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

Phase 4

Completed

• Conditions: Liver Transplantation
• Interventions: Drug: Mycophenolate mofetil, adjusted dose; Drug: Corticosteroids, IV; Drug: Tacrolimus; Drug: Mycophenolate mofetil, Standard dose; Drug: Corticosteroids, PO

• Registration Number: NCT00545402
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2007-10-16
• Study First Submitted QC: 2007-10-16
• Study First Posted: 2007-10-17
• Study Start: 2007-11
• Primary Completion: 2011-07
• Study Completion: 2011-07
• Status Verified: 2014-06
• Results First Submitted: 2014-06-09
• Results First Submitted QC: 2014-06-09
• Last Update Submitted: 2014-06-09
• Results First Posted: 2014-07-14
• Last Update Posted: 2014-07-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 180

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MMF, Adjusted Dose; Tacrolimus; Corticosteroids	Mycophenolate mofetil, adjusted dose	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.
MMF, Standard Dose; Tacrolimus; Corticosteroids	Corticosteroids, IV	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.
MMF, Standard Dose; Tacrolimus; Corticosteroids	Mycophenolate mofetil, Standard dose	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.
MMF, Adjusted Dose; Tacrolimus; Corticosteroids	Corticosteroids, IV	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.
MMF, Standard Dose; Tacrolimus; Corticosteroids	Corticosteroids, PO	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.
MMF, Adjusted Dose; Tacrolimus; Corticosteroids	Tacrolimus	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.
MMF, Standard Dose; Tacrolimus; Corticosteroids	Tacrolimus	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR) According to Banff Criteria up to 12 Months Post-Transplant	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	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12	The percentage of participants with biopsies of grafts evaluated by central review and scored according to Banff criteria at Month 12 post-transplant.
Overall Survival at Month 12	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 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.
Graft Survival	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.	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.
Overall Survival (OS) at Month 12 - Percentage of Participants With an Event	Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12	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.
Percentage of Participants With Graft Loss	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 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.