Conditions: Pediatric Liver Transplantation
• Intervention / Treatment: Drug: Corticosteroids; Drug: Cyclosporine; Drug: mycophenolate mofetil

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143-0116
  • New York
    • New York, New York, United States, 10032-3784

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female participant must be between 3 months and 12 years of age
• Participant is a recipient of a first liver allograft from cadaveric or living donors
• Participant is a single-organ recipient (liver only)
• Female participants of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 milli International Units per milliliter (mIU/mL) within one week prior to PK sampling
• Female participants of childbearing potential must use two reliable forms of contraception simultaneously unless abstinence is the chosen method
• Effective contraception must be used before beginning of PK sampling
• Participants must be able to receive oral medication
• Participants must be at least 6 months post-transplant and had started on MMF in the early post-transplant period (within 2 weeks of transplant)
• Participants must be receiving stable doses of MMF per center practice for at least 7 days prior to PK sampling
• In addition, participants must be receiving stable doses of cyclosporine and corticosteroids, according to center practice
• Participants' parent/guardian are capable of understanding the purposes and risks of the study and must sign an informed consent for the study

Exclusion Criteria:

• Pregnant or nursing adolescents
• Participants who had undergone dialysis within two weeks before PK sampling
• Participants with active systemic infections
• Participants with absolute neutrophil counts (ANC) of less than 1300 per microliter (µL), or platelets counts less than 50 000/µL or hemoglobin at a concentration below a set lower limit (according to center practice, but not less than 8 grams per deciliter) at the time of study entry
• Participants with active peptic ulcer disease
• Participants with severe diarrhea (more than 5 watery stools per day) or other gastrointestinal disorders which might interfere with their ability to absorb oral medication
• History of positive human immunodeficiency virus (HIV) test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Mycophenolate Mofetil+Corticosteroids+Cyclosporine; Part 1: Participants will receive mycophenolate mofetil. Part 2: Participants will receive mycophenolate mofetil along with cyclosporine and corticosteroids.

Drug: Corticosteroids; Corticosteroids will be administered as per center practice. The choice of corticosteroid drug will also be based on center practice.; Drug: Cyclosporine; Cyclosporine will be administered as per center practice.; Drug: mycophenolate mofetil; Part 1: Mycophenolate mofetil will be administered as per center practice. Part 2: Mycophenolate mofetil will be administered as per dose determined in Part 1.; Other Names: CellCept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From 0 to 12 Hours of Mycophenolic Acid Normalized for Dose And for Body Surface Area	The area under the plasma concentration-time curve from time zero to twelve hours (AUC [0-12h]) is area under the plasma concentration-time curve from time zero through 12 hours. AUC (0-12) hours was computed using the linear trapezoidal rule. For the calculations of AUC (0-12h), concentrations below the limit of quantification were assigned a value of zero if they occurred at the beginning of a profile. When such values appeared at the end of a profile they were assigned as missing data. AUC0-12h was normalized to 600 milligram per square meter (mg/m^2) and 1.5 gram. AUC was reported in microgram hour per milliliter (mcg*h/mL).	Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Time Curve From 0-12 Hours for Mycophenolic Acid and Mycophenolic Acid Glucuronide Phenolic Glucuronide of Mycophenolic Acid	The area under the plasma concentration-time curve from time zero to twelve hours (AUC [0-12h]) is area under the plasma concentration-time curve from time zero through 12 hours. AUC (0-12) hours was computed using the linear trapezoidal rule. For the calculations of AUC (0-12h), concentrations below the limit of quantification were assigned a value of zero if they occurred at the beginning of a profile. When such values appeared at the end of a profile they were assigned as missing data. AUC was reported in microgram hour per milliliter (mcg*h/mL).	Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months
Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide	The Plasma Concentration (Cmax) is defined as maximum observed analyte concentration. Cmax was obtained directly from the measured plasma concentration-time curves.	Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants > 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants < 24 months
Time to Maximum Plasma Concentration for Mycophenolic Acid and Mycophenolic Acid Glucuronide	Tmax is the amount of time after dosing to when the maximum concentration of MPA and MPAG was achieved.	Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants > 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants < 24 months
Number of Participants With Adverse Events and Serious Adverse Events	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event.	Up to Day 32
Plasma Concentration of Mycophenolic Acid and Its Metabolite Mycophenolic Acid Glucuronide at Each Time Point	Mycophenolic Acid Glucuronide (MPAG) is an active metabolite of Mycophenolic Acid (MPA).	Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, and 12.0 hours post oral dosing for participants greater than (>) 24 months, and at pre-dose, 0.75, 2.0, 4.0 and 12.0 hours post oral dosing for participants less than (<) 24 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: May 1, 2003
• Primary Completion (Actual): January 1, 2005
• Study Completion (Actual): January 1, 2005

Study Registration Dates

• First Submitted: December 11, 2015
• First Submitted That Met QC Criteria: December 14, 2015
• First Posted (Estimate): December 15, 2015

Study Record Updates

• Last Update Posted (Estimate): May 19, 2016
• Last Update Submitted That Met QC Criteria: April 19, 2016
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: PA16497