Liver Transplantation
Conditions
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.
Interventions
DRUGMycophenolate 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.
DRUGTacrolimus
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
DRUGCorticosteroids, IV
10-15 mg/kg IV pre-operation on Day 0
DRUGMycophenolate mofetil, Standard dose
2 g/d PO BID during meals from Day 0 to Month 12
DRUGCorticosteroids, 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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Adjusted MMF + Tacrolimus + CS Participants received MMF tablets or capsules, 3 g/d, PO, BID with meals from Day 0 to Day 4; thereafter the dose was adjusted based on total exposure (AUC) using the Bayesian method with limited sampling strategy on Days 5 and 14 and Months 1, 3, 6, 9, and 12. Participants also received tacrolimus capsules, adjusted to a target trough level of 8-12 ng/mL from Day 0 through 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 an IV bolus of methylprednisolone 10-15 mg/kg pre-operative on Day 0 per standard practice of the center. | 90 |
| Fixed-Dose MMF + Tacrolimus + CS Participants received MMF capsules or tablets, 2 g/d, PO, BID with meals from Day 0 to Month 12; tacrolimus capsules, 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; and IV bolus of prednisone, 10-15 mg/kg, pre-operative on Day 0 followed by prednisone tablets, 20 mg/d, PO, from Day 0 through Month 1; 15 mg/d, PO, from the end of Month 1 through Month 2; 10 mg/d, PO, from the end of Month 2 through Month 3; and 5 mg/d from the end of Month 3 through Month 6. Prednisone was discontinued from Month 7 through end of treatment. | 90 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 7 |
| Overall Study | Discontinuation of treatment | 17 | 9 |
| Overall Study | Graft loss | 2 | 4 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Reason not specified | 1 | 1 |
| Overall Study | Use of unauthorized immunosuppressant | 8 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Adjusted MMF + Tacrolimus + CS | Fixed-Dose MMF + Tacrolimus + CS | Total |
|---|---|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 8.5 | 55.1 years STANDARD_DEVIATION 8.3 | 54.2 years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 16 Participants | 19 Participants | 35 Participants |
| Sex: Female, Male Male | 74 Participants | 71 Participants | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 91 / 91 | 91 / 92 |
| serious Total, serious adverse events | 70 / 91 | 69 / 92 |
Outcome results
Primary
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.
Time frame: 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
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR) According to Banff Criteria up to 12 Months Post-Transplant | 8.0 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR) According to Banff Criteria up to 12 Months Post-Transplant | 8.2 percentage of participants |
Secondary
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.
Time frame: 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.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adjusted MMF + Tacrolimus + CS | Graft Survival | 12.9 months |
| Fixed-Dose MMF + Tacrolimus + CS | Graft Survival | 12.9 months |
Secondary
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.
Time frame: Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adjusted MMF + Tacrolimus + CS | Overall Survival at Month 12 | 12.9 months |
| Fixed-Dose MMF + Tacrolimus + CS | Overall Survival at Month 12 | 12.9 months |
Secondary
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.
Time frame: Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adjusted MMF + Tacrolimus + CS | Overall Survival (OS) at Month 12 - Percentage of Participants With an Event | 8.9 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Overall Survival (OS) at Month 12 - Percentage of Participants With an Event | 11.1 percentage of participants |
p-value: 0.7091Log Rank
Secondary
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.
Time frame: Days 0, 5, and 14, Month 1, 2, 3, 6, 9, and 12
Population: ITT population; only participants with evaluable biopsies were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Normal liver | 4.8 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Chronic hepatitis | 26.2 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Minor lesions | 4.8 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Acute rejection | 0.0 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Chronic rejection | 7.1 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Vascular lesions | 35.7 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Pathology of biliary obstruction | 4.8 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Lobular hepatitis | 4.8 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Recurrence of initial autoimmune disease | 0.0 percentage of participants |
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Other | 35.7 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Lobular hepatitis | 2.9 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Vascular lesions | 11.4 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Normal liver | 11.4 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Other | 45.7 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Minor lesions | 17.1 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Pathology of biliary obstruction | 5.7 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Acute rejection | 0.0 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Recurrence of initial autoimmune disease | 0.0 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Chronic rejection | 2.9 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants by Graft Histology at 12 Months Post-Transplant - Central Review | Chronic hepatitis | 22.9 percentage of participants |
Secondary
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.
Time frame: 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.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adjusted MMF + Tacrolimus + CS | Percentage of Participants With Graft Loss | 2.2 percentage of participants |
| Fixed-Dose MMF + Tacrolimus + CS | Percentage of Participants With Graft Loss | 5.6 percentage of participants |
p-value: 0.2611Log Rank