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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pediatric Liver Transplantation

Intervention / Treatment
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* Drug: Corticosteroids
* Drug: Cyclosporine
* Drug: mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Months
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: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate Mofetil+Corticosteroids+Cyclosporine<br>Part 1: Participants will receive mycophenolate mofetil. Part 2: Participants will receive mycophenolate mofetil along with cyclosporine and corticosteroids. | Drug: Corticosteroids<br>* Corticosteroids will be administered as per center practice. The choice of corticosteroid drug will also be based on center practice.<br>Drug: Cyclosporine<br>* Cyclosporine will be administered as per center practice.<br>Drug: mycophenolate mofetil<br>* 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.<br>* Other names: CellCept;|

What is the study measuring?
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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 |