A Study of CellCept (Mycophenolate Mofetil) in Combination Therapy in Liver Transplant Patients.

A Randomized, Open Label Study Comparing the Effect of CellCept With Therapeutic Drug Monitoring, Tacrolimus and a Corticosteroid-sparing Regimen Versus Fixed Dose CellCept, Tacrolimus and Corticosteroids Maintained up to 6 Months, on Acute Rejection and Safety in Liver Transplant Patients.

This 2 arm study will compare the efficacy and safety of two CellCept-containing treatment regimens in de novo liver transplant patients. Patients will be randomized into one of two groups, to receive either CellCept (at a starting dose of 3g/day po, adjusted according to exposure) standard dose tacrolimus and corticosteroids (10-15 mg/kg i.v. on day 0), or fixed dose CellCept 2g/day po, standard dose tacrolimus and corticosteroids (10-15mg/kg i.v. on day 0, then reducing from 20mg to 5mg over 6 months, and discontinuing after 6 months). The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: Mycophenolate mofetil, adjusted dose; Drug: Tacrolimus; Drug: Corticosteroids, IV; Drug: Mycophenolate mofetil, Standard dose; Drug: Corticosteroids, PO

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Besancon, France, 25030
  • Bordeaux, France, 33076
  • Caen, France, 14033
  • Clichy, France, 92118
  • Creteil, France, 94010
  • Grenoble, France, 38043
  • Lille, France, 59037
  • Lyon, France, 69317
  • Lyon cedex 3, France, 69437
  • Marseille, France, 13385
  • Montpellier, France, 34295
  • Nice, France, 06202
  • Paris, France, 75679
  • Rennes, France, 35033
  • Toulouse, France, 31059
  • Villejuif, France, 94804

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult patients, >=18 years of age;
• recipient of a first orthotopic liver transplant.

Exclusion Criteria:

• history of organ transplants;
• patient receiving a multi-organ transplant;
• calculated creatinine clearance <=30mL/min before transplant;
• leukocyte count < 2000/mm3 at randomization;
• history of cancer within past 5 years, except for successfully treated basal cell or squamous cell cancer, or in situ cervical cancer;
• pregnant or breast-feeding females, or females of childbearing age not using effective contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MMF, Adjusted Dose; Tacrolimus; Corticosteroids; Participants received mycophenolate mofetil (MMF) 3 grams per day (g/d), orally (PO), twice per day (BID) with meals from Day 0 to Day 4; the dose was adjusted based on total exposure (AUC) using the Bayesian method with limited sampling strategy on Days 5 and 14, Months 1, 13, 6, 9, and 12. Participants also received tacrolimus adjusted to a target trough level of 8 to (-) 12 nanograms per milliliter (ng/mL) from Day 0 to Month 1; the dose was adjusted to reach a target trough level of 3-8 ng/mL from the end of Month 1 through Month 12. Participants also received corticosteroids 10-15 milligrams per kilogram (mg/kg), intravenously (IV), pre-operation on Day 0.	Drug: Mycophenolate mofetil, adjusted dose; 3 g/d PO BID during meals from Day 0 to Day 4, followed by dose adjustment based on AUC using the Bayesian method with limited sampling strategy on Days 5 and 14, Months 1, 13, 6, 9, and 12.; Other Names: CellCept; Drug: Tacrolimus; Target trough level of 8-2 ng/mL from Day 0 to Month 1, adjusted to a target trough level of 3-8 ng/mL from the end of Month 1 through Month 12; Drug: Corticosteroids, IV; 10-15 mg/kg IV pre-operation on Day 0; Other Names: Solu-Medrol
Active Comparator: MMF, Standard Dose; Tacrolimus; Corticosteroids; Participants received MMF 2 g/d, PO, BID with meals from Day 0 to Month 12. Participants also received tacrolimus adjusted to a target trough level of 8-12 ng/mL from Day 0 to Month 1; the dose was reduced to reach a target trough level of 3-8 ng/mL from the end of Month 1 through Month 12. Participants also received corticosteroids 10-15 mg/kg, IV, pre-operation on Day 0; followed by 20 mg/d, PO, 4 times per day (QDS) from Day 0 through Month 1; 15 mg/d, PO, 3 times per day (TID) from the end of Month 1 through Month 2; 10 mg/d, PO, BID from the end of Month 2 through Month 3; and 5 mg/d once per day from the end of Month 3 through Month 6.	Drug: Tacrolimus; Target trough level of 8-2 ng/mL from Day 0 to Month 1, adjusted to a target trough level of 3-8 ng/mL from the end of Month 1 through Month 12; Drug: Corticosteroids, IV; 10-15 mg/kg IV pre-operation on Day 0; Other Names: Solu-Medrol; Drug: Mycophenolate mofetil, Standard dose; 2 g/d PO BID during meals from Day 0 to Month 12; Other Names: CellCept; Drug: Corticosteroids, PO; 20 mg/d QDS from Day 0 through Month 1; 15 mg/day, TID from the end of Month 1 through Month 2; 10 mg/d BID from the end of Month 2 through Month 3; and 5 mg/d once per day from the end of Month 3 through Month 6.; Other Names: Cortancyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR) According to Banff Criteria up to 12 Months Post-Transplant	Banff criteria required at least 2 of the 3 following features for a histopathological diagnosis of acute rejection: portal inflammation, bile duct inflammation, and venous endothelial inflammation. Each item was graded from 0 to 3 where 0 equals (=) mild, 2 = moderate, and 3 = severe. The sum of the 3 individual scores, from 0 to 9, corresponded to the Rejection Activity Index (RAI). If RAI = 0, 1, or 2, there was no evidence of rejection. If RAI = 3, there was borderline acute rejection. If RAI = 4 or 5, there was mild acute rejection. If RAI = 6 or 7, there was moderate acute rejection. If RAI = 8 or 9, there was severe acute rejection.	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12, 28 days after Month 12 or last dose of study treatment, and 6 and 12 months after the last dose of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Graft Loss	Graft survival was defined as the time between the randomization date and the graft loss date. Participants were censored at the date of last follow up, the date of last contact or premature withdrawal, and date of death.	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12, 28 days after Month 12 or last dose of study treatment, and 6 and 12 months after the last dose of study treatment.
Graft Survival	The median time, in months, between randomization and graft loss event. Participants were censored at the date of last follow up, the date of last contact or premature withdrawal, and date of death.	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12, 28 days after Month 12 or last dose of study treatment, and 6 and 12 months after the last dose of study treatment.
Overall Survival (OS) at Month 12 - Percentage of Participants With an Event	OS was defined as the time between the date of randomization and death up to Month 12. Participants were censored at the date of last follow up and the date of last contact or premature withdrawal.	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12
Overall Survival at Month 12	The median time, in months, between randomization and OS event. Participants were censored at the date of last follow up and the date of last contact or premature withdrawal.	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12
Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review	The percentage of participants with biopsies of grafts evaluated by central review and scored according to Banff criteria at Month 12 post-transplant.	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: October 16, 2007
• First Submitted That Met QC Criteria: October 16, 2007
• First Posted (Estimate): October 17, 2007

Study Record Updates

• Last Update Posted (Estimate): July 14, 2014
• Last Update Submitted That Met QC Criteria: June 9, 2014
• Last Verified: June 1, 2014

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; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methylprednisolone Hemisuccinate; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: ML21273