Trial of Calcineurin Inhibitor-Sparing Immunosuppression Regimen in Pediatric Liver Transplantation

Study Overview
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Brief Summary
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The objective of this study is to compare the effects of two liver transplant immunosuppression regimens on renal function. Patients receiving the standard combination of prednisone and high-dose tacrolimus, a drug with known nephrotoxicity (Arm A) will be compared to patients receiving prednisone, low-dose tacrolimus and mycophenolate mofetil (MMF) (Arm B). MMF is an immunosuppression agent that has no associated nephrotoxicity. The primary end point of the study will be renal function as measured by glomerular filtration rate (GFR). Thirty pediatric liver transplant recipients will be randomized to these two arms in a 1:1 ratio (i.e. 15 patients in each group). Secondary end points will measure patient and graft outcome and incidence of immunosuppression-related complications, including: neurotoxicity, diabetes mellitus, growth retardation, vomiting, diarrhea, gastrointestinal hemorrhage, thrombocytopenia, anemia, leukopenia, acute or chronic liver graft rejection, posttransplant lymphoproliferative disease (PTLD), viral infections, fungal infections and bacterial infections.

Detailed Description
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The objective of this study is to compare the effects of two liver transplant immunosuppression regimens on renal function. Patients receiving the standard combination of prednisone and high-dose tacrolimus, a drug with known nephrotoxicity (Arm A) will be compared to patients receiving prednisone, low-dose tacrolimus and mycophenolate mofetil (MMF) (Arm B). MMF is an immunosuppression agent that has no associated nephrotoxicity. The primary end point of the study will be renal function as measured by glomerular filtration rate (GFR). Thirty pediatric liver transplant recipients will be randomized to these two arms in a 1:1 ratio (i.e. 15 patients in each group). Secondary end points will measure patient and graft outcome and incidence of immunosuppression-related complications, including: neurotoxicity, diabetes mellitus, growth retardation, vomiting, diarrhea, gastrointestinal hemorrhage, thrombocytopenia, anemia, leukopenia, acute or chronic liver graft rejection, posttransplant lymphoproliferative disease (PTLD), viral infections, fungal infections and bacterial infections.

Official Title
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A Prospective Randomized Trial of Prednisone and Tacrolimus Versus Prednisone, Tacrolimus and Mycophenolate Mofetil in Pediatric Liver Transplantation

Conditions
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End-stage Liver Disease, Renal Insufficiency, Renal Failure

Intervention / Treatment
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* Drug: mycophenolate mofetil
* Other: placebo medication


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: End-stage liver disease or acute fulminant hepatic failure recalcitrant to conventional medical or surgical therapy. Listed as candidate for pediatric liver transplantation listed with United Network for Organ Sharing (UNOS). Patients must be 18 years of age or younger. Exclusion Criteria: History of autoimmune disease or primary sclerosing cholangitis. History of end-stage renal disease, dialysis treatment or acute renal failure (not including hepatorenal syndrome). Patients with pretransplant renal insufficiency as determined by a glomerular filtration rate (GFR) of <80 mL/min/1.73m2 (see below). Patients with renal agenesis or hypoplasia, polycystic kidney disease, or hydroureter seen on pretransplant renal ultrasound. Patients with malignancy or previous malignancy. Patients with active bacterial, viral, or fungal infections. Patients with a pretransplant diagnosis of diabetes mellitus. Patients with history of previous transplant or multi-organ recipients. Patients with serological evidence of HIV, HBSAg or HCV. Patients with hereditary syndrome that causes genetic deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan or Kelley-Seegmiller syndrome. Patients with history of phenylketonuria. Females that are pregnant or breastfeeding. Sexually active females who are not: a) post-menopausal, or b) surgically sterile, and c) using an acceptable method of contraception (oral contraceptive, implanted devices, injection, and barrier devices are acceptable; condoms used alone are not acceptable). Patients with alcohol abuse, substance abuse or smoking within the previous 6 months. Patients or caretakers of patients with psychogenic factors that preclude therapeutic compliance. Inability to reach participating hospital within 2 hours of notification. Any conditions or any circumstance that makes it unsafe to undergo a liver transplant.

Ages Eligible for Study
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Maximum Age: 16 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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: tacrolimus & corticosteroids<br>Standard post-transplant immunosuppression medications: tacrolimus and corticosteroids | Other: placebo medication<br>* medication that looks like mycophenolate mofetil<br>* Other names: placebo pill;|
| Experimental: low-dose tacrolimus + steroids + MMF<br>Comparison arm: low-dose tacrolimus + steroids + MMF | Drug: mycophenolate mofetil<br>* immunosuppresion medication called mycophenolate mofetil, also known as MMF or CellCept<br>* Other names: MMF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in glomerular filtration rate (GFR) two years after liver transplantation as calculated by the Schwartz formula | change in glomerular filtration rate (GFR) two years after liver transplantation as calculated by the Schwartz formula | two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal insufficiency or failure; liver transplantation